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Sample records for age human progress

  1. Identifying the genomic determinants of aging and longevity in human population studies: progress and challenges.

    PubMed

    Deelen, Joris; Beekman, Marian; Capri, Miriam; Franceschi, Claudio; Slagboom, P Eline

    2013-04-01

    Human lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25-30% and expected to be polygenic. Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research. Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation. The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing. Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data - generated using novel technologies - in a wealth of studies in human populations. Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation. PMID:23423909

  2. PROGRESSIVE MECHANICAL BEHAVIOR OF HUMAN CORTICAL BONE IN TENSION FOR TWO AGE GROUPS

    PubMed Central

    Nyman, Jeffry S.; Roy, Anuradha; Reyes, Michael J.; Wang, Xiaodu

    2007-01-01

    The capacity of bone for post-yield energy dissipation decreases with age. To gain information on the cause of such changes, we examined the mechanical behavior of human cadaveric bone as a function of progressive deformation. In this study, tensile specimens from tibiae of 9 middle aged and 8 elderly donors were loaded till failure in an incremental and cyclic (load-dwell-unload-dwell-reload) scheme. The elastic modulus, maximum stress, permanent strain, stress relaxation, viscoelastic time constant, plastic strain energy, elastic release strain energy, and hysteresis energy were determined at incremental strains of each loading cycle. Experimental results showed that elderly bone failed at much lower strains compared to middle aged bone, but little age-related differences were observed in the mechanical behavior of bone until the premature failure of elderly bone. Energy dissipation and permanent strain appeared to linearly increase with increasing strain, while non-linear changes occurred in the modulus loss and stress relaxation/time constant with increasing strain. Such changes suggest that two distinct stages may exist in the progressive deformation of bone. In Stage I, rapid damage accumulation and increased involvement of collagen in load bearing appeared to dominate the mechanical behavior of bone with limited energy dissipation (<20% of total energy dissipated), whereas Stage II is dominated by continuous plastic deformation, accompanied by major energy dissipation through all three pathways till failure. This study suggests that damaging mechanisms in bone vary with deformation and age affects the post-yield mechanisms causing a significant decline in the capacity of aged bone to dissipate energy. PMID:18437693

  3. Progressive post-yield behavior of human cortical bone in compression for middle-aged and elderly groups

    PubMed Central

    Leng, Huijie; Dong, X. Neil; Wang, Xiaodu

    2010-01-01

    In this study, a progressive loading regimen (load–dwell–unloading–dwell–reloading) was applied on bone samples to examine the compressive post-yield response of bone at increasing strain levels. Cortical bone specimens from human tibiae of two age groups (middle-aged group: 53±2 years, 4 females and 4 males, elderly group: 83±6 years, 4 females and 4 males) were loaded in compression using the progressive loading scheme. Modulus degradation, plastic deformation, viscous response, and energy dissipation of bone during post-yield deformation were assessed. Although initial modulus was not significantly different between the two age groups, the degradation of modulus with the applied strain in the elderly group was faster than in the middle-aged group. The modulus loss (or microdamage accumulation) of bone occurred prior to plastic deformation. Plastic strain had a similar linear relationship with the applied strain for both middle-aged and the elderly group although middle-aged bone yielded at a greater strain. The viscoelastic time constant changed similarly with increasing strain for the two groups, whereas a higher magnitude of stress relaxation was observed in the middle-aged group. Energy dissipation was investigated through three pathways: elastic release strain energy, hysteresis energy, and plastic strain energy. The middle-aged group had significantly greater capacity of energy dissipation than the elderly group in all three pathways. The information obtained may provide important insights in age-related effects on bone fragility. PMID:19150716

  4. Progress and Prospects in Human Genetic Research into Age-Related Hearing Impairment

    PubMed Central

    Sugiura, Saiko; Ueda, Hiromi; Nakashima, Tsutomu

    2014-01-01

    Age-related hearing impairment (ARHI) is a complex, multifactorial disorder that is attributable to confounding intrinsic and extrinsic factors. The degree of impairment shows substantial variation between individuals, as is also observed in the senescence of other functions. This individual variation would seem to refute the stereotypical view that hearing deterioration with age is inevitable and may indicate that there is ample scope for preventive intervention. Genetic predisposition could account for a sizable proportion of interindividual variation. Over the past decade or so, tremendous progress has been made through research into the genetics of various forms of hearing impairment, including ARHI and our knowledge of the complex mechanisms of auditory function has increased substantially. Here, we give an overview of recent investigations aimed at identifying the genetic risk factors involved in ARHI and of what we currently know about its pathophysiology. This review is divided into the following sections: (i) genes causing monogenic hearing impairment with phenotypic similarities to ARHI; (ii) genes involved in oxidative stress, biologic stress responses, and mitochondrial dysfunction; and (iii) candidate genes for senescence, other geriatric diseases, and neurodegeneration. Progress and prospects in genetic research are discussed. PMID:25140308

  5. Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging.

    PubMed

    Dechat, Thomas; Shimi, Takeshi; Adam, Stephen A; Rusinol, Antonio E; Andres, Douglas A; Spielmann, H Peter; Sinensky, Michael S; Goldman, Robert D

    2007-03-20

    Mutations in the gene encoding nuclear lamin A (LA) cause the premature aging disease Hutchinson-Gilford Progeria Syndrome. The most common of these mutations results in the expression of a mutant LA, with a 50-aa deletion within its C terminus. In this study, we demonstrate that this deletion leads to a stable farnesylation and carboxymethylation of the mutant LA (LADelta50/progerin). These modifications cause an abnormal association of LADelta50/progerin with membranes during mitosis, which delays the onset and progression of cytokinesis. Furthermore, we demonstrate that the targeting of nuclear envelope/lamina components into daughter cell nuclei in early G(1) is impaired in cells expressing LADelta50/progerin. The mutant LA also appears to be responsible for defects in the retinoblastoma protein-mediated transition into S-phase, most likely by inhibiting the hyperphosphorylation of retinoblastoma protein by cyclin D1/cdk4. These results provide insights into the mechanisms responsible for premature aging and also shed light on the role of lamins in the normal process of human aging. PMID:17360326

  6. Auto-catalysed progression of aneuploidy explains the Hayflick limit of cultured cells, carcinogen-induced tumours in mice, and the age distribution of human cancer.

    PubMed Central

    Rasnick, D

    2000-01-01

    Evidence continues to accumulate that aneuploidy, an imbalance in the number of chromosomes, is responsible for the characteristic phenotypes of cancer, including the abnormal cellular size and morphology of cancer cells, the appearance of tumour-associated antigens, as well as the high levels of membrane-bound and secreted proteins responsible for invasiveness and loss of contact inhibition. Aneuploidy has also been demonstrated to be the self-perpetuating source of the karyotypic instability of cancer cells. Here it is shown that the auto-catalysed progression of aneuploidy explains the kinetics of the finite lifetime of diploid cells in culture, the time course of the appearance of papillomas and carcinomas in benzo[a]pyrene-treated mice, and the age-dependence of human cancers. Modelling studies indicate that the ease of spontaneous transformation of mouse cells in culture may be due to a chaotic progression of aneuploidy. Conversely, the strong preference towards senescence and resistance to transformation of human cells in culture may be the result of a non-chaotic progression of aneuploidy. Finally, a method is proposed for quantifying the aneuploidogenic potencies of carcinogens. PMID:10839979

  7. Progress and privilege: America in the age of environmentalism

    SciTech Connect

    Tucker, W.

    1982-01-01

    Environmentalism, which was a rarity in the 1960s, approaches a national religion in the 1980s, with some environmentalists experiencing pleasure at the prospect of limited resources and no growth. The author explores this new ambivalence toward progress, and concludes that accomplishment can dampen ambition. His analysis of environmentalism as an expression of privilege examines the political and economic characteristics of environmentalists, the major environmental issues, and the public revolt against science to uncover an aristocratic element that is diappearing from our culture. Progress will continue, however, because of global ambitions. The US can build on what has been learned during the Age of Environmentalism and get on with the progress of humanity. 159 references, 1 figure. (DCK)

  8. The origins of human ageing.

    PubMed Central

    Kirkwood, T B

    1997-01-01

    The origins of human ageing are to be found in the origins and evolution of senescence as a general feature in the life histories of higher animals. Ageing is an intriguing problem in evolutionary biology because a trait that limits the duration of life, including the fertile period, has a negative impact on Darwinian fitness. Current theory suggests that senescence occurs because the force of natural selection declines with age and because longevity is only acquired at some metabolic cost. In effect, organisms may trade late survival for enhanced reproductive investments in earlier life. The comparative study of ageing supports the general evolutionary theory and reveals that human senescence, while broadly similar to senescence in other mammalian species, has distinct features, such as menopause, that may derive from the interplay of biological and social evolution. PMID:9460059

  9. Progress towards the 'Golden Age' of biotechnology.

    PubMed

    Gartland, K M A; Bruschi, F; Dundar, M; Gahan, P B; Viola Magni, M p; Akbarova, Y

    2013-07-01

    Biotechnology uses substances, materials or extracts derived from living cells, employing 22 million Europeans in a € 1.5 Tn endeavour, being the premier global economic growth opportunity this century. Significant advances have been made in red biotechnology using pharmaceutically and medically relevant applications, green biotechnology developing agricultural and environmental tools and white biotechnology serving industrial scale uses, frequently as process feedstocks. Red biotechnology has delivered dramatic improvements in controlling human disease, from antibiotics to overcome bacterial infections to anti-HIV/AIDS pharmaceuticals such as azidothymidine (AZT), anti-malarial compounds and novel vaccines saving millions of lives. Green biotechnology has dramatically increased food production through Agrobacterium and biolistic genetic modifications for the development of 'Golden Rice', pathogen resistant crops expressing crystal toxin genes, drought resistance and cold tolerance to extend growth range. The burgeoning area of white biotechnology has delivered bio-plastics, low temperature enzyme detergents and a host of feedstock materials for industrial processes such as modified starches, without which our everyday lives would be much more complex. Biotechnological applications can bridge these categories, by modifying energy crops properties, or analysing circulating nucleic acid elements, bringing benefits for all, through increased food production, supporting climate change adaptation and the low carbon economy, or novel diagnostics impacting on personalized medicine and genetic disease. Cross-cutting technologies such as PCR, novel sequencing tools, bioinformatics, transcriptomics and epigenetics are in the vanguard of biotechnological progress leading to an ever-increasing breadth of applications. Biotechnology will deliver solutions to unimagined problems, providing food security, health and well-being to mankind for centuries to come. PMID:23797042

  10. Chronological ageing of human hair keratin fibres.

    PubMed

    Thibaut, S; de Becker, E; Bernard, B A; Huart, M; Fiat, F; Baghdadli, N; Luengo, G S; Leroy, F; Angevin, P; Kermoal, A M; Muller, S; Peron, M; Provot, G; Kravtchenko, S; Saint-Léger, D; Desbois, G; Gauchet, L; Nowbuth, K; Galliano, A; Kempf, J Y; Silberzan, I

    2010-12-01

    Examination of very long hair (length > 2.4 m) using a large range of evaluation methods including physical, chemical, biochemical and microscopic techniques has enabled to attain a detailed understanding of natural ageing of human hair keratin fibres. Scrutinizing hair that has undergone little or no oxidative aggression--because of the absence of action of chemical agents such as bleaching or dyeing--from the root to the tip shows the deterioration process, which gradually takes place from the outside to the inside of the hair shaft: first, a progressive abrasion of the cuticle, whilst the cortex structure remains unaltered, is evidenced along a length of roughly 1 m onwards together with constant shine, hydrophobicity and friction characteristics. Further along the fibre, a significant damage to cuticle scales occurs, which correlates well with ceramides and 18-Methyl Eicosanoic Acid (18-MEA) decline, and progressive decrease in keratin-associated protein content. Most physical descriptors of mechanical and optical properties decay significantly. This detailed description of natural ageing of human hair fibres by a fine analysis of hair components and physical parameters in relationship with cosmetic characteristics provides a time-dependent 'damage scale' of human hair, which may help in designing new targeted hair care formulations. PMID:20384898

  11. Biological psychological and social determinants of old age: bio-psycho-social aspects of human aging.

    PubMed

    Dziechciaż, Małgorzata; Filip, Rafał

    2014-01-01

    The aging of humans is a physiological and dynamic process ongoing with time. In accordance with most gerontologists' assertions it starts in the fourth decade of life and leads to death. The process of human aging is complex and individualized, occurs in the biological, psychological and social sphere. Biological aging is characterized by progressive age-changes in metabolism and physicochemical properties of cells, leading to impaired self-regulation, regeneration, and to structural changes and functional tissues and organs. It is a natural and irreversible process which can run as successful aging, typical or pathological. Biological changes that occur with age in the human body affect mood, attitude to the environment, physical condition and social activity, and designate the place of seniors in the family and society. Psychical ageing refers to human awareness and his adaptability to the ageing process. Among adaptation attitudes we can differentiate: constructive, dependence, hostile towards others and towards self attitudes. With progressed age, difficulties with adjustment to the new situation are increasing, adverse changes in the cognitive and intellectual sphere take place, perception process involutes, perceived sensations and information received is lowered, and thinking processes change. Social ageing is limited to the role of an old person is culturally conditioned and may change as customs change. Social ageing refers to how a human being perceives the ageing process and how society sees it. PMID:25528930

  12. Progress in Aging Epidemiology in Japan: The JAGES Project

    PubMed Central

    Kondo, Katsunori

    2016-01-01

    Aging is a prominent topic in global health. The purpose of this report is to document progress in two of our research projects in Japan, which currently is the most aged society in the world. The Japan Gerontological Evaluation Study (JAGES) is one of the largest nation-wide research projects on aging, with more than 100 000 participants in 2010 and 2013. One of the notable findings is that community participation is a significant determinant of older people’s health. We have also made progress in the development of the JAGES Health Equity Assessment and Response Tools (HEART), which is a management tool for developing age-friendly cities. This progress suggests that community perspective and management of health promotion in the communities are valuable and require further research. PMID:27349200

  13. Progress in Aging Epidemiology in Japan: The JAGES Project.

    PubMed

    Kondo, Katsunori

    2016-07-01

    Aging is a prominent topic in global health. The purpose of this report is to document progress in two of our research projects in Japan, which currently is the most aged society in the world. The Japan Gerontological Evaluation Study (JAGES) is one of the largest nation-wide research projects on aging, with more than 100 000 participants in 2010 and 2013. One of the notable findings is that community participation is a significant determinant of older people's health. We have also made progress in the development of the JAGES Health Equity Assessment and Response Tools (HEART), which is a management tool for developing age-friendly cities. This progress suggests that community perspective and management of health promotion in the communities are valuable and require further research. PMID:27349200

  14. A current genetic and epigenetic view on human aging mechanisms.

    PubMed

    Ostojić, Sala; Pereza, Nina; Kapović, Miljenko

    2009-06-01

    The process of aging is one of the most complex and intriguing biological phenomenons. Aging is a genetically regulated process in which the organism's maximum lifespan potential is pre-determined, while the rate of aging is influenced by environmental factors and lifestyle. Considering the complexity of mechanisms involved in the regulation of aging process, up to this date there isn't a major, unifying theory which could explain them. As genetic/epigenetic and environmental factors both inevitably influence the aging process, here we present a review on the genetic and epigenetic regulation of the most important molecular and cellular mechanisms involved in the process of aging. Based on the studies on oxidative stress, metabolism, genome stability, epigenetic modifications and cellular senescence in animal models and humans, we give an overview of key genetic and molecular pathways related to aging. As most of genetic manipulations which influence the aging process also affect reproduction, we discuss aging in humans as a post-reproductive genetically determined process. After the age of reproductive success, aging continously progresses which clinically coincides with the onset of most chronic diseases, cancers and dementions. As evolution shapes the genomes for reproductive success and not for post-reproductive survival, aging could be defined as a protective mechanism which ensures the preservation and progress of species through the modification, trasmission and improvement of genetic material. PMID:19662799

  15. [Experimental models of human skin aging].

    PubMed

    Nikolakis, G; Zoschke, C; Makrantonaki, E; Hausmann, C; Schäfer-Korting, M; Zouboulis, C C

    2016-02-01

    The skin is a representative model for the study of human aging. Despite the high regenerative capacity of the skin, skin physiology changes over the course of life. Medical and cosmetic research is trying to prevent aging, to slow, to stop, or to reverse it. Effects of age-related DNA damage and of changing skin structure on pharmacological parameters are largely unknown. This review article summarizes the state of scientific knowledge in the field of experimental models of human skin aging and shows approaches to improve organotypic skin models, to develop predictive models of aging, and improve aging research. PMID:26743051

  16. Age-progression technology and its application to law enforcement

    NASA Astrophysics Data System (ADS)

    Heafner, Horace

    1996-02-01

    The application of recent computer technology of the National Center for Missing and Exploited Children (NCMEC) has provided the means to age progress faces of long term missing children. In the thousands of cases of missing children that have disappeared for two or more years, there is a particular priority to identify and recover these children. It is apparent that long term solutions to this problem lie in the realm of technology. One of the areas is the computerized aging of children's faces. Forensic artists working with this new technology help this goal become a reality. When imaging a child's face, the forensic artist must consider using photographs of the biological family at an age consistent with the age of the missing child. With these pictures, a reasonable likeness can be produced using computer technology. This image can aid law enforcement, child find and social service agencies and the public in their search for the missing child. Unique features of the system provide for the stretching, merging, pixelation and refining of a completed progression. A knowledge of the steps of facial growth and anatomy is necessary to achieve an accurate image. Future developments in age progression and facial reconstruction may be in the realm of morphing technology. Application of this technology is being tested to provide a more accurate image for investigative use.

  17. Genotype × age interaction in human transcriptional ageing

    PubMed Central

    Kent, Jack W.; Göring, Harald H. H.; Charlesworth, Jac C.; Drigalenko, Eugene; Diego, Vincent P.; Curran, Joanne E.; Johnson, Matthew P.; Dyer, Thomas D.; Cole, Shelley A.; Jowett, Jeremy B. M.; Mahaney, Michael C.; Comuzzie, Anthony G.; Almasy, Laura; Moses, Eric K.; Blangero, John; Williams-Blangero, Sarah

    2012-01-01

    Individual differences in biological ageing (i.e., the rate of physiological response to the passage of time) may be due in part to genotype-specific variation in gene action. However, the sources of heritable variation in human age-related gene expression profiles are largely unknown. We have profiled genome-wide expression in peripheral blood mononuclear cells from 1,240 individuals in large families and found 4,472 human autosomal transcripts, representing ~4,349 genes, significantly correlated with age. We identified 623 transcripts that show genotype by age interaction in addition to a main effect of age, defining a large set of novel candidates for characterization of the mechanisms of differential biological ageing. We applied a novel SNP genotype×age interaction test to one of these candidates, the ubiquilin-like gene UBQLNL, and found evidence of joint cis-association and genotype by age interaction as well as trans-genotype by age interaction for UBQLNL expression. Both UBQLNL expression levels at recruitment and cis genotype are associated with longitudinal cancer risk in our study cohort. PMID:22871458

  18. Age gene expression and coexpression progressive signatures in peripheral blood leukocytes.

    PubMed

    Irizar, Haritz; Goñi, Joaquín; Alzualde, Ainhoa; Castillo-Triviño, Tamara; Olascoaga, Javier; Lopez de Munain, Adolfo; Otaegui, David

    2015-12-01

    Both cellular senescence and organismic aging are known to be dynamic processes that start early in life and progress constantly during the whole life of the individual. In this work, with the objective of identifying signatures of age-related progressive change at the transcriptomic level, we have performed a whole-genome gene expression analysis of peripheral blood leukocytes in a group of healthy individuals with ages ranging from 14 to 93 years. A set of genes with progressively changing gene expression (either increase or decrease with age) has been identified and contextualized in a coexpression network. A modularity analysis has been performed on this network and biological-term and pathway enrichment analyses have been used for biological interpretation of each module. In summary, the results of the present work reveal the existence of a transcriptomic component that shows progressive expression changes associated to age in peripheral blood leukocytes, highlighting both the dynamic nature of the process and the need to complement young vs. elder studies with longitudinal studies that include middle aged individuals. From the transcriptional point of view, immunosenescence seems to be occurring from a relatively early age, at least from the late 20s/early 30s, and the 49-56 year old age-range appears to be critical. In general, the genes that, according to our results, show progressive expression changes with aging are involved in pathogenic/cellular processes that have classically been linked to aging in humans: cancer, immune processes and cellular growth vs. maintenance. PMID:26362218

  19. Modulating Human Aging and Age-Associated Diseases

    PubMed Central

    Fontana, Luigi

    2009-01-01

    Population aging is progressing rapidly in many industrialized countries. The United States population aged 65 and over is expected to double in size within the next 25 years. In sedentary people eating Western diets aging is associated with the development of serious chronic diseases, including type 2 diabetes mellitus, cancer and cardiovascular diseases. About 80 percent of adults over 65 years of age have at least one chronic disease, and 50 percent have at least two chronic diseases. These chronic diseases are the most important cause of illness and mortality burden, and they have become the leading driver of healthcare costs, constituting an important burden for our society. Data from epidemiological studies and clinical trials indicate that many age-associated chronic diseases can be prevented, and even reversed, with the implementation of healthy lifestyle interventions. Several recent studies suggest that more drastic interventions (i.e. calorie restriction without malnutrition and moderate protein restriction with adequate nutrition) may have additional beneficial effects on several metabolic and hormonal factors that are implicated in the biology of aging itself. Additional studies are needed to understand the complex interactions of factors that regulate aging and age-associated chronic disease. PMID:19364477

  20. Viewing Our Aged Selves: Age Progression Simulations Increase Young Adults' Aging Anxiety and Negative Stereotypes of Older Adults.

    PubMed

    Rittenour, Christine E; Cohen, Elizabeth L

    2016-04-01

    This experiment tests the effect of an old-age progression simulation on young adults' (N = 139) reported aging anxiety and perceptions about older adults as a social group. College students were randomly assigned to one of three conditions: self-aged simulation, stranger-aged simulation, or a control group. Compared with the control group, groups exposed to an age progression experienced more negative affect, and individuals in the self-aged condition reported greater aging anxiety. In accordance with stereotype activation theorizing, the self-age simulation group also perceived older adults as less competent and expressed more pity and less envy for older adults. Compared to the stranger-aged group, participants who observed their own age progression were also the more likely to deny the authenticity of their transformed image.These findings highlight potential negative social and psychological consequences of using age simulations to affect positive health outcomes, and they shed light on how virtual experiences can affect stereotyping of older adults. PMID:27076488

  1. Invited review: aging and human temperature regulation.

    PubMed

    Kenney, W Larry; Munce, Thayne A

    2003-12-01

    This mini-review focuses on the effects of aging on human temperature regulation. Although comprehensive reviews have been published on this topic (Kenney WL. Exercise and Sport Sciences Reviews, Baltimore: Williams & Wilkins, 1997, p. 41-76; Pandolf KB. Exp Aging Res 17: 189-204, 1991; Van Someren EJ, Raymann RJ, Scherder EJ, Daanen HA, and Swaab DF. Ageing Res Rev 1: 721-778, 2002; and Young AJ. Exp Aging Res 17: 205-213, 1991), this mini-review concisely summarizes the present state of knowledge about human temperature regulation and aging in thermoneutral conditions, as well as during hypo- and hyperthermic challenges. First, we discuss age-related effects on baseline body core temperature and phasing rhythms of the circadian temperature cycle. We then examine the altered physiological responses to cold stress that result from aging, including attenuated peripheral vasoconstriction and reduced cold-induced metabolic heat production. Finally, we present the age-related changes in sweating and cardiovascular function associated with heat stress. Although epidemiological evidence of increased mortality among older adults from hypo- and hyperthermia exists, this outcome does not reflect an inability to thermoregulate with advanced age. In fact, studies that have attempted to separate the effects of chronological age from concurrent factors, such as fitness level, body composition, and the effects of chronic disease, have shown that thermal tolerance appears to be minimally compromised by age. PMID:14600165

  2. Effect of Age on Regulation of Human Osteoclast Differentiation

    PubMed Central

    Chung, Ping-Lin; Zhou, Shuanhu; Eslami, Behnam; Shen, Longxiang; LeBoff, Meryl S.; Glowacki, Julie

    2014-01-01

    Human skeletal aging is characterized as a gradual loss of bone mass due to an excess of bone resorption not balanced by new bone formation. Using human marrow cells, we tested the hypothesis that there is an age-dependent increase in osteoclastogenesis due to intrinsic changes in regulatory factors [macrophage-colony stimulating factor (M-CSF), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG)] and their receptors [c-fms and RANK]. In bone marrow cells (BMCs), c-fms (r=0.61, p=0.006) and RANK expression (r=0.59, p=0.008) were increased with age (27-82 years, n=19). In vitro generation of osteoclasts was increased with age (r=0.89, p=0.007). In enriched marrow stromal cells (MSCs), constitutive expression of RANKL was increased with age (r=0.41, p=0.049) and expression of OPG was inversely correlated with age (r=-0.43, p=0.039). Accordingly, there was an age-related increase in RANKL/OPG (r=0.56, p=0.005). These data indicate an age-related increase in human osteoclastogenesis that is associated with an intrinsic increase in expression of c-fms and RANK in osteoclast progenitors, and, in the supporting MSCs, an increase in pro-osteoclastogenic RANKL expression and a decrease in anti-osteoclastogenic OPG. These findings support the hypothesis that human marrow cells and their products can contribute to skeletal aging by increasing the generation of bone-resorbing osteoclasts. These findings help to explain underlying molecular mechanisms of progressive bone loss with advancing age in humans. PMID:24700654

  3. Models to explore genetics of human aging.

    PubMed

    Karasik, David; Newman, Anne

    2015-01-01

    Genetic studies have bestowed insight into the biological mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms’ aging. Recent advances in molecular and genetic epidemiology provide tools to explore the genetic sources of the variability in biological aging in humans. To be successful, the genetic study of a complex condition such as aging requires the clear definition of essential traits that can characterize the aging process phenotypically. Phenotypes of human aging have long relied on mortality rate or exceptional longevity. Genome-wide association studies (GWAS) have been shown to present an unbiased approach to the identification of new candidate genes for human diseases. The GWAS approach can also be used for positive health phenotypes such as longevity or a delay in age-related chronic disease, as well as for other age related changes such as loss of telomere length or lens transparency. Sequencing, either in targeted regions or across the whole genome can further identify rare variation that may contribute to the biological aging mechanisms. To date, the results of the GWAS for longevity are rather disappointing, possibly in part due to the small number of individuals with GWAS data who have reached advanced old age.Human aging phenotypes are needed that can be assessed prior to death, and should be both heritable and validated as predictors of longevity. Potentially, phenotypes that focus on “successful” or “healthy” aging will be more powerful as they can be measured in large numbers of people and also are clinically relevant.We postulate that construction of an integrated phenotype of aging can be achieved capitalizing on multiple traits that may have weak correlations, but a shared underlying genetic architecture. This is based on a hypothesis that convergent results from multiple individual aging-related traits will point out the pleiotropic signals responsible for the overall rate of aging of

  4. Relationship between Human Aging Muscle and Oxidative System Pathway

    PubMed Central

    Doria, Enrico; Buonocore, Daniela; Focarelli, Angela; Marzatico, Fulvio

    2012-01-01

    Ageing is a complex process that in muscle is usually associated with a decrease in mass, strength, and velocity of contraction. One of the most striking effects of ageing on muscle is known as sarcopenia. This inevitable biological process is characterized by a general decline in the physiological and biochemical functions of the major systems. At the cellular level, aging is caused by a progressive decline in mitochondrial function that results in the accumulation of reactive oxygen species (ROS) generated by the addition of a single electron to the oxygen molecule. The aging process is characterized by an imbalance between an increase in the production of reactive oxygen species in the organism and the antioxidant defences as a whole. The goal of this review is to examine the results of existing studies on oxidative stress in aging human skeletal muscles, taking into account different physiological factors (sex, fibre composition, muscle type, and function). PMID:22685621

  5. The challenges of human population ageing

    PubMed Central

    Sander, Miriam; Oxlund, Bjarke; Jespersen, Astrid; Krasnik, Allan; Mortensen, Erik Lykke; Westendorp, Rudi Gerardus Johannes; Rasmussen, Lene Juel

    2015-01-01

    The 20th century saw an unprecedented increase in average human lifespan as well as a rapid decline in human fertility in many countries of the world. The accompanying worldwide change in demographics of human populations is linked to unanticipated and unprecedented economic, cultural, medical, social, public health and public policy challenges, whose full implications on a societal level are only just beginning to be fully appreciated. Some of these implications are discussed in this commentary, an outcome of Cultures of Health and Ageing, a conference co-sponsored by the University of Copenhagen (UCPH) and the Center for Healthy Ageing at UCPH, which took place on 20–21 June 2014 in Copenhagen, Denmark. Questions discussed here include the following: what is driving age-structural change in human populations? how can we create ‘age-friendly’ societies and promote ‘ageing-in-community’? what tools will effectively promote social engagement and prevent social detachment among older individuals? is there a risk that further extension of human lifespan would be a greater burden to the individual and to society than is warranted by the potential benefit of longer life? PMID:25452294

  6. Modeling Diverse Pathways to Age Progressive Volcanism in Subduction Zones.

    NASA Astrophysics Data System (ADS)

    Kincaid, C. R.; Szwaja, S.; Sylvia, R. T.; Druken, K. A.

    2015-12-01

    One of the best, and most challenging clues to unraveling mantle circulation patterns in subduction zones comes in the form of age progressive volcanic and geochemical trends. Hard fought geological data from many subduction zones, like Tonga-Lau, the Cascades and Costa-Rica/Nicaragua, reveal striking temporal patterns used in defining mantle flow directions and rates. We summarize results from laboratory subduction models showing a range in circulation and thermal-chemical transport processes. These interaction styles are capable of producing such trends, often reflecting apparent instead of actual mantle velocities. Lab experiments use a glucose working fluid to represent Earth's upper mantle and kinematically driven plates to produce a range in slab sinking and related wedge transport patterns. Kinematic forcing assumes most of the super-adiabatic temperature gradient available to drive major downwellings is in the tabular slabs. Moreover, sinking styles for fully dynamic subduction depend on many complicating factors that are only poorly understood and which can vary widely even for repeated parameter combinations. Kinematic models have the benefit of precise, repeatable control of slab motions and wedge flow responses. Results generated with these techniques show the evolution of near-surface thermal-chemical-rheological heterogeneities leads to age progressive surface expressions in a variety of ways. One set of experiments shows that rollback and back-arc extension combine to produce distinct modes of linear, age progressive melt delivery to the surface through a) erosion of the rheological boundary layer beneath the overriding plate, and deformation and redistribution of both b) mantle residuum produced from decompression melting and c) formerly active, buoyant plumes. Additional experiments consider buoyant diapirs rising in a wedge under the influence of rollback, back-arc spreading and slab-gaps. Strongly deflected diapirs, experiencing variable rise

  7. Characterizing healthy samples for studies of human cognitive aging

    PubMed Central

    Geldmacher, David S.; Levin, Bonnie E.; Wright, Clinton B.

    2012-01-01

    Characterizing the cognitive declines associated with aging, and differentiating them from the effects of disease in older adults, are important goals for human neuroscience researchers. This is also an issue of public health urgency in countries with rapidly aging populations. Progress toward understanding cognitive aging is complicated by numerous factors. Researchers interested in cognitive changes in healthy older adults need to consider these complexities when they design and interpret studies. This paper addresses important factors in study design, patient demographics, co-morbid and incipient medical conditions, and assessment instruments that will allow researchers to optimize the characterization of healthy participants and produce meaningful and generalizable research outcomes from studies of cognitive aging. Application of knowledge from well-designed studies should be useful in clinical settings to facilitate the earliest possible recognition of disease and guide appropriate interventions to best meet the needs of the affected individual and public health priorities. PMID:22988440

  8. Endocrine and metabolic changes in human aging.

    PubMed

    Banks, W A; Morley, J E

    2000-04-01

    Numerous alterations in hormonal secretion occur with aging. In general, these tend towards a disintegration of the normal cyclic secretory patterns resulting in lower total circulating levels. In addition, declines in receptors and postreceptor function further decreases the ability of the hormonal orchestra to maintain coordinated function throughout the organism. Clues to some of these age-related changes in humans may come from the study of simpler organisms where regulatory systems are known to modulate the aging process. In particular, the interactions among the environment, hormones, and insulin receptor genes have led to new insights into the genetic control of longevity and the development of syndrome X. PMID:23604844

  9. Protein Oxidation in Aging: Does It Play a Role in Aging Progression?

    PubMed Central

    Reeg, Sandra

    2015-01-01

    Abstract Significance: A constant accumulation of oxidized proteins takes place during aging. Oxidation of proteins leads to a partial unfolding and, therefore, to aggregation. Protein aggregates impair the activity of cellular proteolytic systems (proteasomes, lysosomes), resulting in further accumulation of oxidized proteins. In addition, the accumulation of highly crosslinked protein aggregates leads to further oxidant formation, damage to macromolecules, and, finally, to apoptotic cell death. Furthermore, protein oxidation seems to play a role in the development of various age-related diseases, for example, neurodegenerative diseases. Recent Advances: The highly oxidized lipofuscin accumulates during aging. Lipofuscin formation might cause impaired lysosomal and proteasomal degradation, metal ion accumulation, increased reactive oxygen species formation, and apoptosis. Critical Issues: It is still unclear to which extent protein oxidation is involved in the progression of aging and in the development of some age-related diseases. Future Directions: An extensive knowledge of the effects of protein oxidation on the aging process and its contribution to the development of age-related diseases could enable further strategies to reduce age-related impairments. Strategies aimed at lowering aggregate formation might be a straightforward intervention to reduce age-related malfunctions of organs. Antioxid. Redox Signal. 23, 239–255. PMID:25178482

  10. Stiffening of Human Skin Fibroblasts with Age

    PubMed Central

    Schulze, Christian; Wetzel, Franziska; Kueper, Thomas; Malsen, Anke; Muhr, Gesa; Jaspers, Soeren; Blatt, Thomas; Wittern, Klaus-Peter; Wenck, Horst; Käs, Josef A.

    2010-01-01

    Changes in mechanical properties are an essential characteristic of the aging process of human skin. Previous studies attribute these changes predominantly to the altered collagen and elastin organization and density of the extracellular matrix. Here, we show that individual dermal fibroblasts also exhibit a significant increase in stiffness during aging in vivo. With the laser-based optical cell stretcher we examined the viscoelastic biomechanics of dermal fibroblasts isolated from 14 human donors aged 27 to 80. Increasing age was clearly accompanied by a stiffening of the investigated cells. We found that fibroblasts from old donors exhibited an increase in rigidity of ∼60% with respect to cells of the youngest donors. A FACS analysis of the content of the cytoskeletal polymers shows a shift from monomeric G-actin to polymerized, filamentous F-actin, but no significant changes in the vimentin and microtubule content. The rheological analysis of fibroblast-populated collagen gels demonstrates that cell stiffening directly results in altered viscoelastic properties of the collagen matrix. These results identify a new mechanism that may contribute to the age-related impairment of elastic properties in human skin. The altered mechanical behavior might influence cell functions involving the cytoskeleton, such as contractility, motility, and proliferation, which are essential for reorganization of the extracellular matrix. PMID:20959083

  11. DNA methylation and healthy human aging.

    PubMed

    Jones, Meaghan J; Goodman, Sarah J; Kobor, Michael S

    2015-12-01

    The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining 'epigenetic age' for human health and outline some important caveats to existing and future studies. PMID:25913071

  12. Glutathione dysregulation and the etiology and progression of human diseases

    PubMed Central

    Ballatori, Nazzareno; Krance, Suzanne M.; Notenboom, Sylvia; Shi, Shujie; Tieu, Kim; Hammond, Christine L.

    2009-01-01

    Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Because of GSH’s pleiotropic effects on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates and/or oxidation state can be compromised by inherited or aquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide (GSSG) ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases such as cancer, Parkinson’s disease, and Alzheimer’s disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases

  13. Aged Garlic Extract Modifies Human Immunity.

    PubMed

    Percival, Susan S

    2016-02-01

    Garlic contains numerous compounds that have the potential to influence immunity. Immune cells, especially innate immune cells, are responsible for the inflammation necessary to kill pathogens. Two innate lymphocytes, γδ-T and natural killer (NK) cells, appear to be susceptible to diet modification. The purpose of this review was to summarize the influence of aged garlic extract (AGE) on the immune system. The author's laboratory is interested in AGE's effects on cell proliferation and activation and inflammation and to learn whether those changes might affect the occurrence and severity of colds and flu. Healthy human participants (n = 120), between 21 and 50 y of age, were recruited for a randomized, double-blind, placebo-controlled parallel-intervention study to consume 2.56 g AGE/d or placebo supplements for 90 d during the cold and flu season. Peripheral blood mononuclear cells were isolated before and after consumption, and γδ-T and NK cell function was assessed by flow cytometry. The effect on cold and flu symptoms was determined by using daily diary records of self-reported illnesses. After 45 d of AGE consumption, γδ-T and NK cells proliferated better and were more activated than cells from the placebo group. After 90 d, although the number of illnesses was not significantly different, the AGE group showed reduced cold and flu severity, with a reduction in the number of symptoms, the number of days participants functioned suboptimally, and the number of work/school days missed. These results suggest that AGE supplementation may enhance immune cell function and may be partly responsible for the reduced severity of colds and flu reported. The results also suggest that the immune system functions well with AGE supplementation, perhaps with less accompanying inflammation. This trial was registered at clinicaltrials.gov as NCT01390116. PMID:26764332

  14. Progress in the development of human parainfluenza virus vaccines.

    PubMed

    Schmidt, Alexander C; Schaap-Nutt, Anne; Bartlett, Emmalene J; Schomacker, Henrick; Boonyaratanakornkit, Jim; Karron, Ruth A; Collins, Peter L

    2011-08-01

    In children under 5 years of age, human parainfluenza viruses (HPIVs) as a group are the second most common etiology of acute respiratory illness leading to hospitalization, surpassed only by respiratory syncytial virus but ahead of influenza viruses. Using reverse genetics systems for HPIV serotypes 1, 2 and 3 (HPIV1, 2 and 3), several live-attenuated HPIVs have been generated and evaluated as intranasal vaccines in adults and in children. Two vaccines against HPIV3 were found to be well tolerated, infectious and immunogenic in Phase I trials in HPIV3-seronegative infants and children and should progress to proof-of-concept trials. Vaccines against HPIV1 and HPIV2 are less advanced and have just entered pediatric trials. PMID:21859271

  15. Human serum metabolic profiles are age dependent.

    PubMed

    Yu, Zhonghao; Zhai, Guangju; Singmann, Paula; He, Ying; Xu, Tao; Prehn, Cornelia; Römisch-Margl, Werner; Lattka, Eva; Gieger, Christian; Soranzo, Nicole; Heinrich, Joachim; Standl, Marie; Thiering, Elisabeth; Mittelstraß, Kirstin; Wichmann, Heinz-Erich; Peters, Annette; Suhre, Karsten; Li, Yixue; Adamski, Jerzy; Spector, Tim D; Illig, Thomas; Wang-Sattler, Rui

    2012-12-01

    Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32-81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10(-04) to 7.8 × 10(-42) , α(corr) = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging. PMID:22834969

  16. Neuronal loss of Drosophila NPC1a causes cholesterol aggregation and age-progressive neurodegeneration.

    PubMed

    Phillips, Scott E; Woodruff, E A; Liang, Ping; Patten, Meaghan; Broadie, Kendal

    2008-06-25

    The mistrafficking and consequent cytoplasmic accumulation of cholesterol and sphingolipids is linked to multiple neurodegenerative diseases. One class of disease, the sphingolipid storage diseases, includes Niemann-Pick disease type C (NPC), caused predominantly (95%) by mutation of the NPC1 gene. A disease model has been established through mutation of Drosophila NPC1a (dnpc1a). Null mutants display early lethality attributable to loss of cholesterol-dependent ecdysone steroid hormone production. Null mutants rescued to adults by restoring ecdysone production mimic human NPC patients with progressive motor defects and reduced life spans. Analysis of dnpc1a null brains shows elevated overall cholesterol levels and progressive accumulation of filipin-positive cholesterol aggregates within brain and retina, as well as isolated cultured brain neurons. Ultrastructural imaging of dnpc1a mutant brains reveals age-progressive accumulation of striking multilamellar and multivesicular organelles, preceding the onset of neurodegeneration. Consistently, electroretinogram recordings show age-progressive loss of phototransduction and photoreceptor synaptic transmission. Early lethality, movement impairments, neuronal cholesterol deposits, accumulation of multilamellar bodies, and age-dependent neurodegeneration are all rescued by targeted neuronal expression of a wild-type dnpc1a transgene. Interestingly, targeted expression of dnpc1a in glia also provides limited rescue of adult lethality. Generation of dnpc1a null mutant neuron clones in the brain reveals cell-autonomous requirements for dNPC1a in cholesterol and membrane trafficking. These data demonstrate a requirement for dNPC1a in the maintenance of neuronal function and viability and show that loss of dNPC1a in neurons mimics the human neurodegenerative condition. PMID:18579730

  17. Neuronal Loss of Drosophila NPC1a Causes Cholesterol Aggregation and Age-Progressive Neurodegeneration

    PubMed Central

    Phillips, Scott E.; Woodruff, E. A.; Liang, Ping; Patten, Meaghan; Broadie, Kendal

    2009-01-01

    The mistrafficking and consequent cytoplasmic accumulation of cholesterol and sphingolipids is linked to multiple neurodegenerative diseases. One class of disease, the sphingolipid storage diseases, includes Niemann-Pick Disease Type C (NPC) caused predominantly (95%) by mutation of the NPC1 gene. A disease model has been established through mutation of Drosophila NPC1a (dnpc1a). Null mutants display early lethality due to loss of cholesterol-dependent ecdysone steroid hormone production. Null mutants rescued to adults by restoring ecdysone production mimic human NPC patients with progressive motor defects and reduced life spans. Analysis of dnpc1a null brains shows elevated overall cholesterol levels and progressive accumulation of filipin-positive cholesterol aggregates within brain and retina, as well as isolated cultured brain neurons. Ultrastructural imaging of dnpc1a mutant brains reveals age-progressive accumulation of striking multilamellar and multivesicular organelles, preceding the onset of neurodegeneration. Consistently, electroretinogram (ERG) recordings show age-progressive loss of phototransduction and photoreceptor synaptic transmission. Early lethality, movement impairments, neuronal cholesterol deposits, accumulation of multilamellar bodies and age-dependent neurodegeneration are all rescued by targeted neuronal expression of a wildtype dnpc1a transgene. Interestingly, targeted expression of dnpc1a in glia also provides limited rescue of adult lethality. Generation of dnpc1a null mutant neuron clones in the brain reveals cell autonomous requirements for dNPC1a in cholesterol and membrane trafficking. These data demonstrate a requirement for dNPC1a in the maintenance of neuronal function and viability, and show that loss of dNPC1a in neurons mimics the human neurodegenerative condition. PMID:18579730

  18. The Age of Human Cerebral Cortex Neurons

    SciTech Connect

    Bhardwaj, R D; Curtis, M A; Spalding, K L; Buchholz, B A; Fink, D; Bjork-Eriksson, T; Nordborg, C; Gage, F H; Druid, H; Eriksson, P S; Frisen, J

    2006-04-06

    The traditional static view of the adult mammalian brain has been challenged by the realization of continuous generation of neurons from stem cells. Based mainly on studies in experimental animals, adult neurogenesis may contribute to recovery after brain insults and decreased neurogenesis has been implicated in the pathogenesis of neurological and psychiatric diseases in man. The extent of neurogenesis in the adult human brain has, however, been difficult to establish. We have taken advantage of the integration of {sup 14}C, generated by nuclear bomb tests during the Cold War, in DNA to establish the age of neurons in the major areas of the human cerebral cortex. Together with the analysis of the cortex from patients who received BrdU, which integrates in the DNA of dividing cells, our results demonstrate that whereas non-neuronal cells turn over, neurons in the human cerebral cortex are not generated postnatally at detectable levels, but are as old as the individual.

  19. Age-progressive volcanism in the Tasman and Coral seas

    NASA Astrophysics Data System (ADS)

    Williams, S.; Gans, P. B.; Mortimer, N. N.; Meffre, S.; Seton, M.

    2014-12-01

    The South West Pacific is the site of widespread Cenozoic volcanism, much of which has formed without a clear spatio-temporal pattern. Exceptions to this overall trend are found in the Tasman Sea, where two chains of age-progressive volcanism are present, the Tasmantids and the Lord Howe seamount chain (LHSC). Both of these follow broadly north-south co-linear trends, recording rapid northwards motion of the Australian plate since >24 Ma. The bathymetric expression of the volcanic trails can be traced northwards towards the Coral Sea, which hosts a complex tapestry of poorly sampled plateaux and rises whose relationship to hotspot volcanism remains enigmatic. We present the results of a marine geophysical and dredging survey to the eastern Coral Sea onboard the RV Southern Surveyor in October-November, 2012. We constrain the timing of basin opening in the South Rennell Trough and Santa Cruz Basin to between ~43-28 Ma, using a combination of magnetic anomaly profiles, seafloor fabric from swath bathymetry data, Ar-Ar dating of basalts and paleontological dating of carbonates. The evolution of this spreading system corresponds to the opening of the Solomon Sea further north, where chrons 19-16 have been identified, suggesting the existence of a single > 2,000 km long back-arc basin. Rocks dredged from the northernmost volcanoes of the LHSC, close to the southern end of the South Rennell Trough, are dated at ~27-28 Ma. Geochemically the LHSC lavas are intraplate tholeiites and contrast with older E-MORB-type basalts formed at the ultra-slow spreading South Rennell Trough until ~28 Ma. These are the oldest rocks recovered from the LHSC, and their age confirms predictions from absolute plate motion modeling.

  20. Bitter Taste Receptor Polymorphisms and Human Aging

    PubMed Central

    Carrai, Maura; Crocco, Paolina; Montesanto, Alberto; Canzian, Federico; Rose, Giuseppina; Rizzato, Cosmeri

    2012-01-01

    Several studies have shown that genetic factors account for 25% of the variation in human life span. On the basis of published molecular, genetic and epidemiological data, we hypothesized that genetic polymorphisms of taste receptors, which modulate food preferences but are also expressed in a number of organs and regulate food absorption processing and metabolism, could modulate the aging process. Using a tagging approach, we investigated the possible associations between longevity and the common genetic variation at the three bitter taste receptor gene clusters on chromosomes 5, 7 and 12 in a population of 941 individuals ranging in age from 20 to 106 years from the South of Italy. We found that one polymorphism, rs978739, situated 212 bp upstream of the TAS2R16 gene, shows a statistically significant association (p = 0.001) with longevity. In particular, the frequency of A/A homozygotes increases gradually from 35% in subjects aged 20 to 70 up to 55% in centenarians. These data provide suggestive evidence on the possible correlation between human longevity and taste genetics. PMID:23133589

  1. Epigenetic Mechanisms of the Aging Human Retina

    PubMed Central

    Pennington, Katie L.; DeAngelis, Margaret M.

    2015-01-01

    Degenerative retinal diseases, such as glaucoma, age-related macular degeneration, and diabetic retinopathy, have complex etiologies with environmental, genetic, and epigenetic contributions to disease pathology. Much effort has gone into elucidating both the genetic and the environmental risk factors for these retinal diseases. However, little is known about how these genetic and environmental risk factors bring about molecular changes that lead to pathology. Epigenetic mechanisms have received extensive attention of late for their promise of bridging the gap between environmental exposures and disease development via their influence on gene expression. Recent studies have identified epigenetic changes that associate with the incidence and/or progression of each of these retinal diseases. Therefore, these epigenetic modifications may be involved in the underlying pathological mechanisms leading to blindness. Further genome-wide epigenetic studies that incorporate well-characterized tissue samples, consider challenges similar to those relevant to gene expression studies, and combine the genome-wide epigenetic data with genome-wide genetic and expression data to identify additional potentially causative agents of disease are needed. Such studies will allow researchers to create much-needed therapeutics to prevent and/or intervene in disease progression. Improved therapeutics will greatly enhance the quality of life and reduce the burden of disease management for millions of patients living with these potentially blinding conditions. PMID:26966390

  2. Human Genome Program Report. Part 1, Overview and Progress

    DOE R&D Accomplishments Database

    1997-11-01

    This report contains Part 1 of a two-part report to reflect research and progress in the U.S. Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 1 consists of the program overview and report on progress.

  3. Human genome program report. Part 1, overview and progress

    SciTech Connect

    1997-11-01

    This report contains Part 1 of a two-part report to reflect research and progress in the U.S. Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 1 consists of the program overview and report on progress.

  4. Aging attenuates the vestibulosympathetic reflex in humans

    NASA Technical Reports Server (NTRS)

    Ray, Chester A.; Monahan, Kevin D.

    2002-01-01

    BACKGROUND: The vestibular system contributes to sympathetic activation by engagement of the otolith organs. However, there is a significant loss of vestibular function with aging. Therefore, the purpose of the present study was to determine if young and older individuals differ in their cardiovascular and sympathetic responses to otolithic stimulation (ie, head-down rotation, HDR). We hypothesized that responses to otolithic stimulation would be attenuated in older adults because of morphological and physiological alterations that occur in the vestibular system with aging. METHODS AND RESULTS: Arterial blood pressure, heart rate, muscle sympathetic nerve activity (MSNA), and head rotation were measured during HDR in 11 young (26 +/- 1 years) and 11 older (64 +/- 1 years) subjects in the prone posture. Five older subjects performed head rotation (chin to chest) in the lateral decubitus position, which simulates HDR but does not alter afferent inputs from the vestibular system. MSNA responses to HDR were significantly attenuated in older as compared with young subjects (P<0.01). MSNA increased in the older subjects by only 12 +/- 5% as compared with 85 +/- 16% in the young. Furthermore, HDR elicited significant reductions in mean arterial blood pressure in older (Delta-6 +/- 1 mm Hg; P<0.01) but not young subjects (Delta1 +/- 1 mm Hg). In contrast to HDR, head rotation performed in the lateral decubitus position did not elicit hypotension. MSNA responses to baroreceptor unloading and the cold pressor test were not different between the age groups. CONCLUSIONS: These data indicate that aging attenuates the vestibulosympathetic reflex in humans and may contribute to the increased prevalence of orthostatic hypotension with age.

  5. GENETICS OF HUMAN AGE RELATED DISORDERS.

    PubMed

    Srivastava, I; Thukral, N; Hasija, Y

    2015-01-01

    Aging is an inevitable biological phenomenon. The incidence of age related disorders (ARDs) such as cardiovascular diseases, cancer, arthritis, dementia, osteoporosis, diabetes, neurodegenerative diseases increase rapidly with aging. ARDs are becoming a key social and economic trouble for the world's elderly population (above 60 years), which is expected to reach 2 billion by 2050. Advancement in understanding of genetic associations, particularly through genome wide association studies (GWAS), has revealed a substantial contribution of genes to human aging and ARDs. In this review, we have focused on the recent understanding of the extent to which genetic predisposition may influence the aging process. Further analysis of the genetic association studies through pathway analysis several genes associated with multiple ARDs have been highlighted such as apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), cadherin 13 (CDH13), CDK5 regulatory subunit associated protein 1 (CDKAL-1), methylenetetrahydrofolate reductase (MTHFR), disrupted in schizophrenia 1 (DISC1), nitric oxide synthase 3 (NOS3), paraoxonase 1 (PON1), indicating that these genes could play a pivotal role in ARD causation. These genes were found to be significantly enriched in Jak-STAT signalling pathway, asthma and allograft rejection. Further, interleukin-6 (IL-6), insulin (INS), vascular endothelial growth factor A (VEGFA), estrogen receptor1 (ESR1), transforming growth factor, beta 1(TGFB1) and calmodulin 1 (CALM1) were found to be highly interconnected in network analysis. We believe that extensive research on the presence of common genetic variants among various ARDs may facilitate scientists to understand the biology behind ARDs causation. PMID:26856084

  6. Modern human origins: progress and prospects.

    PubMed Central

    Stringer, Chris

    2002-01-01

    The question of the mode of origin of modern humans (Homo sapiens) has dominated palaeoanthropological debate over the last decade. This review discusses the main models proposed to explain modern human origins, and examines relevant fossil evidence from Eurasia, Africa and Australasia. Archaeological and genetic data are also discussed, as well as problems with the concept of 'modernity' itself. It is concluded that a recent African origin can be supported for H. sapiens, morphologically, behaviourally and genetically, but that more evidence will be needed, both from Africa and elsewhere, before an absolute African origin for our species and its behavioural characteristics can be established and explained. PMID:12028792

  7. Progress in Human Nutrition, Volume 1.

    ERIC Educational Resources Information Center

    Margen, Sheldon, Ed.

    In view of the international character of nutrition and interrelationships and meaning of food to all people, this annual series of open-ended books has been started to direct attention to the aspects of human nutrition in regard to the quality of life. It is believed the study of the action nutrients, their interrelationships, and their ingestion…

  8. The Role of Calcium in Human Aging

    PubMed Central

    2015-01-01

    Calcium is an essential nutrient that is necessary for many functions in human health. Calcium is the most abundant mineral in the body with 99% found in teeth and bone. Only 1% is found in serum. The serum calcium level is tightly monitored to remain within normal range by a complex metabolic process. Calcium metabolism involves other nutrients including protein, vitamin D, and phosphorus. Bone formation and maintenance is a lifelong process. Early attention to strong bones in childhood and adulthood will provide more stable bone mass during the aging years. Research has shown that adequate calcium intake can reduce the risk of fractures, osteoporosis, and diabetes in some populations. The dietary requirements of calcium and other collaborative nutrients vary slightly around the world. Lactose intolerance due to lactase deficiency is a common cause of low calcium intake. Strategies will be discussed for addressing this potential barrier to adequate intake. The purpose of this narrative review is a) to examine the role of calcium in human health, b) to compare nutrient requirements for calcium across lifecycle groups and global populations, c) to review relationships between calcium intake, chronic disease risk, and fractures, and d) to discuss strategies to address diet deficiencies and lactose intolerance. PMID:25713787

  9. The role of calcium in human aging.

    PubMed

    Beto, Judith A

    2015-01-01

    Calcium is an essential nutrient that is necessary for many functions in human health. Calcium is the most abundant mineral in the body with 99% found in teeth and bone. Only 1% is found in serum. The serum calcium level is tightly monitored to remain within normal range by a complex metabolic process. Calcium metabolism involves other nutrients including protein, vitamin D, and phosphorus. Bone formation and maintenance is a lifelong process. Early attention to strong bones in childhood and adulthood will provide more stable bone mass during the aging years. Research has shown that adequate calcium intake can reduce the risk of fractures, osteoporosis, and diabetes in some populations. The dietary requirements of calcium and other collaborative nutrients vary slightly around the world. Lactose intolerance due to lactase deficiency is a common cause of low calcium intake. Strategies will be discussed for addressing this potential barrier to adequate intake. The purpose of this narrative review is a) to examine the role of calcium in human health, b) to compare nutrient requirements for calcium across lifecycle groups and global populations, c) to review relationships between calcium intake, chronic disease risk, and fractures, and d) to discuss strategies to address diet deficiencies and lactose intolerance. PMID:25713787

  10. Mitochondrial dysfunction in aging: Much progress but many unresolved questions

    PubMed Central

    Payne, Brendan A.I.; Chinnery, Patrick F.

    2015-01-01

    The free radical theory of aging is almost 60 years old. As mitochondria are the principle source of intracellular reactive oxygen species (ROS), this hypothesis suggested a central role for the mitochondrion in normal mammalian aging. In recent years, however, much work has questioned the importance of mitochondrial ROS in driving aging. Conversely new evidence points to other facets of mitochondrial dysfunction which may nevertheless suggest the mitochondrion retains a critical role at the center of a complex web of processes leading to cellular and organismal aging. PMID:26050973

  11. Progressive decline of glucocerebrosidase in aging and Parkinson's disease

    PubMed Central

    Rocha, Emily M; Smith, Gaynor A; Park, Eric; Cao, Hongmei; Brown, Eilish; Hallett, Penelope; Isacson, Ole

    2015-01-01

    The principal risk factor for developing most adult onset neurodegenerative diseases is aging, with incidence rising significantly after age 50. Despite research efforts, the causes of Parkinson's disease (PD) remain unknown. As neurons age, they show signs of diminished lysosomal and mitochondrial function, including increased oxidative stress and accumulation of misfolded proteins, and these changes become exacerbated PD. We show that activity of the lysosomal hydrolase glucocerebrosidase gradually diminishes with age in the substantia nigra and putamen of healthy controls. This reduction is comparable to glucocerebrosidase activity in GBA1-mutation carrier PD patients. These data, demonstrate for the first time that an age-dependent reduction in glucocerebrosidase activity may lower the threshold for developing PD. PMID:25909088

  12. Grading and Reporting Student Progress in an Age of Standards.

    ERIC Educational Resources Information Center

    Trumbull, Elise, Ed.; Farr, Beverly, Ed.

    The essays in this collection offer a comprehensive analysis of the challenges of communicating effectively about student achievement. Discussions of concepts related to grading and reporting progress are mixed with practical advice. The chapters are: (1) "Grading Practices; An Overview of the Issues" (Beverly P. Farr); (2) "Why Do We Grade--and…

  13. Recognizing Age-Separated Face Images: Humans and Machines

    PubMed Central

    Yadav, Daksha; Singh, Richa; Vatsa, Mayank; Noore, Afzel

    2014-01-01

    Humans utilize facial appearance, gender, expression, aging pattern, and other ancillary information to recognize individuals. It is interesting to observe how humans perceive facial age. Analyzing these properties can help in understanding the phenomenon of facial aging and incorporating the findings can help in designing effective algorithms. Such a study has two components - facial age estimation and age-separated face recognition. Age estimation involves predicting the age of an individual given his/her facial image. On the other hand, age-separated face recognition consists of recognizing an individual given his/her age-separated images. In this research, we investigate which facial cues are utilized by humans for estimating the age of people belonging to various age groups along with analyzing the effect of one's gender, age, and ethnicity on age estimation skills. We also analyze how various facial regions such as binocular and mouth regions influence age estimation and recognition capabilities. Finally, we propose an age-invariant face recognition algorithm that incorporates the knowledge learned from these observations. Key observations of our research are: (1) the age group of newborns and toddlers is easiest to estimate, (2) gender and ethnicity do not affect the judgment of age group estimation, (3) face as a global feature, is essential to achieve good performance in age-separated face recognition, and (4) the proposed algorithm yields improved recognition performance compared to existing algorithms and also outperforms a commercial system in the young image as probe scenario. PMID:25474200

  14. Recognizing age-separated face images: humans and machines.

    PubMed

    Yadav, Daksha; Singh, Richa; Vatsa, Mayank; Noore, Afzel

    2014-01-01

    Humans utilize facial appearance, gender, expression, aging pattern, and other ancillary information to recognize individuals. It is interesting to observe how humans perceive facial age. Analyzing these properties can help in understanding the phenomenon of facial aging and incorporating the findings can help in designing effective algorithms. Such a study has two components--facial age estimation and age-separated face recognition. Age estimation involves predicting the age of an individual given his/her facial image. On the other hand, age-separated face recognition consists of recognizing an individual given his/her age-separated images. In this research, we investigate which facial cues are utilized by humans for estimating the age of people belonging to various age groups along with analyzing the effect of one's gender, age, and ethnicity on age estimation skills. We also analyze how various facial regions such as binocular and mouth regions influence age estimation and recognition capabilities. Finally, we propose an age-invariant face recognition algorithm that incorporates the knowledge learned from these observations. Key observations of our research are: (1) the age group of newborns and toddlers is easiest to estimate, (2) gender and ethnicity do not affect the judgment of age group estimation, (3) face as a global feature, is essential to achieve good performance in age-separated face recognition, and (4) the proposed algorithm yields improved recognition performance compared to existing algorithms and also outperforms a commercial system in the young image as probe scenario. PMID:25474200

  15. CYLD regulates keratinocyte differentiation and skin cancer progression in humans

    PubMed Central

    Alameda, J P; Fernández-Aceñero, M J; Moreno-Maldonado, R; Navarro, M; Quintana, R; Page, A; Ramírez, A; Bravo, A; Casanova, M L

    2011-01-01

    CYLD is a gene mutated in familial cylindromatosis and related diseases, leading to the development of skin appendages tumors. Although the deubiquitinase CYLD is a skin tumor suppressor, its role in skin physiology is unknown. Using skin organotypic cultures as experimental model to mimic human skin, we have found that CYLD acts as a regulator of epidermal differentiation in humans through the JNK signaling pathway. We have determined the requirement of CYLD for the maintenance of epidermal polarity, keratinocyte differentiation and apoptosis. We show that CYLD overexpression increases keratinocyte differentiation while CYLD loss of function impairs epidermal differentiation. In addition, we describe the important role of CYLD in the control of human non-melanoma skin cancer progression. Our results show the reversion of the malignancy of human squamous cell carcinomas that express increased levels of CYLD, while its functional inhibition enhances the aggressiveness of these tumors which progress toward spindle cell carcinomas. We have found that the mechanisms through which CYLD regulates skin cancer progression include the control of tumor differentiation, angiogenesis and cell survival. These findings of the role of CYLD in human skin cancer prognosis make our results relevant from a therapeutic point of view, and open new avenues for exploring novel cancer therapies. PMID:21900959

  16. Olfactory phenotypic expression unveils human aging

    PubMed Central

    Mazzatenta, Andrea; Cellerino, Alessandro; Origlia, Nicola; Barloscio, Davide; Sartucci, Ferdinando; Giulio, Camillo Di; Domenici, Luciano

    2016-01-01

    The mechanism of the natural aging of olfaction and its declinein the absence of any overt disease conditions remains unclear. Here, we investigated this mechanism through measurement of one of the parameters of olfactory function, the absolute threshold, in a healthy population from childhood to old age. The absolute olfactory threshold data were collected from an Italian observational study with 622 participants aged 5-105 years. A subjective testing procedure of constant stimuli was used, which was also compared to the ‘staircase’ method, with the calculation of the reliability. The n-butanol stimulus was used as an ascending series of nine molar concentrations that were monitored using an electronic nose. The data were analyzed using nonparametric statistics because of the multimodal distribution. We show that the age-related variations in the absolute olfactory threshold are not continuous; instead, there are multiple olfactory phenotypes. Three distinct age-related phenotypes were defined, termed as ‘juvenile’, ‘mature’ and ‘elder’. The frequency of these three phenotypes depends on age. Our data suggest that the sense of smell does not decrease linearly with aging. Our findings provide the basis for further understanding of olfactory loss as an anticipatory sign of aging and neurodegenerative processes. PMID:27027240

  17. Human information processing in different age.

    PubMed

    Korobeynikov, G

    2002-01-01

    The aim of investigation was to study the aging pecularities of information processing organization. 60 men and 90 women in four age groups: 30-39, 40-49, 50-59 and 60-65 were examined. The information processing was modeled by special computer test with working algorithm changes. The time and accuracy of each assignment were registered for each person. The psychophysiological mechanisms of informational processing were studied by informative mathematical methods. The results are showed that within the aging reduction of perception, processing and speed of reaction in older. As a result of the negative influence of aging shows the decline of mental activity efficiency. Aging decrease on mental capability provokes the compensation of psychophysiological mechanisms of adaptation. The main mechanism increases the psychophysiological organization stochastic and changes the type organization in informational processing to a self-finishing quest response. (Tab. 5, Ref. 22.) PMID:12518996

  18. Three-dimensional human facial morphologies as robust aging markers.

    PubMed

    Chen, Weiyang; Qian, Wei; Wu, Gang; Chen, Weizhong; Xian, Bo; Chen, Xingwei; Cao, Yaqiang; Green, Christopher D; Zhao, Fanghong; Tang, Kun; Han, Jing-Dong J

    2015-05-01

    Aging is associated with many complex diseases. Reliable prediction of the aging process is important for assessing the risks of aging-associated diseases. However, despite intense research, so far there is no reliable aging marker. Here we addressed this problem by examining whether human 3D facial imaging features could be used as reliable aging markers. We collected > 300 3D human facial images and blood profiles well-distributed across ages of 17 to 77 years. By analyzing the morphological profiles, we generated the first comprehensive map of the aging human facial phenome. We identified quantitative facial features, such as eye slopes, highly associated with age. We constructed a robust age predictor and found that on average people of the same chronological age differ by ± 6 years in facial age, with the deviations increasing after age 40. Using this predictor, we identified slow and fast agers that are significantly supported by levels of health indicators. Despite a close relationship between facial morphological features and health indicators in the blood, facial features are more reliable aging biomarkers than blood profiles and can better reflect the general health status than chronological age. PMID:25828530

  19. Three-dimensional human facial morphologies as robust aging markers

    PubMed Central

    Chen, Weiyang; Qian, Wei; Wu, Gang; Chen, Weizhong; Xian, Bo; Chen, Xingwei; Cao, Yaqiang; Green, Christopher D; Zhao, Fanghong; Tang, Kun; Han, Jing-Dong J

    2015-01-01

    Aging is associated with many complex diseases. Reliable prediction of the aging process is important for assessing the risks of aging-associated diseases. However, despite intense research, so far there is no reliable aging marker. Here we addressed this problem by examining whether human 3D facial imaging features could be used as reliable aging markers. We collected > 300 3D human facial images and blood profiles well-distributed across ages of 17 to 77 years. By analyzing the morphological profiles, we generated the first comprehensive map of the aging human facial phenome. We identified quantitative facial features, such as eye slopes, highly associated with age. We constructed a robust age predictor and found that on average people of the same chronological age differ by ± 6 years in facial age, with the deviations increasing after age 40. Using this predictor, we identified slow and fast agers that are significantly supported by levels of health indicators. Despite a close relationship between facial morphological features and health indicators in the blood, facial features are more reliable aging biomarkers than blood profiles and can better reflect the general health status than chronological age. PMID:25828530

  20. Is human cytomegalovirus associated with breast cancer progression?

    PubMed Central

    2013-01-01

    Background It has been hypothesized that human cytomegalovirus (HCMV) may be associated with breast cancer progression. However, the role of HCMV infection in breast cancer remains controversial. We aimed to assess whether HCMV genes (UL122 and UL83) could be detected in breast carcinomas and reinvestigated their possible association with breast cancer progression. DNA from paraffin-embedded tissues was analyzed by real-time PCR. We investigated 20 fibroadenomas and 27 primary breast carcinomas (stages II, III, and IV). Findings Two carcinomas were positive for HCMV, one was positive for two TaqMan viral detection probes, and one was positive for a sole TaqMan viral detection probe (UL83), whereas the remainder of the samples was negative. Conclusions Samples studied showed no association between HCMV infection and breast cancer progression. PMID:23557440

  1. Age, human performance, and physical employment standards.

    PubMed

    Kenny, Glen P; Groeller, Herbert; McGinn, Ryan; Flouris, Andreas D

    2016-06-01

    The proportion of older workers has increased substantially in recent years, with over 25% of the Canadian labour force aged ≥55 years. Along with chronological age comes age-related declines in functional capacity associated with impairments to the cardiorespiratory and muscular systems. As a result, older workers are reported to exhibit reductions in work output and in the ability to perform and/or sustain the required effort when performing work tasks. However, research has presented some conflicting views on the consequences of aging in the workforce, as physically demanding occupations can be associated with improved or maintained physical function. Furthermore, the current methods for evaluating physical function in older workers often lack specificity and relevance to the actual work tasks, leading to an underestimation of physical capacity in the older worker. Nevertheless, industry often lacks the appropriate information and/or tools to accommodate the aging workforce, particularly in the context of physical employment standards. Ultimately, if appropriate workplace strategies and work performance standards are adopted to optimize the strengths and protect against the vulnerability of the aging workers, they can perform as effectively as their younger counterparts. Our aim in this review is to evaluate the impact of different individual (including physiological decline, chronic disease, lifestyle, and physical activity) and occupational (including shift work, sleep deprivation, and cold/heat exposure) factors on the physical decline of older workers, and therefore the risk of work-related injuries or illness. PMID:27277571

  2. Myths of Human Sexuality in the Aging.

    ERIC Educational Resources Information Center

    Andrus, Charles E.

    Human sexuality is discussed in terms of misconceptions about its function and the changing sexual needs of older adults. A review of history indicates that human sexuality has traditionally been connected with ideas of purity and strict importance of procreation. Judaeo-Christian ethics and the doctrine of Saint Augustine illustrate these…

  3. Early Characteristics of Children with ASD Who Demonstrate Optimal Progress Between Age Two and Four.

    PubMed

    Moulton, Emily; Barton, Marianne; Robins, Diana L; Abrams, Danielle N; Fein, Deborah

    2016-06-01

    Although for many children, Autism Spectrum Disorder (ASD) is a lifelong disability, a subset of children with ASD lose their diagnosis and show typical cognitive and adaptive abilities. The ages at which this transition can occur is not known, but it sometimes occurs quite early. Participants in the current study were 207 children with an ASD at age two who were reevaluated at age four. Eighty-three percent retained an ASD diagnosis at reevaluation and 9 % showed "optimal progress": clear ASD at age two but not at age four, and average cognition, language, communication and social skills at age four. Early child-level factors predicted optimal progress: diagnosis of PDD-NOS, fewer repetitive behaviors, less severe symptomatology and stronger adaptive skills. PMID:26895327

  4. Aging and vascular endothelial function in humans

    PubMed Central

    SEALS, Douglas R.; JABLONSKI, Kristen L.; DONATO, Anthony J.

    2012-01-01

    Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor α (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging. PMID

  5. Reliability of the Raven Colored Progressive Matrices Test: Age and Ethnic Group Comparisons.

    ERIC Educational Resources Information Center

    Carlson, Jerry S.; Jensen, C. Mark

    1981-01-01

    Reliabilities for the Raven Colored Progressive Matrices Test (CPM) are reported for three age groups (ages 5 1/2- 6 1/2, 6 1/2-7 1/2, and 7 1/2-8 1/2 years) and three ethnic groups (Anglo, Black, and Hispanic). Results indicate CPM is not equally reliable for all age groups, but appears equally reliable for the three ethnic groups. (Author)

  6. Oxidative Stress in Aging Human Skin

    PubMed Central

    Rinnerthaler, Mark; Bischof, Johannes; Streubel, Maria Karolin; Trost, Andrea; Richter, Klaus

    2015-01-01

    Oxidative stress in skin plays a major role in the aging process. This is true for intrinsic aging and even more for extrinsic aging. Although the results are quite different in dermis and epidermis, extrinsic aging is driven to a large extent by oxidative stress caused by UV irradiation. In this review the overall effects of oxidative stress are discussed as well as the sources of ROS including the mitochondrial ETC, peroxisomal and ER localized proteins, the Fenton reaction, and such enzymes as cyclooxygenases, lipoxygenases, xanthine oxidases, and NADPH oxidases. Furthermore, the defense mechanisms against oxidative stress ranging from enzymes like superoxide dismutases, catalases, peroxiredoxins, and GSH peroxidases to organic compounds such as L-ascorbate, α-tocopherol, beta-carotene, uric acid, CoQ10, and glutathione are described in more detail. In addition the oxidative stress induced modifications caused to proteins, lipids and DNA are discussed. Finally age-related changes of the skin are also a topic of this review. They include a disruption of the epidermal calcium gradient in old skin with an accompanying change in the composition of the cornified envelope. This modified cornified envelope also leads to an altered anti-oxidative capacity and a reduced barrier function of the epidermis. PMID:25906193

  7. Age progressive volcanism in the Comores Archipelago and Northern Madagascar

    NASA Astrophysics Data System (ADS)

    Emerick, C. M.

    The Comores islands and Tertiary volcanic province of Northern Madagascar form a sub-linear trend of alkalic shield volvanoes across the northern Mozambique Channel. Potassium-argon dating of shield building lavas confirms an eastward increase in age of volcanism along the chain, consistent with a hotspot origin for the lineament. The rate of migration of the Somali Plate over the mantle source is approximately 45 mm/yr. This new geochronology for the Comores island chain is used to model the absolute motion of the Somali Plate for the last 10 million years. A systematic departure of the Somali Plate absolute motion from the African Plate absolute motion during this period represents a component of relative motion across the East African Rift at the rate of .330 deg/m.y., about an Euler pole located at 63.6 deg. S,2.3. deg. E. The geometry of older portions of the Comores and Reunion trends indicates that there was no significant relative motion between the African and Somali Plates prior to about 10 m.y. ago. Sequential reconstructions from 200-0 m.y. are presented.

  8. Glyoxalase I activity and immunoreactivity in the aging human lens

    PubMed Central

    Mailankot, Maneesh; Padmanabha, Smitha; Pasupuleti, NagaRekha; Major, Denice; Howell, Scott

    2013-01-01

    Glyoxalase I (GLOI) is the first enzyme of the glyoxalase system that catalyzes the metabolism of reactive dicarbonyls, such as methylglyoxal (MGO). During aging and cataract development, human lens proteins are chemically modified by MGO, which is likely due to inadequate metabolism of MGO by the glyoxalase system. In this study, we have determined the effect of aging on GLOI activity and the immunoreactivity and morphological distribution of GLOI in the human lens. A monoclonal antibody was developed against human GLOI. GLOI immunoreactivity was strongest in the anterior epithelial cells and weaker in rest of the lens. Cultured human lens epithelial cells showed immunostaining throughout the cytoplasm. In the human lens, GLOI activity and immunoreactivity both decreased with age. We believe that this would lead to promotion of MGO-modification in aging lens proteins. PMID:19238574

  9. THE ANOREXIA OF AGING IN HUMANS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Energy intake is reduced in older individuals, with several lines of evidence suggesting that both physiological impairment of food intake regulation and non-physiological mechanisms are important. Non-physiological causes of the anorexia of aging include social (e.g. poverty, isolation), psycholog...

  10. Aging of the Human Vestibular System.

    PubMed

    Zalewski, Christopher K

    2015-08-01

    Aging affects every sensory system in the body, including the vestibular system. Although its impact is often difficult to quantify, the deleterious impact of aging on the vestibular system is serious both medically and economically. The deterioration of the vestibular sensory end organs has been known since the 1970s; however, the measurable impact from these anatomical changes remains elusive. Tests of vestibular function either fall short in their ability to quantify such anatomical deterioration, or they are insensitive to the associated physiologic decline and/or central compensatory mechanisms that accompany the vestibular aging process. When compared with healthy younger individuals, a paucity of subtle differences in test results has been reported in the healthy older population, and those differences are often observed only in response to nontraditional and/or more robust stimuli. In addition, the reported differences are often clinically insignificant insomuch that the recorded physiologic responses from the elderly often fall within the wide normative response ranges identified for normal healthy adults. The damaging economic impact of such vestibular sensory decline manifests itself in an exponential increase in geriatric dizziness and a subsequent higher prevalence of injurious falls. An estimated $10 to $20 billion dollar annual cost has been reported to be associated with falls-related injuries and is the sixth leading cause of death in the elderly population, with a 20% mortality rate. With an estimated 115% increase in the geriatric population over 65 years of age by the year 2050, the number of balanced-disordered patients with a declining vestibular system is certain to reach near epidemic proportions. An understanding of the effects of age on the vestibular system is imperative if clinicians are to better manage elderly patients with balance disorders, dizziness, and vestibular disease. PMID:27516717

  11. Aging of the Human Vestibular System

    PubMed Central

    Zalewski, Christopher K.

    2015-01-01

    Aging affects every sensory system in the body, including the vestibular system. Although its impact is often difficult to quantify, the deleterious impact of aging on the vestibular system is serious both medically and economically. The deterioration of the vestibular sensory end organs has been known since the 1970s; however, the measurable impact from these anatomical changes remains elusive. Tests of vestibular function either fall short in their ability to quantify such anatomical deterioration, or they are insensitive to the associated physiologic decline and/or central compensatory mechanisms that accompany the vestibular aging process. When compared with healthy younger individuals, a paucity of subtle differences in test results has been reported in the healthy older population, and those differences are often observed only in response to nontraditional and/or more robust stimuli. In addition, the reported differences are often clinically insignificant insomuch that the recorded physiologic responses from the elderly often fall within the wide normative response ranges identified for normal healthy adults. The damaging economic impact of such vestibular sensory decline manifests itself in an exponential increase in geriatric dizziness and a subsequent higher prevalence of injurious falls. An estimated $10 to $20 billion dollar annual cost has been reported to be associated with falls-related injuries and is the sixth leading cause of death in the elderly population, with a 20% mortality rate. With an estimated 115% increase in the geriatric population over 65 years of age by the year 2050, the number of balanced-disordered patients with a declining vestibular system is certain to reach near epidemic proportions. An understanding of the effects of age on the vestibular system is imperative if clinicians are to better manage elderly patients with balance disorders, dizziness, and vestibular disease. PMID:27516717

  12. Biomimetic remineralization as a progressive dehydration mechanism of collagen matrices – implications in the aging of resin-dentin bonds

    PubMed Central

    Kim, Young Kyung; Mai, Sui; Mazzoni, Annalisa; Liu, Yan; Tezvergil-Mutluay, Arzu; Takahashi, Kei; Zhang, Kai; Pashley, David H.; Tay, Franklin R.

    2010-01-01

    Biomineralization is a dehydration process in which water from the intrafibrillar compartments of collagen fibrils are progressively replaced by apatites. As water is an important element that precipitates the lack of durability of resin-dentin bonds, this study examined the use of a biomimetic remineralization strategy as a progressive dehydration mechanism for preserving joint integrity and maintaining adhesive strength after aging. Human dentin surfaces were bonded with dentin adhesives, restored with resin composites and sectioned into sticks containing the adhesive joint. Experimental specimens were aged in a biomimetic analog-containing remineralizing medium and control specimens in simulated body fluid for up to 12 months. Specimens retrieved from the designated periods were examined by transmission electron microscopy for manifestation of water-rich regions using a silver tracer and for collagen degradation within the adhesive joints. Tensile testing was performed to determine the potential loss of bond integrity after aging. Control specimens exhibited severe collagen degradation within the adhesive joint after aging. Remineralized specimens exhibited progressive dehydration as manifested by silver tracer reduction and partial remineralization of water-filled micro-channels within the adhesive joint, as well as intrafibrillar remineralization of collagen fibrils that were demineralized initially as part of the bonding procedure. Biomimetic remineralization as a progressive dehydration mechanism of water-rich, resin-sparse collagen matrices enables those adhesive joints to resist degradation over the 12-month aging period, as verified by the conservation of their tensile bond strengths. The ability of the proof-of-concept biomimetic remineralization strategy to prevent bond degradation warrants further development of clinically-relevant delivery systems. PMID:20304110

  13. Markers predicting progression of human immunodeficiency virus-related disease.

    PubMed Central

    Tsoukas, C M; Bernard, N F

    1994-01-01

    Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression. PMID:8118788

  14. T CELL REPLICATIVE SENESCENCE IN HUMAN AGING

    PubMed Central

    Chou, Jennifer P.; Effros, Rita B.

    2013-01-01

    The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of pro-inflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has far-reaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad. PMID:23061726

  15. Human Values in a Technological Age.

    ERIC Educational Resources Information Center

    Gorman, Michael

    2001-01-01

    Discusses technology and its effects on society and humans, particularly library and information technology. Highlights include the evolving history of technology; and values related to technology in libraries, including democracy, stewardship, service, intellectual freedom, privacy, literacy and learning, rationalism, and equity of access. (LRW)

  16. [Research progress on free radicals in human body].

    PubMed

    Wang, Q B; Xu, F P; Wei, C X; Peng, J; Dong, X D

    2016-08-10

    Free radicals are the intermediates of metabolism, widely exist in the human bodies. Under normal circumstances, the free radicals play an important role in the metabolic process on human body, cell signal pathway, gene regulation, induction of cell proliferation and apoptosis, so as to maintain the normal growth and development of human body and to inhibit the growth of bacteria, virus and cancer. However, when organic lesion occurs affected by external factors or when equilibrium of the free radicals is tipped in the human body, the free radicals will respond integratedly with lipids, protein or nucleic acid which may jeopardize the health of human bodies. This paper summarizes the research progress of the free radicals conducted in recent years, in relations to the perspective of the types, origins, test methods of the free radicals and their relationship with human's health. In addition, the possible mechanisms of environmental pollutants (such as polycyclic aromatic hydrocarbons) mediating oxidative stress and free radicals scavenging in the body were also summarized. PMID:27539355

  17. Human microbiota-associated swine: current progress and future opportunities.

    PubMed

    Wang, Mei; Donovan, Sharon M

    2015-01-01

    Gnotobiotic (GN) rodent models have provided insight into the contributions of the gut microbiota to host health and preventing disease. However, rodent models are limited by several important physiological and metabolic differences from humans, and many rodent models do not dependably replicate the clinical manifestations of human diseases. Due to the high degree of similarity in anatomy, physiology, immunology and brain growth, the domestic pig (Sus scrofa) is considered a clinically relevant model to study factors influencing human gastrointestinal, immune, and brain development. Gnotobiotic piglet models have been developed and shown to recapitulate key aspects of GN rodent models. Human microbiota-associated (HMA) piglets have been established using inocula from infants, children, and adults. The gut microbiota of recipient HMA piglets was more similar to that of the human donor than that of conventionally reared piglets harboring a pig microbiota. Moreover, Bifidobacterium and Bacteroides, two predominant bacterial groups of infant gut, were successfully established in the HMA piglets. Thus, the HMA pig model has the potential to be a valuable model for investigating how the gut microbiota composition changes in response to environmental factors, such as age, diet, vaccination, antibiotic use and infection. The HMA also represents a robust model for screening the efficacy of pre- and probiotic interventions. Lastly, HMA piglets can be an ideal model with which to elucidate microbe-host interactions in human health and disease due to the similarities to humans in anatomy, physiology, developmental maturity at birth, and the pathophysiology of many human diseases. PMID:25991699

  18. Age effects on B cells and humoral immunity in humans

    PubMed Central

    Frasca, Daniela; Diaz, Alain; Romero, Maria; Landin, Ana Marie; Blomberg, Bonnie B

    2010-01-01

    Both humoral and cellular immune responses are impaired in aged individuals, leading to decreased vaccine responses. Although T cell defects occur, defects in B cells play a significant role in age-related humoral immune changes. The ability to undergo class switch recombination (CSR), the enzyme for CSR, AID (activation-induced cytidine deaminase) and the transcription factor E47 are all decreased in aged stimulated B cells. We here present an overview of age-related changes in human B cell markers and functions, and also discuss some controversies in the field of B cell aging. PMID:20728581

  19. The Association between Maternal Reproductive Age and Progression of Refractive Error in Urban Students in Beijing

    PubMed Central

    Vasudevan, Balamurali; Jin, Zi Bing; Ciuffreda, Kenneth J.; Jhanji, Vishal; Zhou, Hong Jia; Wang, Ning Li; Liang, Yuan Bo

    2015-01-01

    Purpose To investigate the association between maternal reproductive age and their children’ refractive error progression in Chinese urban students. Methods The Beijing Myopia Progression Study was a three-year cohort investigation. Cycloplegic refraction of these students at both baseline and follow-up vision examinations, as well as non-cycloplegic refraction of their parents at baseline, were performed. Student’s refractive change was defined as the cycloplegic spherical equivalent (SE) of the right eye at the final follow-up minus the cycloplegic SE of the right eye at baseline. Results At the final follow-up, 241 students (62.4%) were reexamined. 226 students (58.5%) with completed refractive data, as well as completed parental reproductive age data, were enrolled. The average paternal and maternal age increased from 29.4 years and 27.5 years in 1993–1994 to 32.6 years and 29.2 years in 2003–2004, respectively. In the multivariate analysis, students who were younger (β = 0.08 diopter/year/year, P<0.001), with more myopic refraction at baseline (β = 0.02 diopter/year/diopter, P = 0.01), and with older maternal reproductive age (β = -0.18 diopter/year/decade, P = 0.01), had more myopic refractive change. After stratifying the parental reproductive age into quartile groups, children with older maternal reproductive age (trend test: P = 0.04) had more myopic refractive change, after adjusting for the children's age, baseline refraction, maternal refraction, and near work time. However, no significant association between myopic refractive change and paternal reproductive age was found. Conclusions In this cohort, children with older maternal reproductive age had more myopic refractive change. This new risk factor for myopia progression may partially explain the faster myopic progression found in the Chinese population in recent decades. PMID:26421841

  20. Comprehensive nucleosome mapping of the human genome in cancer progression

    PubMed Central

    Druliner, Brooke R.; Vera, Daniel; Johnson, Ruth; Ruan, Xiaoyang; Apone, Lynn M.; Dimalanta, Eileen T.; Stewart, Fiona J.; Boardman, Lisa; Dennis, Jonathan H.

    2016-01-01

    Altered chromatin structure is a hallmark of cancer, and inappropriate regulation of chromatin structure may represent the origin of transformation. Important studies have mapped human nucleosome distributions genome wide, but the role of chromatin structure in cancer progression has not been addressed. We developed a MNase-Transcription Start Site Sequence Capture method (mTSS-seq) to map the nucleosome distribution at human transcription start sites genome-wide in primary human lung and colon adenocarcinoma tissue. Here, we confirm that nucleosome redistribution is an early, widespread event in lung (LAC) and colon (CRC) adenocarcinoma. These altered nucleosome architectures are consistent between LAC and CRC patient samples indicating that they may serve as important early adenocarcinoma markers. We demonstrate that the nucleosome alterations are driven by the underlying DNA sequence and potentiate transcription factor binding. We conclude that DNA-directed nucleosome redistributions are widespread early in cancer progression. We have proposed an entirely new hierarchical model for chromatin-mediated genome regulation. PMID:26735342

  1. Heat waves, aging, and human cardiovascular health.

    PubMed

    Kenney, W Larry; Craighead, Daniel H; Alexander, Lacy M

    2014-10-01

    This brief review is based on a President's Lecture presented at the Annual Meeting of the American College of Sports Medicine in 2013. The purpose of this review was to assess the effects of climate change and consequent increases in environmental heat stress on the aging cardiovascular system. The earth's average global temperature is slowly but consistently increasing, and along with mean temperature changes come increases in heat wave frequency and severity. Extreme passive thermal stress resulting from prolonged elevations in ambient temperature and prolonged physical activity in hot environments creates a high demand on the left ventricle to pump blood to the skin to dissipate heat. Even healthy aging is accompanied by altered cardiovascular function, which limits the extent to which older individuals can maintain stroke volume, increase cardiac output, and increase skin blood flow when exposed to environmental extremes. In the elderly, the increased cardiovascular demand during heat waves is often fatal because of increased strain on an already compromised left ventricle. Not surprisingly, excess deaths during heat waves 1) occur predominantly in older individuals and 2) are overwhelmingly cardiovascular in origin. Increasing frequency and severity of heat waves coupled with a rapidly growing at-risk population dramatically increase the extent of future untoward health outcomes. PMID:24598696

  2. Chronologic versus Biologic Aging of the Human Choroid

    PubMed Central

    May, Christian Albrecht

    2013-01-01

    Several aspects of chronologic and biologic aging in the human choroid are reviewed from the literature. They often reveal methodological problems for age-dependent changes of the following parameters: choroidal thickness, choroidal pigmentation, choroidal vasculature and blood flow, and choroidal innervation. On reinterpreting some data of studies concerning Bruch's membrane, changes observed at different age points seem more likely to be nonlinear. Concluding from the data presented so far, chronologic aging should not be used as a factor for physiological changes in the human choroid. Longitudinal study designs are necessary to further establish the impact of age. Meanwhile, a more biologic oriented model of aging processes in the choroid should be established, including specified conditions (e.g., light exposure and refractory state). This would help to define more individual strategies for prevention and early stages of a certain defined disease. PMID:24453840

  3. Developmental pathways during in vitro progression of human islet neogenesis

    PubMed Central

    Dodge, Rikke; Loomans, Cindy; Sharma, Arun; Bonner-Weir, Susan

    2009-01-01

    Islet neogenesis, or the differentiation of islet cells from precursor cells, is seen in vitro and in vivo both embryonically and after birth. However, little is known about the differentiation pathways during embryonic development for human pancreas. Our previously reported in vitro generation of islets from human pancreatic tissue provides a unique system to identify potential markers of neogenesis and to determine the molecular mechanisms underlying this process. To this end, we analyzed the gene expression profiles of three different stages during in vitro islet generation: the Initial Adherent-, Expanded-, and Differentiated- stages. Samples from four human pancreases were hybridized to Affymetrix U95A GeneChips, and data analyzed using GeneSpring 7.0/9.0 software. Using Scatter plots we selected genes with a 2-fold or greater differential expression.. Of the 12,000 genes/ESTs present on these arrays, 295 genes including 38 acinar–enriched genes were selectively lost during the progression from the Initially Adherent stage to the Expanded stage; 468 genes were increased in this progression to Expanded tissue; and 529 genes had a two-fold greater expression in the Differentiated-stage than in the Expanded tissue. Besides the expected increases in insulin, glucagon and duct markers (mucin 6, aquaporin 1 and 5), the beta cell auto-antigen IA-2/phogrin was increased 5-fold in Differentiated. In addition developmentally important pathways, including Notch/jagged, Wnt/Frizzled, TGFβ superfamily (follistatin, BMPs and SMADs), retinoic acid (COUP-TFI, CRABP1, 2 and RAIG1) were differentially regulated during the expansion/differentiation. Two putative markers for islet precursor cells, UCHL1/PGP9.5 and DMBT1, were enhanced during the progression to differentiated cells, but only the latter could be a marker of islet precursor cells. We suggest that appropriate manipulation of these differentiation-associated pathways will enhance the efficiency of differentiation

  4. [Research Progress in Measurement of Human Accommodative Amplitude].

    PubMed

    Long, Erping; Lin, Haotian

    2015-09-01

    Accommodation is an important function of the human eye, which can change the parameters of ocular refractive system and also has a strong correlation with the development of myopia and presbyopia. Several subjective measurements have been applied in accommodation assessment such as push-up test, push-down test and minus-lens procedures. It can be measured objectively by measuring the change in refraction of the eye with dynamic retinoscopy or autorefractor. This article reviews the application of measurement of accommodative amplitude and research progress in accommodation, providing clinical information for further studies. PMID:26930838

  5. Progress in Mining the Human Proteome for Disease Applications

    PubMed Central

    2011-01-01

    Abstract Currently available technologies allow in-depth analysis of multiple facets of the proteome that have clinical relevance and that complement current genomics-based approaches. Although some progress has been made in our knowledge of the human proteome in health and in disease, there is an urgent need to chart a coherent road map with clearly defined milestones to guide proteomics efforts. Areas of emphasis include: (1) building resources, (2) filling gaps in our understanding of biological variation, and (3) systematically characterizing proteome alterations that occur in well-defined disease states, all of which require an organized and collaborative effort. PMID:21375461

  6. Progression of aging in Mexico: the Mexican Health and Aging Study (MHAS) 2012

    PubMed Central

    Wong, Rebeca; Michaels-Obregón, Alejandra; Palloni, Alberto; Gutiérrez-Robledo, Luis Miguel; González-González, César; López-Ortega, Mariana; Téllez-Rojo, Martha María; Mendoza-Alvarado, Laura Rosario

    2015-01-01

    Objective To describe the third wave of the Mexican Health and Aging Study (MHAS), completed in 2012, and present preliminary results. Materials and methods Descriptive analyses by gender and age group of demographic and socioeconomic characteristics, health conditions and health behaviors, as well as social support and life satisfaction measures are presented. In addition, external validations are presented by comparing MHAS 2012 indicators with other national data sources. Results For the panel of older adults in the sample, the rate of health care insurance coverage increased greatly between 2001 and 2012, a significantly higher change in rural compared to urban areas. The results for 2012 are consistent with the previous two waves for the main indicators of health and physical disability prevalence, risk factors, and behaviors. Conclusions The MHAS offers a unique opportunity to study aging in Mexico, as well as to complete cross-national comparisons. The cumulative number of deaths in the cohort should support the study of mortality and its association with health outcomes and behaviors over the life cycle. In addition, the sub-samples of objective markers will enable methodological research on self-reports and associations of biomarkers in old age with similar health outcomes and behaviors. PMID:26172238

  7. Uniquely Human Self-Control Begins at School Age

    ERIC Educational Resources Information Center

    Herrmann, Esther; Misch, Antonia; Hernandez-Lloreda, Victoria; Tomasello, Michael

    2015-01-01

    Human beings have remarkable skills of self-control, but the evolutionary origins of these skills are unknown. Here we compare children at 3 and 6 years of age with one of humans' two nearest relatives, chimpanzees, on a battery of reactivity and self-control tasks. Three-year-old children and chimpanzees were very similar in their abilities to…

  8. Correlation between Gene Expression and Osteoarthritis Progression in Human.

    PubMed

    Zhong, Leilei; Huang, Xiaobin; Karperien, Marcel; Post, Janine N

    2016-01-01

    Osteoarthritis (OA) is a multifactorial disease characterized by gradual degradation of joint cartilage. This study aimed to quantify major pathogenetic factors during OA progression in human cartilage. Cartilage specimens were isolated from OA patients and scored 0-5 according to the Osteoarthritis Research Society International (OARSI) guidelines. Protein and gene expressions were measured by immunohistochemistry and qPCR, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used to detect apoptotic cells. Cartilage degeneration in OA is a gradual progress accompanied with gradual loss of collagen type II and a gradual decrease in mRNA expression of SOX9, ACAN and COL2A1. Expression of WNT antagonists DKK1 and FRZB was lost, while hypertrophic markers (RUNX2, COL10A1 and IHH) increased during OA progression. Moreover, DKK1 and FRZB negatively correlated with OA grading, while RUNX2 and IHH showed a significantly positive correlation with OA grading. The number of apoptotic cells was increased with the severity of OA. Taken together, our results suggested that genetic profiling of the gene expression could be used as markers for staging OA at the molecular level. This helps to understand the molecular pathology of OA and may lead to the development of therapies based on OA stage. PMID:27428952

  9. Correlation between Gene Expression and Osteoarthritis Progression in Human

    PubMed Central

    Zhong, Leilei; Huang, Xiaobin; Karperien, Marcel; Post, Janine N.

    2016-01-01

    Osteoarthritis (OA) is a multifactorial disease characterized by gradual degradation of joint cartilage. This study aimed to quantify major pathogenetic factors during OA progression in human cartilage. Cartilage specimens were isolated from OA patients and scored 0–5 according to the Osteoarthritis Research Society International (OARSI) guidelines. Protein and gene expressions were measured by immunohistochemistry and qPCR, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used to detect apoptotic cells. Cartilage degeneration in OA is a gradual progress accompanied with gradual loss of collagen type II and a gradual decrease in mRNA expression of SOX9, ACAN and COL2A1. Expression of WNT antagonists DKK1 and FRZB was lost, while hypertrophic markers (RUNX2, COL10A1 and IHH) increased during OA progression. Moreover, DKK1 and FRZB negatively correlated with OA grading, while RUNX2 and IHH showed a significantly positive correlation with OA grading. The number of apoptotic cells was increased with the severity of OA. Taken together, our results suggested that genetic profiling of the gene expression could be used as markers for staging OA at the molecular level. This helps to understand the molecular pathology of OA and may lead to the development of therapies based on OA stage. PMID:27428952

  10. Relationship between erythrocyte volume and cell age in humans and baboons. Technical report

    SciTech Connect

    Thompson, C.B.; Galli, R.L.; Melaragno, A.J.; Valeri, C.R.

    1983-03-30

    The relationship of red blood cell size to age during steady-state hematopoiesis has been studied using erythrocytes separated on the basis of size using counterflow centrifugation. The ratio of the age-related enzyme, erythrocyte glutamic oxaloacetic transferase (EGOT), to hemoglobin (Hb) increased progressively through the fractions, suggesting a correlation between erythrocyte volume and age. Reticulocytes, while present in all fractions, were selectively enriched in the larger subpopulations. To verify the biochemical evidence that erythrocytes decrease in volume with aging, in vivo cohort labeling of red blood cells with 59Fe was performed in baboons. A similar relationship of EGOT to Hb was observed to that in the human subpopulations. While a certain amount of erythrocyte volume heterogeneity seems to be present as a result of erythropoeisis, our data support the hypothesis that red blood cells decrease in volume as they age.

  11. Human neuromuscular structure and function in old age: A brief review

    PubMed Central

    Power, Geoffrey A.; Dalton, Brian H.; Rice, Charles L.

    2016-01-01

    Natural adult aging is associated with many functional impairments of the human neuromuscular system. One of the more observable alterations is the loss of contractile muscle mass, termed sarcopenia. The loss of muscle mass occurs primarily due to a progressive loss of viable motor units, and accompanying atrophy of remaining muscle fibers. Not only does the loss of muscle mass contribute to impaired function in old age, but alterations in fiber type and myosin heavy chain isoform expression also contribute to weaker, slower, and less powerful contracting muscles. This review will focus on motor unit loss associated with natural adult aging, age-related fatigability, and the age-related differences in strength across contractile muscle actions. PMID:27011872

  12. Glycosaminoglycans in the Human Cornea: Age-Related Changes

    PubMed Central

    Pacella, Elena; Pacella, Fernanda; De Paolis, Giulio; Parisella, Francesca Romana; Turchetti, Paolo; Anello, Giulia; Cavallotti, Carlo

    2015-01-01

    AIM To investigate possible age-related changes in glycosaminoglycans (GAGs) in the human cornea. The substances today called GAGs were previously referred to as mucopolysaccharides. METHODS Samples of human cornea were taken from 12 younger (age 21 ± 1.2) and 12 older (age 72 ± 1.6) male subjects. Samples were weighed, homogenized, and used for biochemical and molecular analyses. All the quantitative results were statistically analyzed. RESULTS The human cornea appears to undergo age-related changes, as evidenced by our biochemical and molecular results. The total GAG and hyaluronic acid counts were significantly higher in the younger subjects than in the older subjects. The sulfated heavy GAGs, such as chondroitin, dermatan, keratan, and heparan sulfate, were lower in the younger subjects than in the older subjects. DISCUSSION GAGs of the human cornea undergo numerous age-related changes. Their quantity is significantly altered in the elderly in comparison with younger subjects. GAGs play an important role in age-related diseases of the human cornea. PMID:25674020

  13. CHL1 is involved in human breast tumorigenesis and progression

    SciTech Connect

    He, Li-Hong; Ma, Qin; Shi, Ye-Hui; Ge, Jie; Zhao, Hong-Meng; Li, Shu-Fen; Tong, Zhong-Sheng

    2013-08-23

    Highlights: •CHL1 is down-regulation in breast cancer tissues. •Down-regulation of CHL1 is related to high grade. •Overexpression of CHL1 inhibits breast cancer cell proliferation and invasion in vitro. •CHL1 deficiency induces breast cancer cell proliferation and invasion both in vitro and in vivo. -- Abstract: Neural cell adhesion molecules (CAM) play important roles in the development and regeneration of the nervous system. The L1 family of CAMs is comprised of L1, Close Homolog of L1 (CHL1, L1CAM2), NrCAM, and Neurofascin, which are structurally related trans-membrane proteins in vertebrates. Although the L1CAM has been demonstrated play important role in carcinogenesis and progression, the function of CHL1 in human breast cancer is limited. Here, we found that CHL1 is down-regulated in human breast cancer and related to lower grade. Furthermore, overexpression of CHL1 suppresses proliferation and invasion in MDA-MB-231 cells and knockdown of CHL1 expression results in increased proliferation and invasion in MCF7 cells in vitro. Finally, CHL1 deficiency promotes tumor formation in vivo. Our results may provide a strategy for blocking breast carcinogenesis and progression.

  14. The role of human cervical cancer oncogene in cancer progression.

    PubMed

    Li, Xin-Yu; Wang, Xin

    2015-01-01

    Human cervical cancer oncogene (HCCR) was identified by differential display RT-PCR by screened abnormally expressed genes in cervical human cancers. The overexpressed gene is not only identified in cervical tissues, but also in various human cancers as leukemia/lymphoma, breast, stomach, colon, liver, kidney and ovarian cancer. For its special sensitivities and specificities in human breast cancer and hepatocellular carcinoma, it is expected to be a new biomarker to replace or combine with the existing biomarkers in the diagnose. The HCCR manifests as a negative regulator of the p53 tumor suppressor gene, and its expression is regulated by the PI3K/Akt signaling pathway, modulated by TCF/β-catenin, it also participates in induction of the c-kit proto-oncogene, in activation of PKC and telomerase activities, but the accurate biochemical mechanisms of how HCCR contributes to the malignancies is still unknown. The aim of this review is to summarize the roles of HCCR in cancer progression and the molecular mechanisms involved. PMID:26309489

  15. Chronic and progressive Parkinson's disease MPTP model in adult and aged mice.

    PubMed

    Muñoz-Manchado, Ana B; Villadiego, Javier; Romo-Madero, Sonia; Suárez-Luna, Nela; Bermejo-Navas, Alfonso; Rodríguez-Gómez, José A; Garrido-Gil, Pablo; Labandeira-García, José L; Echevarría, Miriam; López-Barneo, José; Toledo-Aral, Juan J

    2016-01-01

    Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches. PMID:26500044

  16. Hematopoietic Age at Onset of Triple-Negative Breast Cancer Dictates Disease Aggressiveness and Progression.

    PubMed

    Marsh, Timothy; Wong, Irene; Sceneay, Jaclyn; Barakat, Amey; Qin, Yuanbo; Sjödin, Andreas; Alspach, Elise; Nilsson, Björn; Stewart, Sheila A; McAllister, Sandra S

    2016-05-15

    Triple-negative breast cancer (TNBC) is considered an early onset subtype of breast cancer that carries with it a poorer prognosis in young rather than older women for reasons that remain poorly understood. Hematopoiesis in the bone marrow becomes altered with age and may therefore affect the composition of tumor-infiltrating hematopoietic cells and subsequent tumor progression. In this study, we investigated how age- and tumor-dependent changes to bone marrow-derived hematopoietic cells impact TNBC progression. Using multiple mouse models of TNBC tumorigenesis and metastasis, we found that a specific population of bone marrow cells (BMC) upregulated CSF-1R and secreted the growth factor granulin to support stromal activation and robust tumor growth in young mice. However, the same cell population in old mice expressed low levels of CSF1R and granulin and failed to promote tumor outgrowth, suggesting that age influences the tumorigenic capacity of BMCs in response to tumor-associated signals. Importantly, BMCs from young mice were sufficient to activate a tumor-supportive microenvironment and induce tumor progression in old mice. These results indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent the protumorigenic effects of activated BMCs. Cancer Res; 76(10); 2932-43. ©2016 AACR. PMID:27197230

  17. The Hippocampal Neuroproteome with Aging and Cognitive Decline: Past Progress and Future Directions

    PubMed Central

    VanGuilder, Heather D.; Freeman, Willard M.

    2011-01-01

    Although steady progress on understanding brain aging has been made over recent decades through standard anatomical, immunohistochemical, and biochemical techniques, the biological basis of non-neurodegenerative cognitive decline with aging remains to be determined. This is due in part to technical limitations of traditional approaches, in which only a small fraction of neurobiologically relevant proteins, mRNAs or metabolites can be assessed at a time. With the development and refinement of proteomic technologies that enable simultaneous quantitative assessment of hundreds to thousands of proteins, neuroproteomic studies of brain aging and cognitive decline are becoming more widespread. This review focuses on the contributions of neuroproteomic investigations to advances in our understanding of age-related deficits of hippocampus-dependent spatial learning and memory. Accumulating neuroproteomic data demonstrate that hippocampal aging involves common themes of dysregulated metabolism, increased oxidative stress, altered protein processing, and decreased synaptic function. Additionally, growing evidence suggests that cognitive decline does not represent a “more aged” phenotype, but rather is associated with specific neuroproteomic changes that occur in addition to age-related alterations. Understanding if and how age-related changes in the hippocampal neuroproteome contribute to cognitive decline and elucidating the pathways and processes that lead to cognitive decline are critical objectives that remain to be achieved. Progress in the field and challenges that remain to be addressed with regard to animal models, behavioral testing, and proteomic reporting are also discussed. PMID:21647399

  18. Comparison of vertebral and intervertebral disc lesions in aging humans and rhesus monkeys

    PubMed Central

    Bailey, Jeannie F.; Fields, Aaron J.; Liebenberg, Ellen; Mattison, Julie A.; Lotz, Jeffrey C.; Kramer, Patricia A.

    2014-01-01

    Objective To compare gross and histologic patterns of age-related degeneration within the intervertebral disc and adjacent vertebra between rhesus monkeys and humans. Materials and methods We examined age-related patterns of disc degeneration from mid-sagittal sections of the intervertebral disc and adjacent vertebral bodies among six rhesus monkey thoracolumbar and seven human lumbar spines. Gross morphology and histopathology were assessed via the Thompson grading scheme and other degenerative features of the disc and adjacent bone. Results Thompson grades ranged from 3 through 5 for rhesus monkey discs (T9-L1) and 2 through 5 for the human discs (T12-S1). In both rhesus monkey and human discs, presence of distinct lesions were positively associated with Thompson grade of the overall segment. Degenerative patterns differed for radial tears, which were more prevalent with advanced disc degeneration in humans only. Additionally, compared to the more uniform anteroposterior disc degeneration patterns of humans, rhesus monkeys showed more severe osteophytosis and degeneration on the anterior border of the vertebral column. Conclusions Rhesus monkey spines evaluated in the present study appear to develop age-related patterns of disc degeneration similar to humans. One exception is the absence of an association between radial tears and disc degeneration, which could reflect species-specific differences in posture and spinal curvature. Considering rhesus monkeys demonstrate similar patterns of disc degeneration, and age at a faster rate than humans, these findings suggest longitudinal studies of rhesus monkeys may be a valuable model for better understanding the progression of human age-related spinal osteoarthritis and disc degeneration. PMID:24821664

  19. Influence of age, irradiation and humanization on NSG mouse phenotypes

    PubMed Central

    Knibbe-Hollinger, Jaclyn S.; Fields, Natasha R.; Chaudoin, Tammy R; Epstein, Adrian A.; Makarov, Edward; Akhter, Sidra P.; Gorantla, Santhi; Bonasera, Stephen J.; Gendelman, Howard E.; Poluektova, Larisa Y.

    2015-01-01

    ABSTRACT Humanized mice are frequently utilized in bench to bedside therapeutic tests to combat human infectious, cancerous and degenerative diseases. For the fields of hematology-oncology, regenerative medicine, and infectious diseases, the immune deficient mice have been used commonly in basic research efforts. Obstacles in true translational efforts abound, as the relationship between mouse and human cells in disease pathogenesis and therapeutic studies requires lengthy investigations. The interplay between human immunity and mouse biology proves ever more complicated when aging, irradiation, and human immune reconstitution are considered. All can affect a range of biochemical and behavioral functions. To such ends, we show age- and irradiation-dependent influences for the development of macrocytic hyper chromic anemia, myelodysplasia, blood protein reductions and body composition changes. Humanization contributes to hematologic abnormalities. Home cage behavior revealed day and dark cycle locomotion also influenced by human cell reconstitutions. Significant age-related day-to-day variability in movement, feeding and drinking behaviors were observed. We posit that this data serves to enable researchers to better design translational studies in this rapidly emerging field of mouse humanization. PMID:26353862

  20. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors.

    PubMed

    Ratliff, Eric P; Mauntz, Ruth E; Kotzebue, Roxanne W; Gonzalez, Arysa; Achal, Madhulika; Barekat, Ayeh; Finley, Kaelyn A; Sparhawk, Jonathan M; Robinson, James E; Herr, Deron R; Harris, Greg L; Joiner, William J; Finley, Kim D

    2015-01-01

    Multiple neurological disorders are characterized by the abnormal accumulation of protein aggregates and the progressive impairment of complex behaviors. Our Drosophila studies demonstrate that middle-aged wild-type flies (WT, ~4-weeks) exhibit a marked accumulation of neural aggregates that is commensurate with the decline of the autophagy pathway. However, enhancing autophagy via neuronal over-expression of Atg8a (Atg8a-OE) reduces the age-dependent accumulation of aggregates. Here we assess basal locomotor activity profiles for single- and group-housed male and female WT flies and observed that only modest behavioral changes occurred by 4-weeks of age, with the noted exception of group-housed male flies. Male flies in same-sex social groups exhibit a progressive increase in nighttime activity. Infrared videos show aged group-housed males (4-weeks) are engaged in extensive bouts of courtship during periods of darkness, which is partly repressed during lighted conditions. Together, these nighttime courtship behaviors were nearly absent in young WT flies and aged Atg8a-OE flies. Previous studies have indicated a regulatory role for olfaction in male courtship partner choice. Coincidently, the mRNA expression profiles of several olfactory genes decline with age in WT flies; however, they are maintained in age-matched Atg8a-OE flies. Together, these results suggest that middle-aged male flies develop impairments in olfaction, which could contribute to the dysregulation of courtship behaviors during dark time periods. Combined, our results demonstrate that as Drosophila age, they develop early behavior defects that are coordinate with protein aggregate accumulation in the nervous system. In addition, the nighttime activity behavior is preserved when neuronal autophagy is maintained (Atg8a-OE flies). Thus, environmental or genetic factors that modify autophagic capacity could have a positive impact on neuronal aging and complex behaviors. PMID:26182057

  1. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors

    PubMed Central

    Kotzebue, Roxanne W.; Gonzalez, Arysa; Achal, Madhulika; Barekat, Ayeh; Finley, Kaelyn A.; Sparhawk, Jonathan M.; Robinson, James E.; Herr, Deron R.; Harris, Greg L.; Joiner, William J.; Finley, Kim D.

    2015-01-01

    Multiple neurological disorders are characterized by the abnormal accumulation of protein aggregates and the progressive impairment of complex behaviors. Our Drosophila studies demonstrate that middle-aged wild-type flies (WT, ~4-weeks) exhibit a marked accumulation of neural aggregates that is commensurate with the decline of the autophagy pathway. However, enhancing autophagy via neuronal over-expression of Atg8a (Atg8a-OE) reduces the age-dependent accumulation of aggregates. Here we assess basal locomotor activity profiles for single- and group-housed male and female WT flies and observed that only modest behavioral changes occurred by 4-weeks of age, with the noted exception of group-housed male flies. Male flies in same-sex social groups exhibit a progressive increase in nighttime activity. Infrared videos show aged group-housed males (4-weeks) are engaged in extensive bouts of courtship during periods of darkness, which is partly repressed during lighted conditions. Together, these nighttime courtship behaviors were nearly absent in young WT flies and aged Atg8a-OE flies. Previous studies have indicated a regulatory role for olfaction in male courtship partner choice. Coincidently, the mRNA expression profiles of several olfactory genes decline with age in WT flies; however, they are maintained in age-matched Atg8a-OE flies. Together, these results suggest that middle-aged male flies develop impairments in olfaction, which could contribute to the dysregulation of courtship behaviors during dark time periods. Combined, our results demonstrate that as Drosophila age, they develop early behavior defects that are coordinate with protein aggregate accumulation in the nervous system. In addition, the nighttime activity behavior is preserved when neuronal autophagy is maintained (Atg8a-OE flies). Thus, environmental or genetic factors that modify autophagic capacity could have a positive impact on neuronal aging and complex behaviors. PMID:26182057

  2. Characterizing cognitive aging in humans with links to animal models

    PubMed Central

    Alexander, Gene E.; Ryan, Lee; Bowers, Dawn; Foster, Thomas C.; Bizon, Jennifer L.; Geldmacher, David S.; Glisky, Elizabeth L.

    2012-01-01

    With the population of older adults expected to grow rapidly over the next two decades, it has become increasingly important to advance research efforts to elucidate the mechanisms associated with cognitive aging, with the ultimate goal of developing effective interventions and prevention therapies. Although there has been a vast research literature on the use of cognitive tests to evaluate the effects of aging and age-related neurodegenerative disease, the need for a set of standardized measures to characterize the cognitive profiles specific to healthy aging has been widely recognized. Here we present a review of selected methods and approaches that have been applied in human research studies to evaluate the effects of aging on cognition, including executive function, memory, processing speed, language, and visuospatial function. The effects of healthy aging on each of these cognitive domains are discussed with examples from cognitive/experimental and clinical/neuropsychological approaches. Further, we consider those measures that have clear conceptual and methodological links to tasks currently in use for non-human animal studies of aging, as well as those that have the potential for translation to animal aging research. Having a complementary set of measures to assess the cognitive profiles of healthy aging across species provides a unique opportunity to enhance research efforts for cross-sectional, longitudinal, and intervention studies of cognitive aging. Taking a cross-species, translational approach will help to advance cognitive aging research, leading to a greater understanding of associated neurobiological mechanisms with the potential for developing effective interventions and prevention therapies for age-related cognitive decline. PMID:22988439

  3. Physical mapping of human chromosome 16. Annual progress report

    SciTech Connect

    Sutherland, G.R.

    1993-08-01

    We aim to isolate cDNAs mapping to human chromosome 16 and localise such cDNAs on the high resolution physical map. In collaboration with LANL, PCR primers will be synthesised from cDNA sequences mapped to chromosome 16 and used as ESTs in the generation of mega-YAC contigs for this chromosome. Probing of high density cosmid grids will enable integration of the ESTs into cosmid contigs and location of the cosmid contigs on the YAC contig. A hn-cDNA library has been constructed from the hybrid CY18 which contains chromosome 16 as the only human chromosome. A modified screening protocol has been successfully developed and 15 hn-cDNA clones have been sequenced and localised on the hybrid map. Sequence analysis of four of these revealed that they were known cDNAs, which are now mapped to chromosome 16. Development of techniques to allow the isolation of longer cDNAs from the identified exons is in progress. This will depend on PCR amplification of cDNAs from a total human CDNA library.

  4. Age and gender specific biokinetic model for strontium in humans

    SciTech Connect

    Shagina, N. B.; Tolstykh, E. I.; Degteva, M. O.; Anspaugh, L. R.; Napier, Bruce A.

    2015-03-01

    A biokinetic model for strontium in humans is necessary for quantification of internal doses due to strontium radioisotopes. The ICRP-recommended biokinetic model for strontium has limitation for use in a population study, because it is not gender specific and does not cover all age ranges. The extensive Techa River data set on 90Sr in humans (tens of thousands of measurements) is a unique source of data on long-term strontium retention for men and women of all ages at intake. These, as well as published data, were used for evaluation of age- and gender-specific parameters for a new compartment biokinetic model for strontium (Sr-AGe model). The Sr-AGe model has similar structure as the ICRP model for the alkaline earth elements. The following parameters were mainly reevaluated: gastro-intestinal absorption and parameters related to the processes of bone formation and resorption defining calcium and strontium transfers in skeletal compartments. The Sr-AGe model satisfactorily describes available data sets on strontium retention for different kinds of intake (dietary and intravenous) at different ages (0–80 years old) and demonstrates good agreement with data sets for different ethnic groups. The Sr-AGe model can be used for dose assessment in epidemiological studies of general population exposed to ingested strontium radioisotopes.

  5. Age and gender specific biokinetic model for strontium in humans.

    PubMed

    Shagina, N B; Tolstykh, E I; Degteva, M O; Anspaugh, L R; Napier, B A

    2015-03-01

    A biokinetic model for strontium in humans is necessary for quantification of internal doses due to strontium radioisotopes. The ICRP-recommended biokinetic model for strontium has limitations for use in a population study, because it is not gender specific and does not cover all age ranges. The extensive Techa River data set on (90)Sr in humans (tens of thousands of measurements) is a unique source of data on long-term strontium retention for men and women of all ages at intake. These, as well as published data, were used for evaluation of age- and gender-specific parameters for a new compartment biokinetic model for strontium (Sr-AGe model). The Sr-AGe model has a similar structure to the ICRP model for the alkaline earth elements. The following parameters were mainly re-evaluated: gastrointestinal absorption and parameters related to the processes of bone formation and resorption defining calcium and strontium transfers in skeletal compartments. The Sr-AGe model satisfactorily describes available data sets on strontium retention for different kinds of intake (dietary and intravenous) at different ages (0-80 years old) and demonstrates good agreement with data sets for different ethnic groups. The Sr-AGe model can be used for dose assessment in epidemiological studies of general populations exposed to ingested strontium radioisotopes. PMID:25574605

  6. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis.

    PubMed

    Ehrenreich, Hannelore; Fischer, Benjamin; Norra, Christine; Schellenberger, Felix; Stender, Nike; Stiefel, Michael; Sirén, Anna-Leena; Paulus, Walter; Nave, Klaus-Armin; Gold, Ralf; Bartels, Claudia

    2007-10-01

    The neurodegenerative aspects of chronic progressive multiple sclerosis (MS) have received increasing attention in recent years, since anti-inflammatory and immunosuppressive treatment strategies have largely failed. However, successful neuroprotection and/or neuroregeneration in MS have not been demonstrated yet. Encouraged by the multifaceted neuroprotective effects of recombinant human erythropoietin (rhEPO) in experimental models, we performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with chronic progressive MS. Main study objectives were (i) evaluating safety of long-term high-dose intravenous rhEPO treatment in MS, and (ii) collecting first evidence of potential efficacy on clinical outcome parameters. Eight MS patients, five randomly assigned to high-dose (48,000 IU), three to low-dose (8000 IU) rhEPO treatment, and, as disease controls, two drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: A 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase. Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale (EDSS), and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for three to six months after cessation of EPO application. In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested. There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings. This first pilot study demonstrates the necessity and feasibility of controlled trials using high-dose rhEPO in chronic progressive MS. PMID:17728357

  7. Dysregulation of Human Toll-like Receptor Function in Aging

    PubMed Central

    Shaw, Albert C.; Panda, Alexander; Joshi, Samit R.; Qian, Feng; Allore, Heather G.; Montgomery, Ruth R.

    2010-01-01

    Studies addressing immunosenescence in the immune system have expanded to focus on the innate as well as the adaptive responses. In particular, aging results in alterations in the function of Toll-like receptors (TLRs), the first described pattern recognition receptor family of the innate immune system. Recent studies have begun to elucidate the consequences of aging on TLR function in human cohorts and add to existing findings performed in animal models. In general, these studies show that human TLR function is impaired in the context of aging, and in addition there is evidence for inappropriate persistence of TLR activation in specific systems. These findings are consistent with an overarching theme of age-associated dysregulation of TLR signaling that likely contributes to the increased morbidity and mortality from infectious diseases found in geriatric patients. PMID:21074638

  8. Deterioration of muscle function in the human esophagus with age.

    PubMed

    Gregersen, Hans; Pedersen, Jan; Drewes, Asbjørn Mohr

    2008-12-01

    Most studies on the effect of aging on esophageal motor function have shown that peristaltic function deteriorates with age. Esophageal motor function is traditionally studied by means of manometry and radiography. Distension of the esophagus with evaluation of active and passive mechanical parameters have become available during recent years. In this study, we did a manometric swallow analysis and used the distension method to study esophageal properties and function during aging. An impedance planimetric probe with a bag for distension was placed in the distal esophagus of 25 healthy volunteers with a median age of 35 (range 23-86) years. Distensions were done at an infusion rate of 25 ml min(-1) with and without relaxation of neuromuscular activity with butylscopolamine. The infusion was reversed when moderate pain was experienced by the subjects. Swallow-induced contraction amplitudes decreased as function of age for persons older than 40 years (P < 0.05). The total and passive tension showed an exponential increase as function of the change in radius, whereas the active tension increased until it reached a local maximum point. The maximum active tension deteriorated as a function of age after the age of 40 years (P < 0.05). Furthermore, esophagus became stiffer with age. In conclusion, age-related changes of increased stiffness and reduced primary and secondary peristalsis were found in the human esophagus with a deterioration of esophageal function after the age of 40 years. Such changes may contribute to the high prevalence of reflux disease in elderly. PMID:18461452

  9. Human Pituitary Adenoma Proteomics: New Progresses and Perspectives.

    PubMed

    Zhan, Xianquan; Wang, Xiaowei; Cheng, Tingting

    2016-01-01

    Pituitary adenoma (PA) is a common intracranial neoplasm that impacts on human health through interfering hypothalamus-pituitary-target organ axis systems. The development of proteomics gives great promises in the clarification of molecular mechanisms of a PA and discovery of effective biomarkers for prediction, prevention, early-stage diagnosis, and treatment for a PA. A great progress in the field of PA proteomics has been made in the past 10 years, including (i) the use of laser-capture microdissection, (ii) proteomics analyses of functional PAs (such as prolactinoma), invasive and non-invasive non-functional pituitary adenomas (NFPAs), protein post-translational modifications such as phosphorylation and tyrosine nitration, NFPA heterogeneity, and hormone isoforms, (iii) the use of protein antibody array, (iv) serum proteomics and peptidomics, (v) the integration of proteomics and other omics data, and (vi) the proposal of multi-parameter systematic strategy for a PA. This review will summarize these progresses of proteomics in PAs, point out the existing drawbacks, propose the future research directions, and address the clinical relevance of PA proteomics data, in order to achieve our long-term goal that is use of proteomics to clarify molecular mechanisms, construct molecular networks, and discover effective biomarkers. PMID:27303365

  10. Korean Contribution to the Progress of Science and Humanity

    NASA Astrophysics Data System (ADS)

    Min, Dong-Pil

    2012-03-01

    Science has problems yet to solve those global issues as the climate change, nuclear waste, water pollution, etc, although science and technology have been major contributors to human progress and will continue to open new doors to economic, medical and environmental advancement. Furthermore the benefits of scientific knowledge are not readily and evenly allocated across the globe. Korea will contribute to the progress of science by providing cooperative opportunities of the future research on the pure and applied scientific issues. Recently Korea launches a project of construction of the rare isotope accelerator, KoRIA, and Institute of Basic Science. Plans are set also to help develop the appropriate technology for developing countries. In this talk two aspects of science policy of Korean government are introduced, which are related to the accelerator KoRIA and to the thought on the establishment of Common Technology Platform. The former is to help the world science society for the expansion of our knowledge on the universe and matter, while the latter is to help the transfer of our knowledge to make our planet more flat.

  11. Human Pituitary Adenoma Proteomics: New Progresses and Perspectives

    PubMed Central

    Zhan, Xianquan; Wang, Xiaowei; Cheng, Tingting

    2016-01-01

    Pituitary adenoma (PA) is a common intracranial neoplasm that impacts on human health through interfering hypothalamus–pituitary–target organ axis systems. The development of proteomics gives great promises in the clarification of molecular mechanisms of a PA and discovery of effective biomarkers for prediction, prevention, early-stage diagnosis, and treatment for a PA. A great progress in the field of PA proteomics has been made in the past 10 years, including (i) the use of laser-capture microdissection, (ii) proteomics analyses of functional PAs (such as prolactinoma), invasive and non-invasive non-functional pituitary adenomas (NFPAs), protein post-translational modifications such as phosphorylation and tyrosine nitration, NFPA heterogeneity, and hormone isoforms, (iii) the use of protein antibody array, (iv) serum proteomics and peptidomics, (v) the integration of proteomics and other omics data, and (vi) the proposal of multi-parameter systematic strategy for a PA. This review will summarize these progresses of proteomics in PAs, point out the existing drawbacks, propose the future research directions, and address the clinical relevance of PA proteomics data, in order to achieve our long-term goal that is use of proteomics to clarify molecular mechanisms, construct molecular networks, and discover effective biomarkers. PMID:27303365

  12. Progress and prospects for L2-based human papillomavirus vaccines.

    PubMed

    Jiang, Rosie T; Schellenbacher, Christina; Chackerian, Bryce; Roden, Richard B S

    2016-07-01

    Human papillomavirus (HPV) is a worldwide public health problem, particularly in resource-limited countries. Fifteen high-risk genital HPV types are sexually transmitted and cause 5% of all cancers worldwide, primarily cervical, anogenital and oropharyngeal carcinomas. Skin HPV types are generally associated with benign disease, but a subset is linked to non-melanoma skin cancer. Licensed HPV vaccines based on virus-like particles (VLPs) derived from L1 major capsid antigen of key high risk HPVs are effective at preventing these infections but do not cover cutaneous types and are not therapeutic. Vaccines targeting L2 minor capsid antigen, some using capsid display, adjuvant and fusions with early HPV antigens or Toll-like receptor agonists, are in development to fill these gaps. Progress and challenges with L2-based vaccines are summarized. PMID:26901354

  13. Progression of Carotid Intima-Media Thickness in a Contemporary Human Immunodeficiency Virus Cohort

    PubMed Central

    Henry, W. Keith; Patel, Pragna; Bush, Timothy J.; Conley, Lois J.; Mack, Wendy J.; Overton, E. Turner; Budoff, Matt; Hammer, John; Carpenter, Charles C.; Hodis, Howard N.; Brooks, John T.

    2011-01-01

    Background. Persons with human immunodeficiency virus (HIV) infection are at risk for premature cardiovascular disease (CVD). Predictors of atherosclerotic disease progression in contemporary patients have not been well described. Methods. Using data from a prospective observational cohort of adults infected with HIV (Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy), we assessed common carotid artery intima-media thickness (CIMT) at baseline and year 2 by ultrasound. We examined HIV-associated predictors of CIMT progression after adjusting for age, sex, race/ethnicity, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol level, and baseline CIMT using linear regression. Results. Among 389 participants (median age at baseline, 42 years; male sex, 77%; median CD4+ cell count at baseline, 485 cells/mm3; 78% receiving antiretroviral therapy), the median 2-year CIMT change was 0.016 mm (interquartile range, −0.003 to 0.033 mm; P < .001). Lesser CIMT progression was associated with a suppressed viral load at baseline (−0.009 mm change; P = .015) and remaining virologically suppressed throughout follow-up (−0.011 mm change; P < .001). After adjusting for additional risk factors and a suppressed viral load during follow-up, nonnucleoside reverse transcriptase inhibitor versus protease inhibitor exposure was associated with lesser CIMT progression (−0.011 mm change; P = .02). Conclusions. Suppressing HIV replication below clinical thresholds was associated with less progression of atherosclerosis. The proatherogenic mechanisms of HIV replication and the net CVD benefit of different antiretroviral drugs should be a focus of future research. PMID:21860012

  14. Do glutathione levels decline in aging human brain?

    PubMed

    Tong, Junchao; Fitzmaurice, Paul S; Moszczynska, Anna; Mattina, Katie; Ang, Lee-Cyn; Boileau, Isabelle; Furukawa, Yoshiaki; Sailasuta, Napapon; Kish, Stephen J

    2016-04-01

    For the past 60 years a major theory of "aging" is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23-99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for "replication" investigations employing the new (1)H MRS imaging procedures in living human brain. PMID:26845616

  15. Age of onset differentially influences the progression of regional dysfunction in sporadic amyotrophic lateral sclerosis.

    PubMed

    Yokoi, Daichi; Atsuta, Naoki; Watanabe, Hazuki; Nakamura, Ryoichi; Hirakawa, Akihiro; Ito, Mizuki; Watanabe, Hirohisa; Katsuno, Masahisa; Izumi, Yuishin; Morita, Mitsuya; Taniguchi, Akira; Oda, Masaya; Abe, Koji; Mizoguchi, Kouichi; Kano, Osamu; Kuwabara, Satoshi; Kaji, Ryuji; Sobue, Gen

    2016-06-01

    The clinical courses of sporadic amyotrophic lateral sclerosis (ALS) show extensive variability. Our objective was to elucidate how age of onset influences the progression of regional symptoms and functional losses in sporadic ALS. We included 648 patients with sporadic ALS from a multicenter prospective ALS cohort. We investigated the distribution of initial symptoms and analyzed the time from onset to events affecting activities of daily living (ADL) as well as the longitudinal changes in each regional functional rating score among four groups with different ages of onset. The frequencies of dysarthria and dysphagia as initial symptoms were higher in the older age groups, whereas weakness of upper limbs was the most common initial symptom in the youngest age group. The survival times and the times from onset to loss of speech and swallowing were significantly shorter in the older age group (p < 0.001), although the times from onset to loss of upper limb function were not significantly different among the age groups. According to joint modeling analysis, the bulbar score declined faster in the older age groups (<50 vs. 60-69 years: p = 0.029, <50 vs. ≥70 years: p < 0.001), whereas there was no significant correlation between the age of onset and decline in the upper limb score. Our results showed that age of onset had a significant influence on survival time and the progression of bulbar symptoms, but had no influence on upper limb function in sporadic ALS. PMID:27083563

  16. Detection of advanced glycation end products (AGEs) on human skin by in vivo confocal Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Martin, A. A.; Pereira, L.; Ali, S. M.; Pizzol, C. D.; Tellez, C. A.; Favero, P. P.; Santos, L.; da Silva, V. V.; Praes, C. E. O.

    2016-03-01

    The aging process involves the reduction in the production of the major components of skin tissue. During intrinsic aging and photoaging processes, in dermis of human skin, fibroblasts become senescent and have decreased activity, which produce low levels of collagen. Moreover, there is accumulation of advanced glycation end products (AGEs). AGEs have incidence in the progression of age-related diseases, principally in diabetes mellitus and in Alzheimer's diseases. AGEs causes intracellular damage and/or apoptosis leading to an increase of the free radicals, generating a crosslink with skin proteins and oxidative stress. The aim of this study is to detect AGEs markers on human skin by in vivo Confocal Raman spectroscopy. Spectra were obtained by using a Rivers Diagnostic System, 785 nm laser excitation and a CCD detector from the skin surface down to 120 μm depth. We analyzed the confocal Raman spectra of the skin dermis of 30 women volunteers divided into 3 groups: 10 volunteers with diabetes mellitus type II, 65-80 years old (DEW); 10 young healthy women, 20-33 years old (HYW); and 10 elderly healthy women, 65-80 years old (HEW). Pentosidine and glucosepane were the principally identified AGEs in the hydroxyproline and proline Raman spectral region (1000-800 cm-1), in the 1.260-1.320 cm-1 region assignable to alpha-helical amide III modes, and in the Amide I region. Pentosidine and glucosepane calculated vibrational spectra were performed through Density Functional Theory using the B3LYP functional with 3-21G basis set. Difference between the Raman spectra of diabetic elderly women and healthy young women, and between healthy elderly women and healthy young women were also obtained with the purpose of identifying AGEs Raman bands markers. AGEs peaks and collagen changes have been identified and used to quantify the glycation process in human skin.

  17. Decreases in Human Semen Quality with Age Among Healthy Men

    SciTech Connect

    Eskenazi, B.; Wyrobek, A.J.; Kidd, S.A.; Moore, L.; Young, S.S.; Moore, D.

    2001-12-01

    The objective of this report is to characterize the associations between age and semen quality among healthy active men after controlling for identified covariates. Ninety-seven healthy, nonsmoking men between 22 and 80 years without known fertility problems who worked for or retired from a large research laboratory. There was a gradual decrease in all semen parameters from 22-80 years of age. After adjusting for covariates, volume decreased 0.03 ml per year (p = 0.001); sperm concentration decreased 2.5% per year (p = 0.005); total count decreased 3.6% per year of age (p < 0.001); motility decreased 0.7% per year (P < 0.001); progressive motility decreased 3.1% per year (p < 0.001); and total progressively motile sperm decreased 4.8% per year (p < 0.001). In a group of healthy active men, semen volume, sperm concentration, total sperm count, and sperm motility decrease continuously between 22-80 years of age, with no evidence of a threshold.

  18. Age-related changes in mucins from human whole saliva.

    PubMed

    Denny, P C; Denny, P A; Klauser, D K; Hong, S H; Navazesh, M; Tabak, L A

    1991-10-01

    The predominant mucins in human whole saliva, MG1 and MG2, serve to protect and to lubricate the oral cavity. In this study, both unstimulated and stimulated whole salivas were collected from two groups of subjects: young (18-35 years of age) and aged (65-83 years of age). The subjects were in apparent good health. Saliva samples from each subject were analyzed by SDS-PAGE. The gels were stained with Stains-all, and both MG1 and MG2 were quantitated by video-image densitometry. The protocol gave reproducible values for each mucin. The stimulated and unstimulated salivas from aged subjects showed significant reductions in concentrations of both MG1 and MG2, as quantitated in mucin dye-binding units. Possible associations of these reductions with the aging process are discussed. PMID:1719051

  19. Aging.

    PubMed

    Park, Dong Choon; Yeo, Seung Geun

    2013-09-01

    Aging is initiated based on genetic and environmental factors that operate from the time of birth of organisms. Aging induces physiological phenomena such as reduction of cell counts, deterioration of tissue proteins, tissue atrophy, a decrease of the metabolic rate, reduction of body fluids, and calcium metabolism abnormalities, with final progression onto pathological aging. Despite the efforts from many researchers, the progression and the mechanisms of aging are not clearly understood yet. Therefore, the authors would like to introduce several theories which have gained attentions among the published theories up to date; genetic program theory, wear-and-tear theory, telomere theory, endocrine theory, DNA damage hypothesis, error catastrophe theory, the rate of living theory, mitochondrial theory, and free radical theory. Although there have been many studies that have tried to prevent aging and prolong life, here we introduce a couple of theories which have been proven more or less; food, exercise, and diet restriction. PMID:24653904

  20. Aging

    PubMed Central

    Park, Dong Choon

    2013-01-01

    Aging is initiated based on genetic and environmental factors that operate from the time of birth of organisms. Aging induces physiological phenomena such as reduction of cell counts, deterioration of tissue proteins, tissue atrophy, a decrease of the metabolic rate, reduction of body fluids, and calcium metabolism abnormalities, with final progression onto pathological aging. Despite the efforts from many researchers, the progression and the mechanisms of aging are not clearly understood yet. Therefore, the authors would like to introduce several theories which have gained attentions among the published theories up to date; genetic program theory, wear-and-tear theory, telomere theory, endocrine theory, DNA damage hypothesis, error catastrophe theory, the rate of living theory, mitochondrial theory, and free radical theory. Although there have been many studies that have tried to prevent aging and prolong life, here we introduce a couple of theories which have been proven more or less; food, exercise, and diet restriction. PMID:24653904

  1. Progressive Bidirectional Age-Related Changes in Default Mode Network Effective Connectivity across Six Decades.

    PubMed

    Li, Karl; Laird, Angela R; Price, Larry R; McKay, D Reese; Blangero, John; Glahn, David C; Fox, Peter T

    2016-01-01

    The default mode network (DMN) is a set of regions that is tonically engaged during the resting state and exhibits task-related deactivation that is readily reproducible across a wide range of paradigms and modalities. The DMN has been implicated in numerous disorders of cognition and, in particular, in disorders exhibiting age-related cognitive decline. Despite these observations, investigations of the DMN in normal aging are scant. Here, we used blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) acquired during rest to investigate age-related changes in functional connectivity of the DMN in 120 healthy normal volunteers comprising six, 20-subject, decade cohorts (from 20-29 to 70-79). Structural equation modeling (SEM) was used to assess age-related changes in inter-regional connectivity within the DMN. SEM was applied both using a previously published, meta-analytically derived, node-and-edge model, and using exploratory modeling searching for connections that optimized model fit improvement. Although the two models were highly similar (only 3 of 13 paths differed), the sample demonstrated significantly better fit with the exploratory model. For this reason, the exploratory model was used to assess age-related changes across the decade cohorts. Progressive, highly significant changes in path weights were found in 8 (of 13) paths: four rising, and four falling (most changes were significant by the third or fourth decade). In all cases, rising paths and falling paths projected in pairs onto the same nodes, suggesting compensatory increases associated with age-related decreases. This study demonstrates that age-related changes in DMN physiology (inter-regional connectivity) are bidirectional, progressive, of early onset and part of normal aging. PMID:27378909

  2. Progressive Bidirectional Age-Related Changes in Default Mode Network Effective Connectivity across Six Decades

    PubMed Central

    Li, Karl; Laird, Angela R.; Price, Larry R.; McKay, D. Reese; Blangero, John; Glahn, David C.; Fox, Peter T.

    2016-01-01

    The default mode network (DMN) is a set of regions that is tonically engaged during the resting state and exhibits task-related deactivation that is readily reproducible across a wide range of paradigms and modalities. The DMN has been implicated in numerous disorders of cognition and, in particular, in disorders exhibiting age-related cognitive decline. Despite these observations, investigations of the DMN in normal aging are scant. Here, we used blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) acquired during rest to investigate age-related changes in functional connectivity of the DMN in 120 healthy normal volunteers comprising six, 20-subject, decade cohorts (from 20–29 to 70–79). Structural equation modeling (SEM) was used to assess age-related changes in inter-regional connectivity within the DMN. SEM was applied both using a previously published, meta-analytically derived, node-and-edge model, and using exploratory modeling searching for connections that optimized model fit improvement. Although the two models were highly similar (only 3 of 13 paths differed), the sample demonstrated significantly better fit with the exploratory model. For this reason, the exploratory model was used to assess age-related changes across the decade cohorts. Progressive, highly significant changes in path weights were found in 8 (of 13) paths: four rising, and four falling (most changes were significant by the third or fourth decade). In all cases, rising paths and falling paths projected in pairs onto the same nodes, suggesting compensatory increases associated with age-related decreases. This study demonstrates that age-related changes in DMN physiology (inter-regional connectivity) are bidirectional, progressive, of early onset and part of normal aging. PMID:27378909

  3. DNA methylation age of human tissues and cell types

    PubMed Central

    2013-01-01

    Background It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. Results I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. Conclusions I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research. PMID:24138928

  4. Microhardness of human cancellous bone tissue in progressive hip osteoarthritis.

    PubMed

    Tomanik, Magdalena; Nikodem, Anna; Filipiak, Jarosław

    2016-12-01

    Bone tissue is a biological system in which the dynamic processes of, among others, bone formation or internal reconstruction will determine the spatial structure of the tissue and its mechanical properties. The appearance of a factor disturbing the balance between biological processes, e.g. a disease, will cause changes in the spatial structure of bones, thus affecting its mechanical properties. One of the bone diseases most common in an increasingly ageing population is osteoarthritis, also referred to as degenerative joint disease. It is estimated that in 2050 about 1300 million people will show symptoms of OA. The appearance of a pathological stimulus disturbs the balance of the processes of degradation and synthesis of articular cartilage, chondrocytes and the extracellular matrix, and the subchondral bone layer. As osteoarthritis progresses, study of the epiphysis reveals increasingly widespread changes of the articular surface and the internal structure of bone tissue. In this paper, the authors point out the differences in the mechanical properties of cancellous bone tissue forming the proximal epiphysis of the femoral bone during the progressive stages of OA. In order to determine microproperties of bone trabeculae, specimens from different stages of the disease (N=9) were subjected to microindentation testing, which made it possible to determine the material properties of bone tissue, such as microhardness HV and Young׳s modulus E. In addition, mechanical tests were supplemented with Raman spectroscopy, which determine the degree of bone mineralization, and measurements of structural properties based on analysis using microCT. The conducted tests were used to establish both quantitative and quantitative description of changes in the structural and mechanical properties connected with reorganization of trabeculae making up the bone in the various stages of osteoarthritis. The proposed description will supplement existing knowledge in the literature about

  5. The many faces of human ageing: toward a psychological culture of old age.

    PubMed

    Baltes, P B

    1991-11-01

    In an effort to distil major findings about the nature of human ageing, seven propositions are presented as a guiding frame of reference. This propositional framework is then used to specify some conditions for a positive culture of old age and to advance one possible model of good psychological ageing. This model focuses on the dynamic interplay between three processes: selection, optimization, and compensation. The model is universal in its basic features, but at the same time emphasizes individual variations in phenotypic manifestation. PMID:1780400

  6. Acetylcholinesterase: an enzymatic marker of human red blood cell aging.

    PubMed

    Prall, Y G; Gambhir, K K; Ampy, F R

    1998-01-01

    The purpose of this investigation was to determine whether acetylcholinesterase (AChE) can be used as a marker of cell aging in human red blood cells (RBCs). This study used consented subjects; both males and females in an age range of 21-42 years. The blood samples (8-9 mL) were drawn in tubes containing sodium heparin or EDTA as anticoagulants. To avoid contamination with other cells, (lymphocytes, monocytes and reticulocytes), RBCs were purified (PRBC) by Hypaque-Ficoll gradient technique. The PRBCs were subfractionated into young (y) (1.08-1.09), mid (m) (1.09-1.11) and old (o) (1.11-1.12) percoll density (g/mL) fractions using a discontinuous percoll gradient. The mean +/- 1 SD AChE per gram hemoglobin (U/g Hgb) activities in whole blood (WB) purified human red blood cells (PRBCs), young human red blood cells (y-RBCs), mid age human red blood cells (m-RBCs) and old human red blood cells (o-RBCs) were 27.4 +/- 2.98, 26.0 +/- 2.33, 25.5 +/- 1.64, 20.3 +/- 3.84, 14.6 +/- 3.42 in males and 26.3 +/- 4.44, 24.8 /- 4.83, 26.4 +/- 4.59, 24.0 +/- 5.50 and 12.4 +/- 7.09 in females respectively. Although there was variation in the data, the results indicated that old human red blood cells showed significantly (p<.05) lower AChE activity compared to young human red blood cells of both sexes. These preliminary but novel observations suggest that AChE can be an excellent enzymatic marker for RBC aging in man. PMID:9698047

  7. Cell Cycle Progression of Human Cells Cultured in Rotating Bioreactor

    NASA Technical Reports Server (NTRS)

    Parks, Kelsey

    2009-01-01

    Space flight has been shown to alter the astronauts immune systems. Because immune performance is complex and reflects the influence of multiple organ systems within the host, scientists sought to understand the potential impact of microgravity alone on the cellular mechanisms critical to immunity. Lymphocytes and their differentiated immature form, lymphoblasts, play an important and integral role in the body's defense system. T cells, one of the three major types of lymphocytes, play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors. Reported studies have shown that spaceflight can affect the expression of cell surface markers. Cell surface markers play an important role in the ability of cells to interact and to pass signals between different cells of the same phenotype and cells of different phenotypes. Recent evidence suggests that cell-cycle regulators are essential for T-cell function. To trigger an effective immune response, lymphocytes must proliferate. The objective of this project is to investigate the changes in growth of human cells cultured in rotating bioreactors and to measure the growth rate and the cell cycle distribution for different human cell types. Human lymphocytes and lymphoblasts will be cultured in a bioreactor to simulate aspects of microgravity. The bioreactor is a cylindrical culture vessel that incorporates the aspects of clinostatic rotation of a solid fluid body around a horizontal axis at a constant speed, and compensates gravity by rotation and places cells within the fluid body into a sustained free-fall. Cell cycle progression and cell proliferation of the lymphocytes will be measured for a number of days. In addition, RNA from the cells will be isolated for expression of genes related in cell cycle regulations.

  8. Variations in Human Capital Investment Activity by Age.

    ERIC Educational Resources Information Center

    Simpson, Patricia A.; Greller, Martin M.; Stroh, Linda K.

    2002-01-01

    Late-career workers (ages 50-65) were more likely to participate in credentialing programs, targeted job-related courses, and on-the-job computer training than younger adults and received similar employer support. However, participation might be a consequence of support received. Human capital investment thus is more complex than conventional…

  9. Recovery of Elasticity of Aged Human Epithelial Cells In-Vitro

    NASA Astrophysics Data System (ADS)

    Sokolov, Igor; Iyer, Swaminathan; Woodworth, Craig

    2006-03-01

    We recently found a considerable increase in rigidity of human epithelial cells during ageing in-vitro. This is important because the loss in elasticity of epithelial tissues with ageing contributes to many human diseases. We also found that cultured cells had three distinct regions of rigidity, and that the increase in rigidity correlated with an increase in density of cytoskeletal fibres. However, it was not clear which type of fibre was important. Atomic Force Microscopy (AFM) and imunofluorescence microscopy were used in this study to characterize aging human epithelial cells in vitro, both before and after treatment with cytochalasin B. We found that the fibres associated with increased rigidity were mostly F-actin microfilaments. Furthermore, using cytochalasin B, a chemical that inhibits polymerization of F-actin, we restored the rigidity of old cells to the young level in all three areas of rigidity simultaneously. In conclusion, these results clarify how the cell mechanics changes during aging in vitro, and they may be relevant for treatment of age-related loss of elasticity in epithelial tissues. The trials of this new treatment are in progress.

  10. The Laboratory Rat: Relating Its Age With Human's

    PubMed Central

    Sengupta, Pallav

    2013-01-01

    By late 18th or early 19th century, albino rats became the most commonly used experimental animals in numerous biomedical researches, as they have been recognized as the preeminent model mammalian system. But, the precise correlation between age of laboratory rats and human is still a subject of debate. A number of studies have tried to detect these correlations in various ways, But, have not successfully provided any proper association. Thus, the current review attempts to compare rat and human age at different phases of their life. The overall findings indicate that rats grow rapidly during their childhood and become sexually mature at about the sixth week, but attain social maturity 5-6 months later. In adulthood, every day of the animal is approximately equivalent to 34.8 human days (i.e., one rat month is comparable to three human years). Numerous researchers performed experimental investigations in albino rats and estimated, in general, while considering their entire life span, that a human month resembles every-day life of a laboratory rat. These differences signify the variations in their anatomy, physiology and developmental processes, which must be taken into consideration while analyzing the results or selecting the dose of any research in rats when age is a crucial factor. PMID:23930179

  11. Interventions to Slow Aging in Humans: Are We Ready?

    PubMed Central

    Longo, Valter D; Antebi, Adam; Bartke, Andrzej; Barzilai, Nir; Brown-Borg, Holly M; Caruso, Calogero; Curiel, Tyler J; de Cabo, Rafael; Franceschi, Claudio; Gems, David; Ingram, Donald K; Johnson, Thomas E; Kennedy, Brian K; Kenyon, Cynthia; Klein, Samuel; Kopchick, John J; Lepperdinger, Guenter; Madeo, Frank; Mirisola, Mario G; Mitchell, James R; Passarino, Giuseppe; Rudolph, Karl L; Sedivy, John M; Shadel, Gerald S; Sinclair, David A; Spindler, Stephen R; Suh, Yousin; Vijg, Jan; Vinciguerra, Manlio; Fontana, Luigi

    2015-01-01

    The workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting. PMID:25902704

  12. Interventions to Slow Aging in Humans: Are We Ready?

    PubMed

    Longo, Valter D; Antebi, Adam; Bartke, Andrzej; Barzilai, Nir; Brown-Borg, Holly M; Caruso, Calogero; Curiel, Tyler J; de Cabo, Rafael; Franceschi, Claudio; Gems, David; Ingram, Donald K; Johnson, Thomas E; Kennedy, Brian K; Kenyon, Cynthia; Klein, Samuel; Kopchick, John J; Lepperdinger, Guenter; Madeo, Frank; Mirisola, Mario G; Mitchell, James R; Passarino, Giuseppe; Rudolph, Karl L; Sedivy, John M; Shadel, Gerald S; Sinclair, David A; Spindler, Stephen R; Suh, Yousin; Vijg, Jan; Vinciguerra, Manlio; Fontana, Luigi

    2015-08-01

    The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR-S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting. PMID:25902704

  13. Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease

    PubMed Central

    Dai, Dao-Fu; Chen, Tony; Johnson, Simon C.; Szeto, Hazel

    2012-01-01

    Abstract Cardiovascular diseases (CVDs) are the major causes of death in the western world. The incidence of cardiovascular disease as well as the rate of cardiovascular mortality and morbidity increase exponentially in the elderly population, suggesting that age per se is a major risk factor of CVDs. The physiologic changes of human cardiac aging mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity. Many of these changes are closely recapitulated in animal models commonly used in an aging study, including rodents, flies, and monkeys. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as mitochondrial oxidative stress, insulin/insulin-like growth factor/PI3K pathway, adrenergic and renin angiotensin II signaling, and nutrient signaling pathways. This article also reviews the central role of mitochondrial oxidative stress in CVDs and the plausible mechanisms underlying the progression toward heart failure in the susceptible aging hearts. Finally, the understanding of the molecular mechanisms of cardiac aging may support the potential clinical application of several “anti-aging” strategies that treat CVDs and improve healthy cardiac aging. PMID:22229339

  14. Human iPSC-based modeling of late-onset disease via progerin-induced aging.

    PubMed

    Miller, Justine D; Ganat, Yosif M; Kishinevsky, Sarah; Bowman, Robert L; Liu, Becky; Tu, Edmund Y; Mandal, Pankaj K; Vera, Elsa; Shim, Jae-won; Kriks, Sonja; Taldone, Tony; Fusaki, Noemi; Tomishima, Mark J; Krainc, Dimitri; Milner, Teresa A; Rossi, Derrick J; Studer, Lorenz

    2013-12-01

    Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models. PMID:24315443

  15. Human iPSC-based Modeling of Late-Onset Disease via Progerin-induced Aging

    PubMed Central

    Miller, Justine D.; Ganat, Yosif M.; Kishinevsky, Sarah; Bowman, Robert L.; Liu, Becky; Tu, Edmund Y.; Mandal, Pankaj; Vera, Elsa; Shim, Jae-won; Kriks, Sonja; Taldone, Tony; Fusaki, Noemi; Tomishima, Mark J.; Krainc, Dimitri; Milner, Teresa A.; Rossi, Derrick J.; Studer, Lorenz

    2014-01-01

    Summary Reprogramming somatic cells to induced pluripotent stem cells (iPSCs), resets their identity back to an embryonic age, and thus presents a significant hurdle for modeling late-onset disorders. In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson’s disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine-hydroxylase (TH) expression and enlarged mitochondria or Lewy body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models. PMID:24315443

  16. Anterior Lamina Cribrosa Surface Depth, Age, and Visual Field Sensitivity in the Portland Progression Project

    PubMed Central

    Ren, Ruojin; Yang, Hongli; Gardiner, Stuart K.; Fortune, Brad; Hardin, Christy; Demirel, Shaban; Burgoyne, Claude F.

    2014-01-01

    Purpose. To assess the effect of age on spectral-domain optical coherence tomography (SDOCT)-detected lamina cribrosa depth while controlling for visual field (VF) status and retinal nerve fiber layer thickness (RNFLT) in 221 high-risk ocular hypertension and glaucoma patients enrolled in the Portland Progression Project. Methods. In this cross-sectional study, each participant underwent 870-nm SDOCT to obtain high-resolution radial B-scans centered on the optic nerve head (ONH) and a standardized ophthalmologic examination, including automated perimetry, on the same day. For each ONH, an anterior lamina cribrosa surface depth (ALCSD) parameter was generated as the average perpendicular distance from each anterior lamina cribrosa surface point relative to Bruch's membrane opening (BMO) reference plane within all 24 delineated B-scans. The relative effects of age, age-corrected VF status (mean deviation [MD]), and RNFLT on ALCSD were analyzed. Results. The mean age ± SD of participants was 64 ± 11 years (range, 33–90 years). The relationship between ALCSD and MD was age-dependent. ALCSD = 407.68 − 67.13 × MD − 0.08 × Age + 0.89 × MD × Age (MD, P = 0.001; MD × Age, P = 0.004). The relationship between ALCSD and RNFLT may also be age-dependent but did not achieve significance (interaction term, P = 0.067). ALCSD increased with worse VF status in younger eyes but not in older eyes. In older eyes, the anterior lamina was shallower than in younger eyes for the same VF status and RNFLT. Conclusions. These data are consistent with the concept that structure/structure and structure/function relationships change with age. PMID:24474264

  17. Pathogenesis of Age-Related Bone Loss in Humans

    PubMed Central

    2013-01-01

    Background. Although data from rodent systems are extremely useful in providing insights into possible mechanisms of age-related bone loss, concepts evolving from animal models need to ultimately be tested in humans. Methods. This review provides an update on mechanisms of age-related bone loss in humans based on the author’s knowledge of the field and focused literature reviews. Results. Novel imaging, experimental models, biomarkers, and analytic techniques applied directly to human studies are providing new insights into the patterns of bone mass acquisition and loss as well as the role of sex steroids, in particular estrogen, on bone metabolism and bone loss with aging in women and men. These studies have identified the onset of trabecular bone loss at multiple sites that begins in young adulthood and remains unexplained, at least based on current paradigms of the mechanisms of bone loss. In addition, estrogen appears to be a major regulator of bone metabolism not only in women but also in men. Studies assessing mechanisms of estrogen action on bone in humans have identified effects of estrogen on RANKL expression by several different cell types in the bone microenvironment, a role for TNF-α and IL-1β in mediating effects of estrogen deficiency on bone, and possible regulation of the Wnt inhibitor, sclerostin, by estrogen. Conclusions. There have been considerable advances in our understanding of age-related bone loss in humans. However, there are also significant gaps in knowledge, particularly in defining cell autonomous changes in bone in human studies to test or validate concepts emerging from studies in rodents. Decision Editor: Luigi Ferrucci, MD, PhD PMID:22923429

  18. Total body potassium in aging humans: A longitudinal study

    SciTech Connect

    Flynn, M.A.; Nolph, G.B.; Baker, A.S.; Martin, W.M.; Krause, G. )

    1989-10-01

    Total body potassium (TBK) data calculated from longitudinal measurements over 18 y of 40K by whole-body counting of 564 male and 61 female healthy humans in a 2-pi liquid scintillation counter show little change in females younger than 50 y compared with males of those ages. Males show less TBK from 41 y onward as they age, with most rapid rate of loss between 41 and 60 y. Females have a rapid loss of TBK when they are older than 60 y; the loss is at a greater rate than that of males. Percent total body fat calculated from total body weight and lean body mass (LBM) derived from TBK document greater adiposity in females at all ages except ages 51-60 y when females are similar to males in change in percent fat per year per centimeter.

  19. A network model of human aging: Limits, errors, and information

    NASA Astrophysics Data System (ADS)

    Farrell, Spencer; Mitnitski, Arnold; Rockwood, Kenneth; Rutenberg, Andrew

    The Frailty Index (FI) quantifies human aging using the fraction of accumulated age-related deficits. The FI correlates strongly with mortality and accumulates non-linearly and stochastically with age. Clinical data shows a nearly universal limit of FI <= 0 . 7 . We computationally model an aging population using a network model of interacting deficits. Deficits damage and repair at rates that depend upon the average damage of connected nodes. The model is parametrized to fit clinical data. We find that attribution errors, especially false negative, allow the model to recover the frailty limit. Mutual information allows us to assess how well the FI can predict mortality. Mutual information provides a non-parametric measure of how the FI predicts mortality. We find that attribution errors have a small effect on the mutual information when many deficits are included in the model. The mutual information of our model and of the clinical data are comparable.

  20. Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress.

    PubMed

    Al-Khalaf, Huda H; Aboussekhra, Abdelilah

    2013-06-01

    Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, γ-rays or H2O2 as compared to their younger counterparts. In response to γ-rays and H2O2, the levels of Bcl-2 and both forms of survivin were up-regulated in old cells, but not in their corresponding young ones. This repression of survivin and phospho-survivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer. PMID:22252435

  1. Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy

    PubMed Central

    Oudit, Gavin Y.; Liu, George C.; Zhong, JiuChang; Basu, Ratnadeep; Chow, Fung L.; Zhou, Joyce; Loibner, Hans; Janzek, Evelyne; Schuster, Manfred; Penninger, Josef M.; Herzenberg, Andrew M.; Kassiri, Zamaneh; Scholey, James W.

    2010-01-01

    OBJECTIVE Diabetic nephropathy is one of the most common causes of end-stage renal failure. Inhibition of ACE2 function accelerates diabetic kidney injury, whereas renal ACE2 is downregulated in diabetic nephropathy. We examined the ability of human recombinant ACE2 (hrACE2) to slow the progression of diabetic kidney injury. RESEARCH DESIGN AND METHODS Male 12-week-old diabetic Akita mice (Ins2WT/C96Y) and control C57BL/6J mice (Ins2WT/WT) were injected daily with placebo or with rhACE2 (2 mg/kg, i.p.) for 4 weeks. Albumin excretion, gene expression, histomorphometry, NADPH oxidase activity, and peptide levels were examined. The effect of hrACE2 on high glucose and angiotensin II (ANG II)–induced changes was also examined in cultured mesangial cells. RESULTS Treatment with hrACE2 increased plasma ACE2 activity, normalized blood pressure, and reduced the urinary albumin excretion in Akita Ins2WT/C96Y mice in association with a decreased glomerular mesangial matrix expansion and normalization of increased α-smooth muscle actin and collagen III expression. Human recombinant ACE2 increased ANG 1–7 levels, lowered ANG II levels, and reduced NADPH oxidase activity. mRNA levels for p47phox and NOX2 and protein levels for protein kinase Cα (PKCα) and PKCβ1 were also normalized by treatment with hrACE2. In vitro, hrACE2 attenuated both high glucose and ANG II–induced oxidative stress and NADPH oxidase activity. CONCLUSIONS Treatment with hrACE2 attenuates diabetic kidney injury in the Akita mouse in association with a reduction in blood pressure and a decrease in NADPH oxidase activity. In vitro studies show that the protective effect of hrACE2 is due to reduction in ANG II and an increase in ANG 1–7 signaling. PMID:19934006

  2. Report on TRP Analyses of Issues Concerning Within-Age versus Cross-Age Scales for the National Assessment of Educational Progress.

    ERIC Educational Resources Information Center

    Haertel, Edward H.

    The National Assessment Governing Board of Educational Progress has recently adopted the position that the National Assessment of Educational Progress (NAEP) should employ within-age scaling whenever feasible. The NAEP Technical Review panel (TRP) has studied the issue at some length, and reports on it in this analysis. The first section reviews…

  3. Vestibulosympathetic reflex during orthostatic challenge in aging humans

    NASA Technical Reports Server (NTRS)

    Monahan, Kevin D.; Ray, Chester A.

    2002-01-01

    Aging attenuates the increase in muscle sympathetic nerve activity (MSNA) and elicits hypotension during otolith organ engagement in humans. The purpose of the present study was to determine the neural and cardiovascular responses to otolithic engagement during orthostatic stress in older adults. We hypothesized that age-related impairments in the vestibulosympathetic reflex would persist during orthostatic challenge in older subjects and might compromise arterial blood pressure regulation. MSNA, arterial blood pressure, and heart rate responses to head-down rotation (HDR) performed with and without lower body negative pressure (LBNP) in prone subjects were measured. Ten young (27 +/- 1 yr) and 11 older subjects (64 +/- 1 yr) were studied prospectively. HDR performed alone elicited an attenuated increase in MSNA in older subjects (Delta106 +/- 28 vs. Delta20 +/- 7% for young and older subjects). HDR performed during simultaneous orthostatic stress increased total MSNA further in young (Delta53 +/- 15%; P < 0.05) but not older subjects (Delta-5 +/- 4%). Older subjects demonstrated consistent significant hypotension during HDR performed both alone (Delta-6 +/- 2 mmHg) and during LBNP (Delta-7 +/- 2 mmHg). These data provide experimental support for the concept that age-related impairments in the vestibulosympathetic reflex persist during orthostatic challenge in older adults. Furthermore, these findings are consistent with the concept that age-related alterations in vestibular function might contribute to altered orthostatic blood pressure regulation with age in humans.

  4. Thinking Differently About Aging: Changing Attitudes Through the Humanities.

    PubMed

    Marshall, Leni

    2015-08-01

    Ageism has many cumulative negative health effects, so reducing ageism in college-age youths can have a significant, long-term impact on public health. Reduced ageism decreases the prevalence and severity of many negative health events, such as myocardial infarctions, and can add an average of 7.5 years to the life span. One of the few proven methods for reducing ageist ideation is through participation in a video screening and a pair of follow-up conversations. This intervention is similar to the regular activities of many faculty members in the humanities. Gerontologists' expertise with quantitative studies, qualitative studies, and data analysis is needed to determine what factors can improve the efficacy of the intervention and to demonstrate the long-term health impact of specific interventions. Humanities research also will benefit from expanded understandings of aging and old age. Organizations such as the Gerontological Society of America, the European Network in Aging Studies, and the North American Network in Aging Studies can facilitate interdisciplinary collaboration. PMID:24997596

  5. Effects of Age and Dysfunction on Human Meibomian Glands

    PubMed Central

    Nien, Chyong Jy; Massei, Salina; Lin, Gloria; Nabavi, Cameron; Tao, Jeremiah; Brown, Donald J.; Paugh, Jerry R.; Jester, James V.

    2015-01-01

    Objective To identify age-related changes in human meibomian glands that may be associated with meibomian gland dysfunction (MGD). Methods Excess eyelid tissue from 36 patients (age range, 18–95 years, 19 female, 17 male) who underwent canthoplasty procedures were used. Dermatologic history, age, and presence of MGD were recorded. Samples were frozen, sectioned, and stained with specific antibodies against peroxisome proliferator–activated receptor γ(PPARγ) to identify meibocyte differentiation, Ki67 nuclear antigen to identify cycling cells, and CD45 to identify inflammatory cell infiltration. Results Staining for PPARγ showed cytoplasmic and nuclear localization in the 2 youngest subjects (ages, 18 and 44 years). Older individuals (>60 years) showed predominantly nuclear staining, with cytoplasmic staining limited to the basal acinar cells in 17 of 31 subjects. The number of Ki67 positively stained basal cells were significantly elevated in the younger compared with older subjects based on linear regression analysis (r2= 0.35; P <.001). There was also a significant correlation between MG expression grade and CD45 cell infiltration (r =0.414; P =.05). Conclusions These results indicate that aging human meibomian glands show decreased meibocyte differentiation and cell cycling that is associated with the development of MGD. Findings also suggest that altered PPARγ signaling may lead to acinar atrophy and development of an age-related hyposecretory MGD. Clinical Relevance Meibomian gland dysfunction and evaporative dry eye are common age-related eyelid disorders. Understanding the underlying mechanism of MGD may lead to the development of novel therapeutic strategies to treat this disease. PMID:21482872

  6. Donor's age and replicative senescence favour the in-vitro mineralization potential of human fibroblasts.

    PubMed

    Boraldi, Federica; Bartolomeo, Angelica; Di Bari, Caterina; Cocconi, Andrea; Quaglino, Daniela

    2015-12-01

    Aberrant mineralization of soft connective tissues (ectopic calcification) may occur as a frequent age-related complication. Still, it remains unclear the role of mesenchymal cell donor's age and of replicative senescence on ectopic calcification. Therefore, the ability of cells to deposit in-vitro hydroxyapatite crystals and the expression of progressive ankylosis protein homolog (ANKH), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), tissue non specific alkaline phosphatase (TNAP) and osteopontin (OPN) have been evaluated in human dermal fibroblasts derived from neonatal (nHDF) and adult (aHDF) donors (ex-vivo ageing model) or at low and high cumulative population doublings (CPD) up to replicative senescence (in-vitro ageing model). This study demonstrates that: 1) replicative senescence favours hydroxyapatite formation in cultured fibroblasts; 2) donor's age acts as a major modulator of the mineralizing potential of HDF, since nHDF are less prone than aHDF to induce calcification; 3) donor's age and replicative senescence play in concert synergistically increasing the calcification process; 4) the ANKH+ENPP1/TNAP ratio, being crucial for pyrophosphate/inorganic phosphate balance, is greatly influenced by donor's age, as well as by replicative senescence, and regulates mineral deposition; 5) OPN is only modulated by replicative senescence. PMID:26494600

  7. Effect of Progressive Muscle Relaxation on the Fatigue and Quality of Life Among Iranian Aging Persons.

    PubMed

    Hassanpour-Dehkordi, Ali; Jalali, Amir

    2016-07-01

    Since the elderly population is increasing rapidly in developing countries which may decrease the physical activity and exercise and in turn could affect the elderly's quality of life, this study aimed to investigate the effect of progressive muscle relaxation on the elderly's quality of life in Iran. In a randomized clinical trial, participants were randomly divided into intervention and control groups. For the intervention group, muscular progressive relaxation was run three days per week for three months (totally 36 sessions). In relaxation, a patient contract a group of his/her muscles in each step and relaxes them after five seconds and finally loosens all muscles and takes five deep breaths. Each session lasts for 45 minutes. The instrument of data gathering consisted of questionnaires on individual's demographic data and quality of life SF-36. After intervention, quality of life increased significantly in the patients undergoing muscular progressive relaxation and fatigue severity decreased significantly in the intervention group compared to prior to intervention. In addition, there was a statistically significant difference in mean score of physical performance, restricted activity after physical problem, energy, socially function, physical pain, overall hygiene, and quality of life between intervention and control groups. By implementing regular and continuous progressive muscle relaxation, quality of life could be increased in different dimensions in the elderly and the context could be provided to age healthily and enjoy higher health and autonomy. Therefore, all of the therapeutic staffs are recommended to implement this plan to promote the elderly's quality of life. PMID:27424013

  8. Determination of Dideoxyosone Precursors of AGEs in Human Lens Proteins

    PubMed Central

    Linetsky, Mikhail; Johar, Kaid; Meltretter, Jasmin; Padmanabha, Smitha; Parmar, Trilok; Vasavada, Abhay R.; Pischetsrieder, Monika; Nagaraj, Ram H.

    2011-01-01

    Dideoxyosones (DDOs) are intermediates in the synthesis of advanced glycation end products (AGEs), such as pentosidine and glucosepane. Although the formation of pentosidine and glucosepane in the human lens has been firmly established, the formation of DDOs has not been demonstrated. The aim of this study was to develop a reliable method to detect DDOs in lens proteins. A specific DDO trapping agent, biotinyl-diaminobenzene (3,4-diamino-N-(3-{[5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]aminopropyl) benzamide) (BDAB) was added during in vitro protein glycation or during protein extraction from human lenses. In vitro glycated human lens protein showed strong reaction in monomeric and polymeric crosslinked proteins by western blot and ELISA. Glycation of BSA in the presence of BDAB resulted in covalent binding of BDAB to the protein and inhibited pentosidine formation. Mass spectrometric analysis of lysozyme glycated in the presence of BDAB showed the presence of quinoxalines at lysine residues at positions K1, K33, K96, and K116. The ELISA results indicated that cataractous lens proteins contain significantly higher levels of DDO than non-cataractous lenses (101.9±67.8 AU/mg protein vs. 31.7±19.5 AU/mg protein, p<0.0001). This study provides first direct evidence of DDO presence in human tissue proteins and establishes that AGE crosslink synthesis in the human lens occurs via DDO intermediates. PMID:21820400

  9. Determination of dideoxyosone precursors of AGEs in human lens proteins.

    PubMed

    Linetsky, Mikhail; Kaid Johar, S R; Meltretter, Jasmin; Padmanabha, Smitha; Parmar, Trilok; Vasavada, Abhay R; Pischetsrieder, Monika; Nagaraj, Ram H

    2011-10-01

    Dideoxyosones (DDOs) are intermediates in the synthesis of advanced glycation endproducts (AGEs), such as pentosidine and glucosepane. Although the formation of pentosidine and glucosepane in the human lens has been firmly established, the formation of DDOs has not been demonstrated. The aim of this study was to develop a reliable method to detect DDOs in lens proteins. A specific DDO trapping agent, biotinyl-diaminobenzene (3,4-diamino-N-(3-[5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]aminopropyl)benzamide) (BDAB) was added during in vitro protein glycation or during protein extraction from human lenses. In vitro glycated human lens protein showed strong reaction in monomeric and polymeric crosslinked proteins by Western blot and ELISA. Glycation of BSA in the presence of BDAB resulted in covalent binding of BDAB to the protein and inhibited pentosidine formation. Mass spectrometric analysis of lysozyme glycated in the presence of BDAB showed the presence of quinoxalines at lysine residues at positions K1, K33, K96, and K116. The ELISA results indicated that cataractous lens proteins contain significantly higher levels of DDO than non-cataractous lenses (101.9±67.8 vs. 31.7±19.5AU/mg protein, p<0.0001). This study provides first direct evidence of DDO presence in human tissue proteins and establishes that AGE crosslink synthesis in the human lens occurs via DDO intermediates. PMID:21820400

  10. Motor memory preservation in aged monkeys mirrors that of aged humans on a similar task.

    PubMed

    Walton, Ashley; Scheib, Jami L; McLean, Sheila; Zhang, Zhiming; Grondin, Richard

    2008-10-01

    We studied long-term motor memory preservation in rhesus monkeys tested on a task similar to that employed in humans. First, motor speed and rate of motor decline was measured in 23 animals ranging from 4 to 26 years old. The task for the animals consisted of removing a food reward from a curved rod within the inner chamber of an automated panel. Young animals performed twice as fast as the aged animals. Second, young (n=6) and aged (n=10) animals were re-tested 1 year later on the same task with no intervening practice. We anticipated a decline in motor speed of 144 ms/year, instead the average performance time recorded during the repeat session improved significantly by 17% in the aged animals. This finding mirrors that of a longitudinal study conducted in humans using a similar test panel and supports that, while initial performance times of a novel motor task decline with age, motor memory traces are preserved over an extended time interval, even without continued practice. The data also support that the rhesus monkey could be used as a model to study the mechanisms by which long-term retention of motor memory occurs in aging. PMID:17428582

  11. Human Respiratory Syncytial Virus: Role of Innate Immunity in Clearance and Disease Progression.

    PubMed

    Farrag, Mohamed A; Almajhdi, Fahad N

    2016-01-01

    Human respiratory syncytial virus (HRSV) infections have worldwide records. The virus is responsible for bronchiolitis, pneumonia, and asthma in humans of different age groups. Premature infants, young children, and immunocompromised individuals are prone to severe HRSV infection that may lead to death. Based on worldwide estimations, millions of cases were reported in both developed and developing countries. In fact, HRSV symptoms develop mainly as a result of host immune response. Due to inability to establish long lasting adaptive immunity, HRSV infection is recurrent and hence impairs vaccine development. Once HRSV attached to the airway epithelia, interaction with the host innate immune components starts. HRSV interaction with pulmonary innate defenses is crucial in determining the disease outcome. Infection of alveolar epithelial cells triggers a cascade of events that lead to recruitment and activation of leukocyte populations. HRSV clearance is mediated by a number of innate leukocytes, including macrophages, natural killer cells, eosinophils, dendritic cells, and neutrophils. Regulation of these cells is mediated by cytokines, chemokines, and other immune mediators. Although the innate immune system helps to clear HRSV infection, it participates in disease progression such as bronchiolitis and asthma. Resolving the mechanisms by which HRSV induces pathogenesis, different possible interactions between the virus and immune components, and immune cells interplay are essential for developing new effective vaccines. Therefore, the current review focuses on how the pulmonary innate defenses mediate HRSV clearance and to what extent they participate in disease progression. In addition, immune responses associated with HRSV vaccines will be discussed. PMID:26679242

  12. Age-associated glycopeptide pigment in human costal cartilage.

    PubMed Central

    van der Korst, J. K.; Willekens, F. L.; Lansink, A. G.; Henrichs, A. M.

    1977-01-01

    Age-associated pigmentation of human costal cartilage is caused by the accumulation of a brown water-soluble substance which can be only be extracted after proteolytic disruption of the cartilage. After isolation by gel filtration and ion exchange chromatography, the compound was identified as an acid glycopeptide. In contrast to ochronotic pigment and an artificial pigment derived by oxidation of homogentistic acid in alkaline solution, the age-associated cartilage pigment was strongly fluorescent and did not form insoluble complexes with cetylpyridinium chloride. Moreover, age-associated cartilage pigment is alkali resistant, in contrast to the ochronotic pigment. The pigment differs from lipofuscin in being strongly hydrophilic and having no affinity for fat stains. The unidentified chromophore could not be separated from the glycopeptide molecule. PMID:596418

  13. Human mortality at very advanced age might be constant.

    PubMed

    Klemera, P; Doubal, S

    1997-11-01

    An attempt was made to identify the course of the mortality rate at the upper tail of human age. The only known data suitable for this purpose were published by Riggs and Millecchia (J.E. Riggs, R.J. Millecchia, Mech. Ageing Dev. 62 (1992) 191-199) and our analysis follows up their results. By means of mathematical elaboration it was proved that these data imply a constant mortality rate (approx. 25% per year) at ages above 113 years for men and above 116 years for women. Indirect arguments supporting the validity of the source data are discussed. Nevertheless, even if the source data are mistaken, we proved they cannot be the product of purely random errors and our results may contribute to the elucidation of the origin of those systematic errors. PMID:9379712

  14. Molecular networks of human muscle adaptation to exercise and age.

    PubMed

    Phillips, Bethan E; Williams, John P; Gustafsson, Thomas; Bouchard, Claude; Rankinen, Tuomo; Knudsen, Steen; Smith, Kenneth; Timmons, James A; Atherton, Philip J

    2013-03-01

    Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ~580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4 × 10(-30)). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6 × 10(-13)) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = -2.3; P = 3 × 10(-7))) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent "generic" physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18-78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ~500 genes highly enriched in post-transcriptional processes (P = 1 × 10(-6)) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to

  15. Molecular Networks of Human Muscle Adaptation to Exercise and Age

    PubMed Central

    Phillips, Bethan E.; Williams, John P.; Gustafsson, Thomas; Bouchard, Claude; Rankinen, Tuomo; Knudsen, Steen; Smith, Kenneth

    2013-01-01

    Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ∼580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4×10−30). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6×10−13) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = −2.3; P = 3×10−7)) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent “generic” physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18–78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ∼500 genes highly enriched in post-transcriptional processes (P = 1×10−6) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR

  16. Basement membrane changes in capillaries of the ageing human retina

    PubMed Central

    Powner, Michael B; Scott, Andrew; Zhu, Meidong; Munro, Peter M G; Foss, Alexander J E; Hageman, Gregory S; Gillies, Mark C; Fruttiger, Marcus

    2014-01-01

    Objectives The ultrastructural appearance of retinal capillaries can yield important information about disease mechanisms, but is not well characterised in human post mortem samples. We therefore aimed to create a baseline for the appearance of capillaries and establish how this is influenced by post mortem fixation delays and donor age. Methods Electron microscopy was used to characterise retinal capillaries in 20 anonymous donors (with no known eye diseases) of various ages and with various post mortem fixation delays. In addition, samples from six patients with conditions that are known to affect the retinal vasculature (four cases of type 2 diabetes without diabetic retinopathy, one case of diabetic retinopathy and one case of macular telangiectasia type 2) were analysed. Results Vacuoles were found in capillary basement membranes at the vessel—glia interface in all samples, from both the normal and disease cases. Vacuole frequency increased with donor age but was not influenced by post mortem fixation delays. Conclusion Vacuoles in the basement membrane are a normal feature of adult human retinal capillaries and do not indicate disease. Their incidence increases with age and might be a contributing factor to late-onset pathologies of the retinal vasculature. PMID:21606466

  17. Human aging alters the neural computation and representation of space.

    PubMed

    Schuck, Nicolas W; Doeller, Christian F; Polk, Thad A; Lindenberger, Ulman; Li, Shu-Chen

    2015-08-15

    The hippocampus and striatum are core neural circuits involved in spatial learning and memory. Although both neural systems support spatial navigation, experimental and theoretical evidence indicate that they play different roles. In particular, whereas hippocampal place cells generate allocentric neural representations of space that are sensitive to geometric information, striatum-dependent learning is influenced by local landmarks. How human aging affects these different neural representations, however, is still not well understood. In this paper, we combined virtual reality, computational modeling, and neuroimaging to investigate the effects of age upon the neural computation and representation of space in humans. We manipulated the geometry and local landmarks of a virtual environment and examined the effects on memory performance and brain activity during spatial learning. In younger adults, both behavior and brain activity in the medial-temporal lobe were consistent with predictions of a computational model of hippocampus-dependent boundary processing. In contrast, older adults' behavior and medial-temporal lobe activity were primarily influenced by local cue information, and spatial learning was more associated with activity in the caudate nucleus rather than the hippocampus. Together these results point to altered spatial representations and information processing in the hippocampal-striatal circuitry with advancing adult age, which may contribute to spatial learning and memory deficits associated with normal and pathological aging. PMID:26003855

  18. Maternal Age and Contractility of Human Myometrium in Pregnancy.

    PubMed

    Crankshaw, Denis J; O'Brien, Yvonne M; Crosby, David A; Morrison, John J

    2015-10-01

    There is controversy as to whether maternal age exerts an influence on the contractility of human myometrium in pregnancy. The aim of this study was to examine a series of functional contractile parameters of human myometrium in vitro, over a broad range of maternal ages. Myometrial tissue specimens were obtained at cesarean delivery from 32 women with maternal ages ranging from 28 to 52 years. Using in vitro recordings, a number of contractile parameters including maximal amplitude, mean contractile force, time to maximal amplitude, maximum rate of rise, and occurrence of simple and complex (biphasic and multiphasic) contractions were examined for spontaneous and induced contractile activity. The relationship between maternal age and individual parameters was evaluated using linear regression analysis. For all contractile parameters examined, for both spontaneous and induced contractions, no significant correlation was observed with maternal age between 28 and 52 years. The mean maximum amplitude values for spontaneous and oxytocin-induced contractions were 23 ± 3 and 43 ± 5 mN, respectively. The mean contractile forces for spontaneous and oxytocin-induced contractions were 1.5 ± 0.2 and 6.5 ± 0.9 mN, respectively. There was no variation in the proportion of biphasic or multiphasic contractions with maternal age. These results indicate there is no significant functional impairment of uterine contractility and no lack in responsiveness of myometrium in vitro, in the older mother. These findings do not support the concept that there may be a biological basis for dysfunctional labor or increased cesarean delivery rates in older parturients. PMID:25759369

  19. Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

    PubMed Central

    Rakoczy, Piroska Elizabeth; Zhang, Dan; Robertson, Terry; Barnett, Nigel L.; Papadimitriou, John; Constable, Ian Jeffrey; Lai, Chooi-May

    2002-01-01

    Age-related macular degeneration (AMD) is the major cause of blindness in the developed world. Its pathomechanism is unknown and its late onset, complex genetics and strong environmental components have all hampered investigations. Here we demonstrate the development of an animal model for AMD that reproduces features associated with geographic atrophy; a transgenic mouse line (mcd/mcd) expressing a mutated form of cathepsin D that is enzymatically inactive thus impairing processing of phagocytosed photoreceptor outer segments in the retinal pigment epithelial (RPE) cells. Pigmentary changes indicating RPE cell atrophy and a decreased response to flash electroretinograms were observed in 11- to 12-month-old mcd/mcd mice. Histological studies showed RPE cell proliferation, photoreceptor degeneration, shortening of photoreceptor outer segments, and accumulation of immunoreactive photoreceptor breakdown products in the RPE cells. An accelerated photoreceptor cell death was detected in 12-month-old mcd/mcd mice. Transmission electron microscopy demonstrated presence of basal laminar and linear deposits that are considered to be the hallmarks of AMD. Small hard drusen associated with human age-related maculopathy were absent in the mcd/mcd mouse model at the ages analyzed. In summary, this model presents several features of AMD, thus providing a valuable tool for investigating the underlying biological processes and pathomechanism of AMD. PMID:12368224

  20. Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention.

    PubMed

    Kidd, Parris M

    2008-06-01

    Alzheimer's disease, AD, is the most common form of dementia. AD initially targets memory and progressively destroys the mind. The brain atrophies as the neocortex suffers neuronal, synaptic, and dendritic losses, and the hallmark amyloid plaques and neurofibrillary tangles proliferate. Pharmacological management, at best, is palliative and transiently effective, with marked adverse effects. Certain nutrients intrinsic to human biochemistry (orthomolecules) match or exceed pharmacological drug benefits in double-blind, randomized, controlled trials, with superior safety. Early intervention is feasible because its heritability is typically minimal and pathological deterioration is detectable years prior to diagnosis. The syndrome amnestic mild cognitive impairment exhibits AD pathology and to date has frustrated attempts at intervention. The condition age-associated memory impairment is a nonpathological extreme of normal brain aging, but with less severe cognitive impairment than amnestic mild cognitive impairment. Age-associated memory impairment is a feasible target for early intervention against AD, beginning with the modifiable AD risk factors - smoking, hypertension, homocysteine, type 2 diabetes, insulin resistance, and obesity. Stress reduction, avoidance of toxins, and mental and physical exercise are important aspects of prevention. The diet should emphasize omega-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid; flavonoids and other antioxidant nutrients; and B vitamins, especially folate, B6 and B12. Dietary supplementation is best focused on those proven from randomized, controlled trials: the phospholipids phosphatidylserine and glycerophosphocholine, the energy nutrient acetyl-L-carnitine, vitamins C and E, and other antioxidants. A comprehensive integrative strategy initiated early in cognitive decline is the most pragmatic approach to controlling progression to Alzheimer's disease. PMID:18590347

  1. Age-associated modifications of intestinal permeability and innate immunity in human small intestine.

    PubMed

    Man, Angela L; Bertelli, Eugenio; Rentini, Silvia; Regoli, Mari; Briars, Graham; Marini, Mario; Watson, Alastair J M; Nicoletti, Claudio

    2015-10-01

    The physical and immunological properties of the human intestinal epithelial barrier in aging are largely unknown. Ileal biopsies from young (7-12 years), adult (20-40 years) and aging (67-77 years) individuals not showing symptoms of gastrointestinal (GI) pathologies were used to assess levels of inflammatory cytokines, barrier integrity and cytokine production in response to microbial challenges. Increased expression of interleukin (IL)-6, but not interferon (IFN)γ, tumour necrosis factor (TNF)-α and IL-1β was observed during aging; further analysis showed that cluster of differentiation (CD)11c(+) dendritic cells (DCs) are one of the major sources of IL-6 in the aging gut and expressed higher levels of CD40. Up-regulated production of IL-6 was accompanied by increased expression of claudin-2 leading to reduced transepithelial electric resistance (TEER); TEER could be restored in in vitro and ex vivo cultures by neutralizing anti-IL-6 antibody. In contrast, expression of zonula occludens-1 (ZO-1), occludin and junctional-adhesion molecule-A1 did not vary with age and overall permeability to macromolecules was not affected. Finally, cytokine production in response to different microbial stimuli was assessed in a polarized in vitro organ culture (IVOC). IL-8 production in response to flagellin declined progressively with age although the expression and distribution of toll-like receptor (TLR)-5 on intestinal epithelial cells (IECs) remained unchanged. Also, flagellin-induced production of IL-6 was less pronounced in aging individuals. In contrast, TNF-α production in response to probiotics (VSL#3) did not decline with age; however, in our experimental model probiotics did not down-regulate the production of IL-6 and expression of claudin-2. These data suggested that aging affects properties of the intestinal barrier likely to impact on age-associated disturbances, both locally and systemically. PMID:25948052

  2. Human gut microbiome viewed across age and geography.

    PubMed

    Yatsunenko, Tanya; Rey, Federico E; Manary, Mark J; Trehan, Indi; Dominguez-Bello, Maria Gloria; Contreras, Monica; Magris, Magda; Hidalgo, Glida; Baldassano, Robert N; Anokhin, Andrey P; Heath, Andrew C; Warner, Barbara; Reeder, Jens; Kuczynski, Justin; Caporaso, J Gregory; Lozupone, Catherine A; Lauber, Christian; Clemente, Jose Carlos; Knights, Dan; Knight, Rob; Gordon, Jeffrey I

    2012-06-14

    Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization. PMID:22699611

  3. Long-term treatment with aldosterone slows the progression of age-related hearing loss.

    PubMed

    Halonen, Joshua; Hinton, Ashley S; Frisina, Robert D; Ding, Bo; Zhu, Xiaoxia; Walton, Joseph P

    2016-06-01

    Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL. PMID:27157488

  4. Predicting human age with bloodstains by sjTREC quantification.

    PubMed

    Ou, Xue-ling; Gao, Jun; Wang, Huan; Wang, Hong-sheng; Lu, Hui-ling; Sun, Hong-yu

    2012-01-01

    The age-related decline of signal joint T-cell receptor rearrangement excision circles (sjTRECs) in human peripheral blood has been demonstrated in our previous study and other reports. Until now, only a few studies on sjTREC detection in bloodstain samples were reported, which were based on a small sample of subjects of a limited age range, although bloodstains are much more frequently encountered in forensic practice. In this present study, we adopted the sensitive Taqman real-time quantitative polymerase chain reaction (qPCR) method to perform sjTREC quantification in bloodstains from individuals ranging from 0-86 years old (n = 264). The results revealed that sjTREC contents in human bloodstains were declined in an age-dependent manner (r = -0.8712). The formula of age estimation was Age = -7.1815Y-42.458 ± 9.42 (Y dCt(TBP-sjTREC); 9.42 standard error). Furthermore, we tested for the influence of short- or long- storage time by analyzing fresh and stored bloodstains from the same individuals. Remarkably, no statistically significant difference in sjTREC contents was found between the fresh and old DNA samples over a 4-week of storage time. However, significant loss (0.16-1.93 dCt) in sjTREC contents was detected after 1.5 years of storage in 31 samples. Moreover, preliminary sjTREC quantification from up to 20-year-old bloodstains showed that though the sjTREC contents were detectable in all samples and highly correlated with donor age, a time-dependent decrease in the correlation coefficient r was found, suggesting the predicting accuracy of this described assay would be deteriorated in aged samples. Our findings show that sjTREC quantification might be also suitable for age prediction in bloodstains, and future researches into the time-dependent or other potential impacts on sjTREC quantification might allow further improvement of the predicting accuracy. PMID:22879970

  5. Telocytes and putative stem cells in ageing human heart

    PubMed Central

    Popescu, Laurentiu M; Curici, Antoanela; Wang, Enshi; Zhang, Hao; Hu, Shengshou; Gherghiceanu, Mihaela

    2015-01-01

    Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes (CMs). Anyway, the presence of telocytes (TCs) has been overlooked, since they were described in 2010 (visit http://www.telocytes.com). Also, the number of cardiac stem cells (CSCs) has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium (appendages). Three age-related groups were studied: newborns (17 days–1 year), children (6–17 years) and adults (34–60 years). Morphometry was performed on low-magnification electron microscope images using computer-assisted technology. We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm2) increased with several hundreds in children and adults versus newborns. CMs are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Images of CMs mitoses were seen in the 17-day newborns. Interestingly, no lipofuscin granules were found in CMs of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52–62%; vascular smooth muscle cells and pericytes 22–28%, Schwann cells with nerve endings 6–7%, fibroblasts 3–10%, macrophages 1–8%, TCs about 1% and stem cells less than 1%. We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, TCs represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports CSCs. The myocardial (very) low capability to regenerate may be explained by the number of CSCs, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults). PMID:25545142

  6. Impact of Age and Myopia on the Rate of Visual Field Progression in Glaucoma Patients.

    PubMed

    Park, Hae-Young Lopilly; Hong, Kyung Euy; Park, Chan Kee

    2016-05-01

    Myopia is rapidly increasing in young populations and patients with glaucoma associated with myopia are reported to be young aged in East Asia. These young patients have a longer life expectancy, which increases their risk of end-of-life visual disabilities. There is a need to understand the clinical course of myopic glaucoma patients, which may be important for the care of these myopic populations. In this study, we evaluated the relationship between the age at presentation and the rate of glaucoma progression in the visual field (VF) according to the presence of myopia. The study was conducted as a prospective observational study including 179 patients with open-angle glaucoma who had undergone at least 5 VF examinations with a follow-up of at least 5 years. The progression rate of the mean deviation (MD) and the pattern standard deviation (PSD) are expressed as change in decibels (dB) per year. The slopes of the MD and PSD were calculated by linear regression analyses. Factors related to the slope of VF MD changes were analyzed with correlation and regression analyses. The slope of the linear fit line plotted against age at presentation and the rate of change in the VF MD was -0.026 (P < 0.001) in the myopic group and -0.008 (P = 0.167) in the nonmyopic group; the relationship was more prominent in the myopic group than the nonmyopic group. In the myopic group, age (β = -0.417; 95% confidence intervals (CI), -0.651 to -0.200; P = 0.050) and baseline untreated intraocular pressure (β = -0.179; 95% CI, -0.331 to -0.028; P = 0.022) were significantly related to the rate of change in the MD, which was only the presence of disc hemorrhage (β = -0.335; 95% CI, -0.568 to -0.018; P = 0.022) in the nonmyopic group. Age at presentation was significantly related to the rate of change in the VF in glaucomatous eyes with myopia compared to eyes without myopia. Older age was significantly related to the rate of change in the VF only in

  7. Impact of Age and Myopia on the Rate of Visual Field Progression in Glaucoma Patients

    PubMed Central

    Park, Hae-Young Lopilly; Hong, Kyung Euy; Park, Chan Kee

    2016-01-01

    Abstract Myopia is rapidly increasing in young populations and patients with glaucoma associated with myopia are reported to be young aged in East Asia. These young patients have a longer life expectancy, which increases their risk of end-of-life visual disabilities. There is a need to understand the clinical course of myopic glaucoma patients, which may be important for the care of these myopic populations. In this study, we evaluated the relationship between the age at presentation and the rate of glaucoma progression in the visual field (VF) according to the presence of myopia. The study was conducted as a prospective observational study including 179 patients with open-angle glaucoma who had undergone at least 5 VF examinations with a follow-up of at least 5 years. The progression rate of the mean deviation (MD) and the pattern standard deviation (PSD) are expressed as change in decibels (dB) per year. The slopes of the MD and PSD were calculated by linear regression analyses. Factors related to the slope of VF MD changes were analyzed with correlation and regression analyses. The slope of the linear fit line plotted against age at presentation and the rate of change in the VF MD was −0.026 (P < 0.001) in the myopic group and −0.008 (P = 0.167) in the nonmyopic group; the relationship was more prominent in the myopic group than the nonmyopic group. In the myopic group, age (β = −0.417; 95% confidence intervals (CI), −0.651 to −0.200; P = 0.050) and baseline untreated intraocular pressure (β = −0.179; 95% CI, −0.331 to −0.028; P = 0.022) were significantly related to the rate of change in the MD, which was only the presence of disc hemorrhage (β = −0.335; 95% CI, −0.568 to −0.018; P = 0.022) in the nonmyopic group. Age at presentation was significantly related to the rate of change in the VF in glaucomatous eyes with myopia compared to eyes without myopia. Older age was significantly related to the rate of

  8. Exercise enhances wound healing and prevents cancer progression during aging by targeting macrophage polarity.

    PubMed

    Goh, Jorming; Ladiges, Warren C

    2014-07-01

    Physical activity, which can include regular and repetitive exercise training, has been shown to decrease the incidence of age-related diseases. Aging is characterized by aberrant immune responses, including impaired wound healing and increased cancer risk. The behavior and polarized phenotype of tissue macrophages are distinct between young and old organisms. The balance of M1 and M2 macrophages is altered in the aged tissue microenvironment, with a tilt towards an M2-dominant macrophage population, as well as its associated signaling pathways. These M2-type responses may result in unresolved inflammation and create an environment that impairs wound healing and is favorable for cancer growth. We discuss the concept that exercise training can improve the regulation of macrophage polarization and normalize the inflammatory process, and thereby exert anticancer effects and enhance wound healing in older humans. PMID:24932991

  9. Neural Control of the Circulation: How Sex and Age Differences Interact in Humans

    PubMed Central

    Joyner, Michael J.; Barnes, Jill N.; Hart, Emma C.; Wallin, B. Gunnar; Charkoudian, Nisha

    2015-01-01

    The autonomic nervous system is a key regulator of cardiovascular system. In this review we focus on how sex and aging influence autonomic regulation of blood pressure in humans in an effort to understand general issues related to how the autonomic nervous system regulates blood pressure, and the cardiovascular system as a whole. Younger women generally have lower blood pressure and sympathetic activity than younger men. However, both sexes show marked inter-individual variability across age groups with significant overlap seen. Additionally, while men across the lifespan show a clear relationship between markers of whole body sympathetic activity and vascular resistance, such a relationship is not seen in young women. In this context, the ability of the sympathetic nerves to evoke vasoconstriction is lower in young women likely as a result of concurrent β2 mediated vasodilation that offsets α-adrenergic vasoconstriction. These differences reflect both central sympatho-inhibitory effects of estrogen and also its influence on peripheral vasodilation at the level of the vascular smooth muscle and endothelium. By contrast post-menopausal women show a clear relationship between markers of whole body sympathetic traffic and vascular resistance, and sympathetic activity rises progressively in both sexes with aging. These central findings in humans are discussed in the context of differences in population-based trends in blood pressure and orthostatic intolerance. The many areas where there is little sex-specific data on how the autonomic nervous system participates in the regulation of the human cardiovascular system are highlighted. PMID:25589269

  10. Neural control of the circulation: how sex and age differences interact in humans.

    PubMed

    Joyner, Michael J; Barnes, Jill N; Hart, Emma C; Wallin, B Gunnar; Charkoudian, Nisha

    2015-01-01

    The autonomic nervous system is a key regulator of the cardiovascular system. In this review, we focus on how sex and aging influence autonomic regulation of blood pressure in humans in an effort to understand general issues related to the cardiovascular system as a whole. Younger women generally have lower blood pressure and sympathetic activity than younger men. However, both sexes show marked interindividual variability across age groups with significant overlap seen. Additionally, while men across the lifespan show a clear relationship between markers of whole body sympathetic activity and vascular resistance, such a relationship is not seen in young women. In this context, the ability of the sympathetic nerves to evoke vasoconstriction is lower in young women likely as a result of concurrent β2-mediated vasodilation that offsets α-adrenergic vasoconstriction. These differences reflect both central sympatho-inhibitory effects of estrogen and also its influence on peripheral vasodilation at the level of the vascular smooth muscle and endothelium. By contrast postmenopausal women show a clear relationship between markers of whole body sympathetic traffic and vascular resistance, and sympathetic activity rises progressively in both sexes with aging. These major findings in humans are discussed in the context of differences in population-based trends in blood pressure and orthostatic intolerance. The many areas where there is little sex-specific data on how the autonomic nervous system participates in the regulation of the human cardiovascular system are highlighted. PMID:25589269

  11. Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs.

    PubMed

    Steegenga, Wilma T; Boekschoten, Mark V; Lute, Carolien; Hooiveld, Guido J; de Groot, Philip J; Morris, Tiffany J; Teschendorff, Andrew E; Butcher, Lee M; Beck, Stephan; Müller, Michael

    2014-06-01

    Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (ΔYO > 5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression. PMID:24789080

  12. Sympathetic regulation during thermal stress in human aging and disease.

    PubMed

    Greaney, Jody L; Kenney, W Larry; Alexander, Lacy M

    2016-04-01

    Humans control their core temperature within a narrow range via precise adjustments of the autonomic nervous system. In response to changing core and/or skin temperature, several critical thermoregulatory reflex effector responses are initiated and include shivering, sweating, and changes in cutaneous blood flow. Cutaneous vasomotor adjustments, mediated by modulations in sympathetic nerve activity (SNA), aid in the maintenance of thermal homeostasis during cold and heat stress since (1) they serve as the first line of defense of body temperature and are initiated before other thermoregulatory effectors, and (2) they are on the efferent arm of non-thermoregulatory reflex systems, aiding in the maintenance of blood pressure and organ perfusion. This review article highlights the sympathetic responses of humans to thermal stress, with a specific focus on primary aging as well as impairments that occur in both heart disease and type 2 diabetes mellitus. Age- and pathology-related changes in efferent muscle and skin SNA during cold and heat stress, measured directly in humans using microneurography, are discussed. PMID:26627337

  13. Reproductive aging patterns in primates reveal that humans are distinct

    PubMed Central

    Alberts, Susan C.; Altmann, Jeanne; Brockman, Diane K.; Cords, Marina; Fedigan, Linda M.; Pusey, Anne; Stoinski, Tara S.; Strier, Karen B.; Morris, William F.; Bronikowski, Anne M.

    2013-01-01

    Women rarely give birth after ∼45 y of age, and they experience the cessation of reproductive cycles, menopause, at ∼50 y of age after a fertility decline lasting almost two decades. Such reproductive senescence in mid-lifespan is an evolutionary puzzle of enduring interest because it should be inherently disadvantageous. Furthermore, comparative data on reproductive senescence from other primates, or indeed other mammals, remains relatively rare. Here we carried out a unique detailed comparative study of reproductive senescence in seven species of nonhuman primates in natural populations, using long-term, individual-based data, and compared them to a population of humans experiencing natural fertility and mortality. In four of seven primate species we found that reproductive senescence occurred before death only in a small minority of individuals. In three primate species we found evidence of reproductive senescence that accelerated throughout adulthood; however, its initial rate was much lower than mortality, so that relatively few individuals experienced reproductive senescence before death. In contrast, the human population showed the predicted and well-known pattern in which reproductive senescence occurred before death for many women and its rate accelerated throughout adulthood. These results provide strong support for the hypothesis that reproductive senescence in midlife, although apparent in natural-fertility, natural-mortality populations of humans, is generally absent in other primates living in such populations. PMID:23898189

  14. Progress in predicting human ADME parameters in silico.

    PubMed

    Ekins, S; Waller, C L; Swaan, P W; Cruciani, G; Wrighton, S A; Wikel, J H

    2000-01-01

    Understanding the development of a scientific approach is a valuable exercise in gauging the potential directions the process could take in the future. The relatively short history of applying computational methods to absorption, distribution, metabolism and excretion (ADME) can be split into defined periods. The first began in the 1960s and continued through the 1970s with the work of Corwin Hansch et al. Their models utilized small sets of in vivo ADME data. The second era from the 1980s through 1990s witnessed the widespread incorporation of in vitro approaches as surrogates of in vivo ADME studies. These approaches fostered the initiation and increase in interpretable computational ADME models available in the literature. The third era is the present were there are many literature data sets derived from in vitro data for absorption, drug-drug interactions (DDI), drug transporters and efflux pumps [P-glycoprotein (P-gp), MRP], intrinsic clearance and brain penetration, which can theoretically be used to predict the situation in vivo in humans. Combinatorial synthesis, high throughput screening and computational approaches have emerged as a result of continual pressure on pharmaceutical companies to accelerate drug discovery while decreasing drug development costs. The goal has become to reduce the drop-out rate of drug candidates in the latter, most expensive stages of drug development. This is accomplished by increasing the failure rate of candidate compounds in the preclinical stages and increasing the speed of nomination of likely clinical candidates. The industry now understands the reasons for clinical failure other than efficacy are mainly related to pharmacokinetics and toxicity. The late 1990s saw significant company investment in ADME and drug safety departments to assess properties such as metabolic stability, cytochrome P-450 inhibition, absorption and genotoxicity earlier in the drug discovery paradigm. The next logical step in this process is the

  15. Progression of Retinal Pigment Epithelial Atrophy in Antiangiogenic Therapy of Neovascular Age-Related Macular Degeneration

    PubMed Central

    Schütze, Christopher; Wedl, Manuela; Baumann, Bernhard; Pircher, Michael; Hitzenberger, Christoph K.; Schmidt-Erfurth, Ursula

    2015-01-01

    Purpose To monitor retinal pigment epithelial (RPE) atrophy progression during antiangiogenic therapy of neovascular age-related macular degeneration (AMD) over 2 years using polarization-sensitive optical coherence tomography (OCT). Design Prospective interventional case series. Methods setting: Clinical practice. study population: Thirty patients (31 eyes) with treatment-naïve neovascular AMD. observation procedures: Standard intravitreal therapy (0.5 mg ranibizumab) was administered monthly during the first year and pro re nata (PRN; as-needed) during the second year. Spectral-domain (SD) OCT and polarization-sensitive OCT (selectively imaging the RPE) examinations were performed at baseline and at 1, 3, 6, 12, and 24 months using a standardized protocol. RPE-related changes were evaluated using a semi-automated polarization-sensitive OCT segmentation algorithm and correlated with SD OCT and fundus autofluorescence (FAF) findings. main outcome measures: RPE response, geographic atrophy (GA) progression. Results Atrophic RPE changes included RPE thinning, RPE porosity, focal RPE atrophy, and development of GA. Early RPE loss (ie, RPE porosity, focal atrophy) increased progressively during initial monthly treatment and remained stable during subsequent PRN-based therapy. GA developed in 61% of eyes at month 24. Mean GA area increased from 0.77 mm2 at 12 months to 1.10 mm2 (standard deviation = 1.09 mm2) at 24 months. Reactive accumulation of RPE-related material at the lesion borders increased until month 3 and subsequently decreased. Conclusions Progressive RPE atrophy and GA developed in the majority of eyes. RPE migration signifies certain RPE plasticity. Polarization-sensitive OCT specifically images RPE-related changes in neovascular AMD, contrary to conventional imaging methods. Polarization-sensitive OCT allows for precisely monitoring the sequence of RPE-related morphologic changes. PMID:25769245

  16. Age-dependent motor unit remodelling in human limb muscles.

    PubMed

    Piasecki, Mathew; Ireland, Alex; Jones, David A; McPhee, Jamie S

    2016-06-01

    Voluntary control of skeletal muscle enables humans to interact with and manipulate the environment. Lower muscle mass, weakness and poor coordination are common complaints in older age and reduce physical capabilities. Attention has focused on ways of maintaining muscle size and strength by exercise, diet or hormone replacement. Without appropriate neural innervation, however, muscle cannot function. Emerging evidence points to a neural basis of muscle loss. Motor unit number estimates indicate that by age around 71 years, healthy older people have around 40 % fewer motor units. The surviving low- and moderate-threshold motor units recruited for moderate intensity contractions are enlarged by around 50 % and show increased fibre density, presumably due to collateral reinnervation of denervated fibres. Motor unit potentials show increased complexity and the stability of neuromuscular junction transmissions is decreased. The available evidence is limited by a lack of longitudinal studies, relatively small sample sizes, a tendency to examine the small peripheral muscles and relatively few investigations into the consequences of motor unit remodelling for muscle size and control of movements in older age. Loss of motor neurons and remodelling of surviving motor units constitutes the major change in ageing muscles and probably contributes to muscle loss and functional impairments. The deterioration and remodelling of motor units likely imposes constraints on the way in which the central nervous system controls movements. PMID:26667009

  17. Humanized mice for immune system investigation: progress, promise and challenges

    PubMed Central

    Shultz, Leonard D.; Brehm, Michael A.; Garcia, J. Victor; Greiner, Dale L.

    2013-01-01

    Preface Significant advances in our understanding of the in vivo functions of human cells, tissues and immune systems have resulted from the development of mouse strains that are based on severely immunodeficient mice expressing mutations in the interleukin-2 (IL-2) receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analysis of human immune biology, development and functions. In this Review, we discuss recent advances in the development of humanized mice, the lessons learned, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology. PMID:23059428

  18. Raman spectroscopy of human skin: looking for a quantitative algorithm to reliably estimate human age.

    PubMed

    Pezzotti, Giuseppe; Boffelli, Marco; Miyamori, Daisuke; Uemura, Takeshi; Marunaka, Yoshinori; Zhu, Wenliang; Ikegaya, Hiroshi

    2015-06-01

    The possibility of examining soft tissues by Raman spectroscopy is challenged in an attempt to probe human age for the changes in biochemical composition of skin that accompany aging. We present a proof-of-concept report for explicating the biophysical links between vibrational characteristics and the specific compositional and chemical changes associated with aging. The actual existence of such links is then phenomenologically proved. In an attempt to foster the basics for a quantitative use of Raman spectroscopy in assessing aging from human skin samples, a precise spectral deconvolution is performed as a function of donors' ages on five cadaveric samples, which emphasizes the physical significance and the morphological modifications of the Raman bands. The outputs suggest the presence of spectral markers for age identification from skin samples. Some of them appeared as authentic "biological clocks" for the apparent exactness with which they are related to age. Our spectroscopic approach yields clear compositional information of protein folding and crystallization of lipid structures, which can lead to a precise identification of age from infants to adults. Once statistically validated, these parameters might be used to link vibrational aspects at the molecular scale for practical forensic purposes. PMID:26112367

  19. Raman spectroscopy of human skin: looking for a quantitative algorithm to reliably estimate human age

    NASA Astrophysics Data System (ADS)

    Pezzotti, Giuseppe; Boffelli, Marco; Miyamori, Daisuke; Uemura, Takeshi; Marunaka, Yoshinori; Zhu, Wenliang; Ikegaya, Hiroshi

    2015-06-01

    The possibility of examining soft tissues by Raman spectroscopy is challenged in an attempt to probe human age for the changes in biochemical composition of skin that accompany aging. We present a proof-of-concept report for explicating the biophysical links between vibrational characteristics and the specific compositional and chemical changes associated with aging. The actual existence of such links is then phenomenologically proved. In an attempt to foster the basics for a quantitative use of Raman spectroscopy in assessing aging from human skin samples, a precise spectral deconvolution is performed as a function of donors' ages on five cadaveric samples, which emphasizes the physical significance and the morphological modifications of the Raman bands. The outputs suggest the presence of spectral markers for age identification from skin samples. Some of them appeared as authentic "biological clocks" for the apparent exactness with which they are related to age. Our spectroscopic approach yields clear compositional information of protein folding and crystallization of lipid structures, which can lead to a precise identification of age from infants to adults. Once statistically validated, these parameters might be used to link vibrational aspects at the molecular scale for practical forensic purposes.

  20. AGING AND THE REDUCTION IN FRACTURE TOUGHNESS OF HUMAN DENTIN

    PubMed Central

    Nazari, A.; Bajaj, D.; Zhang, D.; Romberg, E.; Arola, D.

    2009-01-01

    An evaluation of the crack growth resistance of human coronal dentin was performed on tissue obtained from patients between ages 18 and 83. Stable crack extension was achieved over clinically relevant lengths (0 ≤ a ≤1 mm) under Mode I quasi-static loading and perpendicular to the nominal tubule direction. Results distinguished that human dentin exhibits an increase in crack growth resistance with extension (i.e. rising R-curve) and that there is a significant reduction in both the initiation (Ko) and plateau (Kp) components of toughness with patient age. In the young dentin (18≤age≤35) there was a 25 % increase in the crack growth resistance from the onset of extension (Ko =1.34 MPa·m0.5) to the maximum or “plateau” toughness (Kp = 1.65 MPa·m0.5). In comparison, the crack growth resistance of the old dentin (55≤age) increased with extension by less than 10 % from Ko = 1.08 MPa·m0.5 to Kp = 1.17 MPa·m0.5. In young dentin toughening was achieved by a combination of inelastic deformation of the mineralized collagen matrix and microcracking of the peritubular cuffs. These mechanisms facilitated further toughening via the development of unbroken ligaments of tissue and posterior crack-bridging. Microstructural changes with aging decreased the capacity for near-tip inelastic deformation and microcracking of the tubules, which in turn suppressed the formation of unbroken ligaments and the degree of extrinsic toughening. PMID:19627862

  1. Assessment of Functional Change and Cognitive Correlates in the Progression from Healthy Cognitive Aging to Dementia

    PubMed Central

    Schmitter-Edgecombe, Maureen; Parsey, Carolyn M.

    2014-01-01

    Objective There is currently limited understanding of the course of change in everyday functioning that occurs with normal aging and dementia. To better characterize the nature of this change, we evaluated the types of errors made by participants as they performed everyday tasks in a naturalistic environment. Method Participants included cognitively healthy younger adults (YA; N = 55) and older adults (OA; N =88), and individuals with mild cognitive impairment (MCI: N =55) and dementia (N = 18). Participants performed eight scripted everyday activities (e.g., filling a medication dispenser) while under direct observation in a campus apartment. Task performances were coded for the following errors: inefficient actions, omissions, substitutions, and irrelevant actions. Results Performance accuracy decreased with age and level of cognitive impairment. Relative to the YAs, the OA group exhibited more inefficient actions which were linked to performance on neuropsychological measures of executive functioning. Relative to the OAs, the MCI group committed significantly more omission errors which were strongly linked to performance on memory measures. All error types were significantly more prominent in individuals with dementia. Omission errors uniquely predicted everyday functional status as measured by both informant-report and a performance-based measure. Conclusions These findings suggest that in the progression from healthy aging to MCI, everyday task difficulties may evolve from task inefficiencies to task omission errors, leading to inaccuracies in task completion that are recognized by knowledgeable informants. Continued decline in cognitive functioning then leads to more substantial everyday errors, which compromise ability to live independently. PMID:24933485

  2. Sympathetic activity during passive heat stress in healthy aged humans

    PubMed Central

    Gagnon, Daniel; Schlader, Zachary J; Crandall, Craig G

    2015-01-01

    Abstract Cardiovascular adjustments during heat stress are generally attenuated in healthy aged humans, which could be due to lower increases in sympathetic activity compared to the young. We compared muscle sympathetic nerve activity (MSNA) between 11 young (Y: 28 ± 4 years) and 10 aged (A: 70 ± 5 years) subjects prior to and during passive heating. Furthermore, MSNA responses were compared when a cold pressor test (CPT) and lower body negative pressure (LBNP) were superimposed upon heating. Baseline MSNA burst frequency (Y: 15 ± 4 vs. A: 31 ± 3 bursts min−1, P ≤ 0.01) and burst incidence (Y: 26 ± 8 vs. A: 50 ± 7 bursts (100 cardiac cycles (CC))−1, P ≤ 0.01) were greater in the aged. Heat stress increased core temperature to a similar extent in both groups (Y: +1.2 ± 0.1 vs. A: +1.2 ± 0.0°C, P = 0.99). Absolute levels of MSNA remained greater in the aged during heat stress (burst frequency: Y: 47 ± 6 vs. A: 63 ± 11 bursts min−1, P ≤ 0.01; burst incidence: Y: 48 ± 8 vs. A: 67 ± 9 bursts (100 CC)−1, P ≤ 0.01); however, the increase in both variables was similar between groups (both P ≥ 0.1). The CPT and LBNP further increased MSNA burst frequency and burst incidence, although the magnitude of increase was similar between groups (both P ≥ 0.07). These results suggest that increases in sympathetic activity during heat stress are not attenuated in healthy aged humans. Key points Cardiovascular adjustments to heat stress are attenuated in healthy aged individuals, which could contribute to their greater prevalence of heat-related illnesses and deaths during heat waves. The attenuated cardiovascular adjustments in the aged could be due to lower increases in sympathetic nerve activity during heat stress. We examined muscle sympathetic nerve activity (MSNA) and plasma catecholamine concentrations in healthy young and aged individuals during whole-body passive heat stress. The main finding

  3. Progressive outer retinal necrosis: manifestation of human immunodeficiency virus infection.

    PubMed

    Lo, Phey Feng; Lim, Rongxuan; Antonakis, Serafeim N; Almeida, Goncalo C

    2015-01-01

    We present the case of a 54-year-old man who developed progressive outer retinal necrosis (PORN) as an initial manifestation of HIV infection without any significant risk factors for infection with HIV. PORN is usually found as a manifestation of known AIDS late in the disease. Our patient presented with transient visual loss followed by decrease in visual acuity and facial rash. Subsequent investigation revealed anterior chamber tap positive for varicella zoster virus (VZV), as well as HIV positivity, with an initial CD4 count of 48 cells/µL. Systemic and intravitreal antivirals against VZV, and highly active antiretroviral therapy against HIV were started, which halted further progression of retinal necrosis. This case highlights the importance of suspecting PORN where there is a rapidly progressive retinitis, and also testing the patient for HIV, so appropriate treatment can be started. PMID:25948844

  4. The Biology of Aging: Citizen Scientists and Their Pets as a Bridge Between Research on Model Organisms and Human Subjects.

    PubMed

    Kaeberlein, M

    2016-03-01

    A fundamental goal of research into the basic mechanisms of aging is to develop translational strategies that improve human health by delaying the onset and progression of age-related pathology. Several interventions have been discovered that increase life span in invertebrate organisms, some of which have similar effects in mice. These include dietary restriction and inhibition of the mechanistic target of rapamycin by treatment with rapamycin. Key challenges moving forward will be to assess the extent to which these and other interventions improve healthy longevity and increase life span in mice and to develop practical strategies for extending this work to the clinic. Companion animals may provide an optimal intermediate between laboratory models and humans. By improving healthy longevity in companion animals, important insights will be gained regarding human aging while improving the quality of life for people and their pets. PMID:26077786

  5. Experimental evidence of age-related adaptive changes in human acinar airways.

    PubMed

    Quirk, James D; Sukstanskii, Alexander L; Woods, Jason C; Lutey, Barbara A; Conradi, Mark S; Gierada, David S; Yusen, Roger D; Castro, Mario; Yablonskiy, Dmitriy A

    2016-01-15

    The progressive decline of lung function with aging is associated with changes in lung structure at all levels, from conducting airways to acinar airways (alveolar ducts and sacs). While information on conducting airways is becoming available from computed tomography, in vivo information on the acinar airways is not conventionally available, even though acini occupy 95% of lung volume and serve as major gas exchange units of the lung. The objectives of this study are to measure morphometric parameters of lung acinar airways in living adult humans over a broad range of ages by using an innovative MRI-based technique, in vivo lung morphometry with hyperpolarized (3)He gas, and to determine the influence of age-related differences in acinar airway morphometry on lung function. Pulmonary function tests and MRI with hyperpolarized (3)He gas were performed on 24 healthy nonsmokers aged 19-71 years. The most significant age-related difference across this population was a 27% loss of alveolar depth, h, leading to a 46% increased acinar airway lumen radius, hence, decreased resistance to acinar air transport. Importantly, the data show a negative correlation between h and the pulmonary function measures forced expiratory volume in 1 s and forced vital capacity. In vivo lung morphometry provides unique information on age-related changes in lung microstructure and their influence on lung function. We hypothesize that the observed reduction of alveolar depth in subjects with advanced aging represents a remodeling process that might be a compensatory mechanism, without which the pulmonary functional decline due to other biological factors with advancing age would be significantly larger. PMID:26542518

  6. Age and Smoking Related Changes in Metal Ion Levels in Human Lens: Implications for Cataract Formation

    PubMed Central

    Langford-Smith, Alex; Tilakaratna, Viranga; Lythgoe, Paul R.; Clark, Simon J.; Bishop, Paul N.; Day, Anthony J.

    2016-01-01

    Age-related cataract formation is the primary cause of blindness worldwide and although treatable by surgical removal of the lens the majority of sufferers have neither the finances nor access to the medical facilities required. Therefore, a better understanding of the pathogenesis of cataract may identify new therapeutic targets to prevent or slow its progression. Cataract incidence is strongly correlated with age and cigarette smoking, factors that are often associated with accumulation of metal ions in other tissues. Therefore this study evaluated the age-related changes in 14 metal ions in 32 post mortem human lenses without known cataract from donors of 11 to 82 years of age by inductively coupled plasma mass spectrometry; smoking-related changes in 10 smokers verses 14 non-smokers were also analysed. A significant age-related increase in selenium and decrease in copper ions was observed for the first time in the lens tissue, where cadmium ion levels were also increased as has been seen previously. Aluminium and vanadium ions were found to be increased in smokers compared to non-smokers (an analysis that has only been carried out before in lenses with cataract). These changes in metal ions, i.e. that occur as a consequence of normal ageing and of smoking, could contribute to cataract formation via induction of oxidative stress pathways, modulation of extracellular matrix structure/function and cellular toxicity. Thus, this study has identified novel changes in metal ions in human lens that could potentially drive the pathology of cataract formation. PMID:26794210

  7. Gut Bifidobacteria Populations in Human Health and Aging.

    PubMed

    Arboleya, Silvia; Watkins, Claire; Stanton, Catherine; Ross, R Paul

    2016-01-01

    The intestinal microbiota has increasingly been shown to have a vital role in various aspects of human health. Indeed, several studies have linked alterations in the gut microbiota with the development of different diseases. Among the vast gut bacterial community, Bifidobacterium is a genus which dominates the intestine of healthy breast-fed infants whereas in adulthood the levels are lower but relatively stable. The presence of different species of bifidobacteria changes with age, from childhood to old age. Bifidobacterium longum, B. breve, and B. bifidum are generally dominant in infants, whereas B. catenulatum, B. adolescentis and, as well as B. longum are more prevalent in adults. Increasingly, evidence is accumulating which shows beneficial effects of supplementation with bifidobacteria for the improvement of human health conditions ranging from protection against infection to different extra- and intra-intestinal positive effects. Moreover, bifidobacteria have been associated with the production of a number of potentially health promoting metabolites including short chain fatty acids, conjugated linoleic acid and bacteriocins. The aim of this mini-review is to describe the bifidobacteria compositional changes associated with different stages in life, highlighting their beneficial role, as well as their presence or absence in many disease states. PMID:27594848

  8. Gut Bifidobacteria Populations in Human Health and Aging

    PubMed Central

    Arboleya, Silvia; Watkins, Claire; Stanton, Catherine; Ross, R. Paul

    2016-01-01

    The intestinal microbiota has increasingly been shown to have a vital role in various aspects of human health. Indeed, several studies have linked alterations in the gut microbiota with the development of different diseases. Among the vast gut bacterial community, Bifidobacterium is a genus which dominates the intestine of healthy breast-fed infants whereas in adulthood the levels are lower but relatively stable. The presence of different species of bifidobacteria changes with age, from childhood to old age. Bifidobacterium longum, B. breve, and B. bifidum are generally dominant in infants, whereas B. catenulatum, B. adolescentis and, as well as B. longum are more prevalent in adults. Increasingly, evidence is accumulating which shows beneficial effects of supplementation with bifidobacteria for the improvement of human health conditions ranging from protection against infection to different extra- and intra-intestinal positive effects. Moreover, bifidobacteria have been associated with the production of a number of potentially health promoting metabolites including short chain fatty acids, conjugated linoleic acid and bacteriocins. The aim of this mini-review is to describe the bifidobacteria compositional changes associated with different stages in life, highlighting their beneficial role, as well as their presence or absence in many disease states. PMID:27594848

  9. Aging of microstructural compartments in human compact bone

    NASA Technical Reports Server (NTRS)

    Akkus, Ozan; Polyakova-Akkus, Anna; Adar, Fran; Schaffler, Mitchell B.

    2003-01-01

    Composition of microstructural compartments in compact bone of aging male subjects was assessed using Raman microscopy. Secondary mineralization of unremodeled fragments persisted for two decades. Replacement of these tissue fragments with secondary osteons kept mean composition constant over age, but at a fully mineralized limit. Slowing of remodeling may increase fracture susceptibility through an increase in proportion of highly mineralized tissue. In this study, the aging process in the microstructural compartments of human femoral cortical bone was investigated and related to changes in the overall tissue composition within the age range of 17-73 years. Raman microprobe analysis was used to assess the mineral content, mineral crystallinity, and carbonate substitution in fragments of primary lamellar bone that survived remodeling for decades. Tissue composition of the secondary osteonal population was investigated to determine the composition of turned over tissue volume. Finally, Raman spectral analysis of homogenized tissue was performed to evaluate the effects of unremodeled and newly formed tissue on the overall tissue composition. The chemical composition of the primary lamellar bone exhibited two chronological stages. Organic matrix became more mineralized and the crystallinity of the mineral improved during the first stage, which lasted for two decades. The mineral content and the mineral crystallinity did not vary during the second stage. The results for the primary lamellar bone demonstrated that physiological mineralization, as evidenced by crystal growth and maturation, is a continuous process that may persist as long as two decades, and the growth and maturation process stops after the organic matrix becomes "fully mineralized." The average mineral content and the average mineral crystallinity of the homogenized tissue did not change with age. It was also observed that the mineral content of the homogenized tissue was consistently greater than the

  10. Generative FDG-PET and MRI model of aging and disease progression in Alzheimer's disease.

    PubMed

    Dukart, Juergen; Kherif, Ferath; Mueller, Karsten; Adaszewski, Stanislaw; Schroeter, Matthias L; Frackowiak, Richard S J; Draganski, Bogdan

    2013-04-01

    The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation. PMID:23592957

  11. Age-related changes in angiogenesis in human dermis.

    PubMed

    Gunin, Andrei G; Petrov, Vadim V; Golubtzova, Natalia N; Vasilieva, Olga V; Kornilova, Natalia K

    2014-07-01

    Present research is aimed to examine the number of dermal blood vessels, vascular endothelial growth factor (VEGF), delta-like ligand 4(Dll4) and Jagged-1 (Jag-1) in dermal blood vessels of human from 20weeks of pregnancy to 85years old. Numbers and proliferative activity of dermal fibroblast-like cells were also examined. Blood vessels were viewed with immunohistochemical staining for von Willebrand factor or CD31. VEGF, Dll4, Jag-1, and proliferating cell nuclear antigen (PCNA) were detected immunohistochemically. Results showed that the numbers of fibroblast-like cells, PCNA positive fibroblast-like cells, von Willebrand factor positive or CD31 positive blood vessels in dermis are dramatically decreased with age. The intensity of immunohistochemical staining for VEGF or Jag-1 in blood vessels of dermis is increased from antenatal to deep old period. The degree of immunohistochemical staining of dermal blood vessels for Dll4 has gone up from 20-40weeks of pregnancy to early life period (0-20years), and further decreased below antenatal values. Age-related decrease in the number of dermal blood vessels is suggested to be due to an impairment of VEGF signaling and to be mediated by Dll4 and Jag-1. It may be supposed that diminishing in blood supply of dermis occurring with age is a cause of a decrease in the number and proliferative pool of dermal fibroblasts. PMID:24768823

  12. Fluoride deposition in the aged human pineal gland.

    PubMed

    Luke, J

    2001-01-01

    The purpose was to discover whether fluoride (F) accumulates in the aged human pineal gland. The aims were to determine (a) F-concentrations of the pineal gland (wet), corresponding muscle (wet) and bone (ash); (b) calcium-concentration of the pineal. Pineal, muscle and bone were dissected from 11 aged cadavers and assayed for F using the HMDS-facilitated diffusion, F-ion-specific electrode method. Pineal calcium was determined using atomic absorption spectroscopy. Pineal and muscle contained 297+/-257 and 0.5+/-0.4 mg F/kg wet weight, respectively; bone contained 2,037+/-1,095 mg F/kg ash weight. The pineal contained 16,000+/-11,070 mg Ca/kg wet weight. There was a positive correlation between pineal F and pineal Ca (r = 0.73, p<0.02) but no correlation between pineal F and bone F. By old age, the pineal gland has readily accumulated F and its F/Ca ratio is higher than bone. PMID:11275672

  13. Mitochondrial-Nuclear Epistasis: Implications for Human Aging and Longevity

    PubMed Central

    Tranah, Gregory

    2010-01-01

    There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genomes. Results from Drosophila suggest that the effects of mtDNA haplotypes on longevity vary among different nuclear allelic backgrounds, which could account for the inconsistent associations that have been observed between mitochondrial DNA (mtDNA) haplogroups and survival in humans. A diversity of pathways may influence the way mitochondria and nuclear – mitochondrial interactions modulate longevity, including: oxidative phosphorylation; mitochondrial uncoupling; antioxidant defenses; mitochondrial fission and fusion; and sirtuin regulation of mitochondrial genes. We hypothesize that aging and longevity, as complex traits having a significant genetic component, are likely to be controlled by nuclear gene variants interacting with both inherited and somatic mtDNA variability. PMID:20601194

  14. "Human Potential" and Progressive Pedagogy: A Long Cultural History of the Ambiguity of "Race" and "Intelligence"

    ERIC Educational Resources Information Center

    Oland, Trine

    2012-01-01

    This article examines the cultural constructs of progressive pedagogy in Danish school pedagogy and its emerging focus on the child's human potential from the 1920s to the 1950s. It draws on Foucault's notion of "dispositifs" and the "elements of history," encircling a complex transformation of continuity and discontinuity of progressive pedagogy.…

  15. Progress and challenges in probing the human brain.

    PubMed

    Poldrack, Russell A; Farah, Martha J

    2015-10-15

    Perhaps one of the greatest scientific challenges is to understand the human brain. Here we review current methods in human neuroscience, highlighting the ways that they have been used to study the neural bases of the human mind. We begin with a consideration of different levels of description relevant to human neuroscience, from molecules to large-scale networks, and then review the methods that probe these levels and the ability of these methods to test hypotheses about causal mechanisms. Functional MRI is considered in particular detail, as it has been responsible for much of the recent growth of human neuroscience research. We briefly review its inferential strengths and weaknesses and present examples of new analytic approaches that allow inferences beyond simple localization of psychological processes. Finally, we review the prospects for real-world applications and new scientific challenges for human neuroscience. PMID:26469048

  16. Rejuvenation of senescent cells-the road to postponing human aging and age-related disease?

    PubMed

    Sikora, Ewa

    2013-07-01

    Cellular senescence is the state of permanent inhibition of cell proliferation. Replicative senescence occurs due to the end replication problem and shortening telomeres with each cell division leading to DNA damage response (DDR). The number of short telomeres increases with age and age-related pathologies. Stress induced senescence, although not accompanied by attrition of telomeres, is also attributed to the DDR induced by irreparable DNA lesions in telomeric DNA. Senescent cells characterized by the presence of γH2AX, the common marker of double DNA strand breaks, and other senescence markers including activity of SA-β-gal, accumulate in tissues of aged animals and humans as well as at sites of pathology. It is believed that cellular senescence evolved as a cancer barrier since non-proliferating senescent cells cannot be transformed to neoplastic cells. On the other hand senescent cells favor cancer development, just like other age-related pathologies, by creating a low grade inflammatory state due to senescence associated secretory phenotype (SASP). Reversal/inhibition of cellular senescence could prolong healthy life span, thus many attempts have been undertaken to influence cellular senescence. The two main approaches are genetic and pharmacological/nutritional modifications of cell fate. The first one concerns cell reprogramming by induced pluripotent stem cells (iPSCs), which in vitro is effective even in cells undergoing senescence, or derived from very old or progeroid patients. The second approach concerns modification of senescence signaling pathways just like TOR-induced by pharmacological or with natural agents. However, knowing that aging is unavoidable we cannot expect its elimination, but prolonging healthy life span is a goal worth serious consideration. PMID:23064316

  17. An Evaluation of the Complex Age Progression along the Cook-Austral Islands Using High-resolution 40Ar/39Ar Incremental Heating Ages

    NASA Astrophysics Data System (ADS)

    Rose, J.; Koppers, A. A. P.

    2014-12-01

    Until recently, the hotspot hypothesis has been generally accepted to explain the presence of linear volcanic chains. The hypothesis predicts a linear age progression along each chain, as well as consistent angular rotation velocities for all chains on a single plate. While such age progressions have been observed at places such as Hawaii and Louisville, several young (0-30 Ma) volcanic chains that formed on the Pacific plate show age progressions and associated angular velocities that are in disagreement with one another. The Cook-Austral island chain has age distributions that are particularly difficult to resolve based on the hotspot hypothesis, due to its location on the "hotspot highway" (Jackson et al. 2010) and a wide geographic range of recent volcanism. Several of these islands were previously studied by Turner and Jarrard (1982) who interpreted this age progression to suggest the presence of three active hotspots positioned along a "hot line" above a sheet-like upwelling area in the mantle as opposed to a singular "hot spot". However, this study was performed using the K/Ar dating method, and it has been shown that K and/or Ar loss (and addition of K) due to weathering and alteration can have significant effects on the age and uncertainty of samples dated with this technique. Here we present high-resolution 40Ar/39Ar incremental heating ages for several of the same samples previously analyzed in this study, as well as some unpublished samples. Analyses were conducted using the ARGUS-VI multicollector mass spectrometer, employing incremental heating procedures that provide more precise and more accurate ages compared to K/Ar and total fusion 40Ar/39Ar measurements. These new data will be used in conjunction with existing plate motion models and geochemical data to assess whether they support a point source or line source hypothesis. This in turn will allow us to improve our overall knowledge of mantle anomaly geometry and absolute plate motion.

  18. The Age-Related Orientational Changes of Human Semicircular Canals

    PubMed Central

    Lyu, Hui-Ying; Chen, Ke-Guang; Yin, Dong-Ming; Hong, Juan; Yang, Lin; Zhang, Tian-Yu; Dai, Pei-Dong

    2016-01-01

    Objectives Some changes are found in the labyrinth anatomy during postnatal development. Although the spatial orientation of semicircular canals was thought to be stable after birth, we investigated the age-related orientational changes of human semicircular canals during development. Methods We retrospectively studied the computed tomography (CT) images of both ears of 76 subjects ranged from 1 to 70 years old. They were divided into 4 groups: group A (1–6 years), group B (7–12 years), group C (13–18 years), and group D (>18 years). The anatomical landmarks of the inner ear structures were determined from CT images. Their coordinates were imported into MATLAB software for calculating the semicircular canals orientation, angles between semicircular canal planes and the jugular bulb (JB) position. Differences between age groups were analyzed using multivariate statistics. Relationships between variables were analyzed using Pearson analysis. Results The angle between the anterior semicircular canal plane and the coronal plane, and the angle between the horizontal semicircular canal plane and the coronal plane were smaller in group D than those in group A (P<0.05). The JB position, especially the anteroposterior position of right JB, correlated to the semicircular canals orientation (P<0.05). However, no statistically significant differences in the angles between ipsilateral canal planes among different age groups were found. Conclusion The semicircular canals had tendencies to tilt anteriorly simultaneously as a whole with age. The JB position correlated to the spatial arrangement of semicircular canals, especially the right JB. Our calculation method helps detect developmental and pathological changes in vestibular anatomy. PMID:27090280

  19. Aging and Fracture of Human Cortical Bone and Tooth Dentin

    SciTech Connect

    Ager, Joel; Koester, Kurt J.; Ager III, Joel W.; Ritchie, Robert O.

    2008-05-07

    Mineralized tissues, such as bone and tooth dentin, serve as structural materials in the human body and, as such, have evolved to resist fracture. In assessing their quantitative fracture resistance or toughness, it is important to distinguish between intrinsic toughening mechanisms which function ahead of the crack tip, such as plasticity in metals, and extrinsic mechanisms which function primarily behind the tip, such as crack bridging in ceramics. Bone and dentin derive their resistance to fracture principally from extrinsic toughening mechanisms which have their origins in the hierarchical microstructure of these mineralized tissues. Experimentally, quantification of these toughening mechanisms requires a crack-growth resistance approach, which can be achieved by measuring the crack-driving force, e.g., the stress intensity, as a function of crack extension ("R-curve approach"). Here this methodology is used to study of the effect of aging on the fracture properties of human cortical bone and human dentin in order to discern the microstructural origins of toughness in these materials.

  20. Human gut microbiome viewed across age and geography

    PubMed Central

    Yatsunenko, Tanya; Rey, Federico E.; Manary, Mark J.; Trehan, Indi; Dominguez-Bello, Maria Gloria; Contreras, Monica; Magris, Magda; Hidalgo, Glida; Baldassano, Robert N.; Anokhin, Andrey P.; Heath, Andrew C.; Warner, Barbara; Reeder, Jens; Kuczynski, Justin; Caporaso, J. Gregory; Lozupone, Catherine A.; Lauber, Christian; Clemente, Jose Carlos; Knights, Dan; Knight, Rob; Gordon, Jeffrey I.

    2012-01-01

    Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ between human populations when viewed from the perspective of component microbial lineages, encoded metabolic functions, stage of postnatal development, and environmental exposures, we characterized bacterial species present in fecal samples obtained from 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas, as well as the gene content of 110 of their microbiomes. This cohort encompassed infants, children, teenagers and adults, parents and offspring, and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the representation of genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial species assemblages and functional gene repertoires were noted between individuals residing in the USA compared to the other two countries. These distinctive features are evident in early infancy as well as adulthood. In addition, the similarity of fecal microbiomes among family members extends across cultures. These findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations, and the impact of Westernization. PMID:22699611

  1. Human Health and Support Systems Capability Roadmap Progress Review

    NASA Technical Reports Server (NTRS)

    Grounds, Dennis; Boehm, Al

    2005-01-01

    The Human Health and Support Systems Capability Roadmap focuses on research and technology development and demonstration required to ensure the health, habitation, safety, and effectiveness of crews in and beyond low Earth orbit. It contains three distinct sub-capabilities: Human Health and Performance. Life Support and Habitats. Extra-Vehicular Activity.

  2. Age-associated changes in rich-club organisation in autistic and neurotypical human brains

    PubMed Central

    Watanabe, Takamitsu; Rees, Geraint

    2015-01-01

    Macroscopic structural networks in the human brain have a rich-club architecture comprising both highly inter-connected central regions and sparsely connected peripheral regions. Recent studies show that disruption of this functionally efficient organisation is associated with several psychiatric disorders. However, despite increasing attention to this network property, whether age-associated changes in rich-club organisation occur during human adolescence remains unclear. Here, analysing a publicly shared diffusion tensor imaging dataset, we found that, during adolescence, brains of typically developing (TD) individuals showed increases in rich-club organisation and inferred network functionality, whereas individuals with autism spectrum disorders (ASD) did not. These differences between TD and ASD groups were statistically significant for both structural and functional properties. Moreover, this typical age-related changes in rich-club organisation were characterised by progressive involvement of the right anterior insula. In contrast, in ASD individuals, did not show typical increases in grey matter volume, and this relative anatomical immaturity was correlated with the severity of ASD social symptoms. These results provide evidence that rich-club architecture is one of the bases of functionally efficient brain networks underpinning complex cognitive functions in adult human brains. Furthermore, our findings suggest that immature rich-club organisation might be associated with some neurodevelopmental disorders. PMID:26537477

  3. Age-related characteristics of risky decision-making and progressive expectation formation.

    PubMed

    Kardos, Zsófia; Kóbor, Andrea; Takács, Ádám; Tóth, Brigitta; Boha, Roland; File, Bálint; Molnár, Márk

    2016-10-01

    During daily encounters, it is inevitable that people take risks. Investigating the sequential processing of risk hazards involve expectation formation about outcome contingencies. The present study aimed to explore risk behavior and its neural correlates in sequences of decision making, particularly in old age, which represents a critical period regarding risk-taking propensity. The Balloon Analogue Risk Task was used in an electrophysiological setting with young and elderly age groups. During the task each additional pump on a virtual balloon increased the likelihood of a balloon burst but also increased the chance to collect more reward. Event-related potentials associated with rewarding feedback were analyzed based on the forthcoming decisions (whether to continue or to stop) in order to differentiate between states of expectation towards gain or loss. In the young, the reward positivity ERP component increased as a function of reward contingencies with the largest amplitude for rewarding feedback followed by the decision to stop. In the elderly, however, reward positivity did not reflect the effect of reward structure. Behavioral indices of risk-taking propensity suggest that the performance of the young and the elderly were dissociable only with respect to response times: The elderly was characterized by hesitation and more deliberative decision making throughout the experiment. These findings signify that sequential tracking of outcome contingencies has a key role in cost-efficient action planning and progressive expectation formation. PMID:27385088

  4. Age-dependent variation of the Gradient Index profile in human crystalline lenses

    PubMed Central

    de Castro, A.; Siedlecki, D.; Borja, David; Uhlhorn, Stephen; Parel, Jean-Marie; Manns, Fabrice; Marcos, S.

    2011-01-01

    Purpose To reconstruct the gradient index (GRIN) profile of human crystalline lenses ex-vivo using Optical Coherence Tomography (OCT) imaging with an optimization technique and to study the dependence of the GRIN profile with age. Methods Cross-sectional images of nine isolated human crystalline lenses with ages ranging from 6 to 72 (post mortem time 1 to 4 days) were obtained using a custom-made OCT system. Lenses were extracted from whole cadaver globes and placed in a measurement chamber filled with preservation medium (DMEM). Lenses were imaged with the anterior surface up and then flipped over and imaged again, to obtain posterior lens surface profiles both undistorted and distorted by the refraction through the anterior crystalline lens and GRIN. The GRIN distribution of the lens was described with three variables by means of power function, with variables being the nucleus and surface index, and a power coefficient that describes the decay of the refractive index from the nucleus to the surface. An optimization method was used to search for the parameters that produced the best match of the distorted posterior surface. Results The distorted surface was simulated with accuracy around the resolution of the OCT system (under 15 µm). The reconstructed refractive index values ranged from 1.356 to 1.388 for the surface, and from 1.396 to 1.434 for the nucleus. The power coefficient ranged between 3 and 18. The power coefficient increased significantly with age, at a rate of 0.24 per year. Conclusion Optical Coherence Tomography allowed optical, non-invasive measurement of the 2-D gradient index profile of the isolated human crystalline lens ex vivo. The age-dependent variation of the changes is consistent with previous data using magnetic resonance imaging, and the progressive formation of a refractive index plateau. PMID:22865954

  5. Age-dependent variation of the gradient index profile in human crystalline lenses

    NASA Astrophysics Data System (ADS)

    de Castro, Alberto; Siedlecki, Damian; Borja, David; Uhlhorn, Stephen; Parel, Jean-Marie; Manns, Fabrice; Marcos, Susana

    2011-11-01

    An investigation was carried out with the aim of reconstructing the gradient index (GRIN) profile of human crystalline lenses ex-vivo using optical coherence tomography (OCT) imaging with an optimization technique and to study the dependence of the GRIN profile with age. Cross-sectional images of nine isolated human crystalline lenses with ages ranging from 6 to 72 (post-mortem time 1 to 4 days) were obtained using a custom-made OCT system. Lenses were extracted from whole cadaver globes and placed in a measurement chamber filled with preservation medium (DMEM). Lenses were imaged with the anterior surface up and then flipped over and imaged again, to obtain posterior lens surface profiles both undistorted and distorted by the refraction through the anterior crystalline lens and GRIN. The GRIN distribution of the lens was described with three variables by means of power function, with variables being the nucleus and surface index, and a power coefficient that describes the decay of the refractive index from the nucleus to the surface. An optimization method was used to search for the parameters that produced the best match of the distorted posterior surface. The distorted surface was simulated with accuracy around the resolution of the OCT system (under 15 µm). The reconstructed refractive index values ranged from 1.356 to 1.388 for the surface, and from 1.396 to 1.434 for the nucleus. The power coefficient ranged between 3 and 18. The power coefficient increased significantly with age, at a rate of 0.24 per year. Optical coherence tomography allowed optical, non-invasive measurement of the 2D gradient index profile of the isolated human crystalline lens ex vivo. The age-dependent variation of the changes is consistent with previous data using magnetic resonance imaging, and the progressive formation of a refractive index plateau.

  6. Catalog of genetic progression of human cancers: breast cancer.

    PubMed

    Desmedt, Christine; Yates, Lucy; Kulka, Janina

    2016-03-01

    With the rapid development of next-generation sequencing, deeper insights are being gained into the molecular evolution that underlies the development and clinical progression of breast cancer. It is apparent that during evolution, breast cancers acquire thousands of mutations including single base pair substitutions, insertions, deletions, copy number aberrations, and structural rearrangements. As a consequence, at the whole genome level, no two cancers are identical and few cancers even share the same complement of "driver" mutations. Indeed, two samples from the same cancer may also exhibit extensive differences due to constant remodeling of the genome over time. In this review, we summarize recent studies that extend our understanding of the genomic basis of cancer progression. Key biological insights include the following: subclonal diversification begins early in cancer evolution, being detectable even in in situ lesions; geographical stratification of subclonal structure is frequent in primary tumors and can include therapeutically targetable alterations; multiple distant metastases typically arise from a common metastatic ancestor following a "metastatic cascade" model; systemic therapy can unmask preexisting resistant subclones or influence further treatment sensitivity and disease progression. We conclude the review by describing novel approaches such as the analysis of circulating DNA and patient-derived xenografts that promise to further our understanding of the genomic changes occurring during cancer evolution and guide treatment decision making. PMID:26951551

  7. [Multiplex mapping of human cDNAs]. Technical progress report

    SciTech Connect

    Nierman, W.C.

    1992-11-01

    We have tested and implemented several protocols to increase productivity for mapping expressed sequence tags EST sequences to human chromosomes. These protocols include adopting PRIMER which permits utilization of batch files, as the standard software for PCR primer design; adding a human 21-only cell line to the NIGMS panel No. 1 to improve discrimination in discordancy analyses involving chromosome 21, adding a monochromosomal hybrid panel to facilitate chromosome assignment of sequences that are amplified from more than 1 chromosome; combining the products of multiple PCR reactions for electrophoretic analysis (pseudoplexing); routinely multiplexing PCR reactions; and automating data entry and analysis as much as possible. We have applied these protocols to assign an overall total of 132 human brain CDNA sequences to individual human chromosomes. PCR primers were designed from ESTS and tested for specific amplification from human genomic DNA. DNA was then amplified using DNA from somatic cell hybrid mapping panels as templates. The amplification products were identified using an automated fluorescence detection system. Chromosomal assignments were made by discordancy analysis. The localized cDNAs include 2 for known human genes, 2 that map to 2 different human chromosomes, and 25 for cDNAs matching existing database records.

  8. Regional variation of intracortical porosity in the midshaft of the human femur: age and sex differences

    PubMed Central

    Thomas, C David L; Feik, Sophie A; Clement, John G

    2005-01-01

    This study investigated age and sex differences in patterns of porosity distribution in the midshaft of the human femur. Cross-sections were obtained from 168 individuals from a modern Australian population. The sample comprised 73 females and 95 males, aged between 20 and 97 years. Microradiographs were made of 100-µm sections and pore and bone areas were determined using image processing software. Initially the sample was divided by age: young (20–44 years), middle (45–64 years) and old (65+ years), but it was found that analysis on the basis of the ratio of medullary area to total subperiosteal area gave clearer results. The cortex was divided into three rings radially and into octants circumferentially and the porosity of each segment was calculated. Results showed that a pattern with raised porosity in the posterior and anterolateral regions, and with greater porosity in the inner parts of the cortex, becomes more pronounced with age. In males this pattern develops steadily; in females there are much greater differences between the middle and older groups than earlier in life. The patterns observed are consistent with progressive bone loss occurring along a neutral axis of the cortex where bending stress is lowest and the mechanical advantage of the bone is least. PMID:15730477

  9. Age-related changes in proliferation, the numbers of mast cells, eosinophils, and cd45-positive cells in human dermis.

    PubMed

    Gunin, Andrei G; Kornilova, Natalia K; Vasilieva, Olga V; Petrov, Vadim V

    2011-04-01

    Skin aging is an extremely important medical and social problem in the modern world. Therefore, a goal of the present work was to estimate changes in the numbers of fibroblast-like cells, proliferating cells nuclear antigen-positive cells, CD45-positive cells, mast cells, and eosinophils in human dermis at different ages. Skin specimens from human fetuses that died antenatally from 20 to 40 weeks of pregnancy and humans who died from different causes from 1 day to 85 years of life were used for the study. Results showed a decrease in a total number and the number of proliferating cells nuclear antigen-positive fibroblast-like cells in dermis with progression of age. The numbers of CD45-positive cells and mast cells are gradually increased with aging. Eosinophils are almost absent in dermis independently on age. Mast cells are probably a main factor that potentially can be involved in tissue damage and aging changes in skin. Mast cells should be regarded as an important target for anti-aging therapy. PMID:21106704

  10. Valuable human capital: the aging health care worker.

    PubMed

    Collins, Sandra K; Collins, Kevin S

    2006-01-01

    With the workforce growing older and the supply of younger workers diminishing, it is critical for health care managers to understand the factors necessary to capitalize on their vintage employees. Retaining this segment of the workforce has a multitude of benefits including the preservation of valuable intellectual capital, which is necessary to ensure that health care organizations maintain their competitive advantage in the consumer-driven market. Retaining the aging employee is possible if health care managers learn the motivators and training differences associated with this category of the workforce. These employees should be considered a valuable resource of human capital because without their extensive expertise, intense loyalty and work ethic, and superior customer service skills, health care organizations could suffer severe economic repercussions in the near future. PMID:16905991

  11. Middle holocene age of the sunnyvale human skeleton.

    PubMed

    Taylor, R E; Payen, L A; Gerow, B; Donahue, D J; Zabel, T H; Jull, A J; Damon, P E

    1983-06-17

    A morphologically modern human skeleton from Sunnyvale, California, previously dated by aspartic acid racemization to be approximately 70,000 years old and by uranium series isotopic ratios to be 8300 and 9000 years old, appears to be younger when dated by the carbon-14 method. Four carbon-14 determinations made by both decay and direct counting on three organic fractions of postcranial bone support a middle Holocene age assignment for the skeleton, probably in the range of 3500 to 5000 carbon-14 years before the present. This dating evidence is consistent with the geologic, archeological, and anthropometric relationships of the burial as well as previously determined carbon-14 determinations on associated materials. PMID:17769367

  12. Age-Dependent Changes in Pb Concentration in Human Teeth.

    PubMed

    Fischer, Agnieszka; Wiechuła, Danuta

    2016-09-01

    The result of exposure to Pb is its accumulation in mineralized tissues. In human body, they constitute a reservoir of approx. 90 % of the Pb reserve. The conducted research aimed at determining the accumulation of Pb in calcified tissues of permanent teeth. The concentration of Pb in 390 samples of teeth taken from a selected group of Polish people was determined using the AAS method. Average concentration of Pb in teeth amounted to 14.3 ± 8.18 μg/g, range of changes: 2.21-54.8 μgPb/g. Accumulation of Pb in human body was determined based on changes in Pb concentration in teeth of subjects aged 13-84 years. It was found that in calcified tissues of teeth, the increase in concentration of Pb that occurs with age is a statistically significant process (p = 0.02, the ANOVA Kruskal-Wallis test). It was determined that the annual increase in concentration of Pb in tissues of teeth is approx. 0.1 μg/g. Moreover, a different course of changes in Pb concentration in tissues of teeth in people born in different years was observed. The level of Pb concentration in teeth of the oldest subjects (>60 years) decreased for those born in the 1930s compared to those in the 1950s. Teeth from younger persons (<60 years) were characterized by an increasing level of Pb concentration. The analysis of changes of Pb indicates that for low exposure, a relatively greater accumulation of Pb concentration in calcified tissues of teeth can occur. PMID:26888348

  13. Aging affects the cardiovascular responses to cold stress in humans

    PubMed Central

    Hess, Kari L.; Wilson, Thad E.; Sauder, Charity L.; Gao, Zhaohui; Ray, Chester A.

    2009-01-01

    Cardiovascular-related mortality peaks during cold winter months, particularly in older adults. Acute physiological responses, such as increases in blood pressure, in response to cold exposure may contribute to these associations. To determine whether the blood pressure-raising effect (pressor response) of non-internal body temperature-reducing cold stress is greater with age, we measured physiological responses to 20 min of superficial skin cooling, via water-perfused suit, in 12 younger [25 ± 1 (SE) yr old] and 12 older (65 ± 2 yr old) adults. We found that superficial skin cooling elicited an increase in blood pressure from resting levels (pressor response; P < 0.05) in younger and older adults. However, the magnitude of this pressor response (systolic and mean blood pressure) was more than twofold higher in older adults (P < 0.05 vs. younger adults). The magnitude of the pressor response was similar at peripheral (brachial) and central (estimated in the aorta) measurement sites. Regression analysis revealed that aortic pulse wave velocity, a measure of central arterial stiffness obtained before cooling, was the best predictor of the increased pressor response to superficial skin cooling in older adults, explaining ∼63% of its variability. These results indicate that there is a greater pressor response to non-internal body temperature-reducing cold stress with age in humans that may be mediated by increased levels of central arterial stiffness. PMID:19679742

  14. Progress and Standardization in Eye Movement Work with Human Infants

    ERIC Educational Resources Information Center

    Haith, Marshall M.

    2004-01-01

    This article presents the author's comments on a set of articles representing an unusual collation of work by investigators from different parts of the world, using similar high-tech instrumentation and procedures to measure eye movements in infants who lie in a fairly constrained age range. Although the articles in this thematic collection share…

  15. Research on human genetics in Iceland. Progress report

    SciTech Connect

    1980-10-31

    Records of the Icelandic Population are being used to investigate the possible inheritance of disabilities and diseases as well as other characters and the effect of environment on man. The progress report of research covers the period 1977 to 1980. The investigation was begun in 1965 by the Genetical Committee of the University of Iceland and the materials used are demographic records from the year 1840 to present and various medical information. The records are being computerized and linked together to make them effective for use in hereditary studies.

  16. Progress report on research on human genetics in Iceland

    SciTech Connect

    1980-10-31

    Records of the Icelandic population are being used to investigate the possible inheritance of disabilities and diseases as well as other characteristics and the effect of environment on man. The progress report of research covers the period from 1977 to 1980. The investigation was begun in 1965 by the Genetical Committee of the University of Iceland and the materials used are demographic records from the year 1840 to present and various medical information. The records are being computerized and linked together to make them effective for use in hereditary studies.

  17. Is atherosclerosis fundamental to human aging? Lessons from ancient mummies.

    PubMed

    Clarke, Emily M; Thompson, Randall C; Allam, Adel H; Wann, L Samuel; Lombardi, Guido P; Sutherland, M Linda; Sutherland, James D; Cox, Samantha L; Soliman, Muhammad Al-Tohamy; Abd el-Maksoud, Gomaa; Badr, Ibrahem; Miyamoto, Michael I; Frohlich, Bruno; Nur el-din, Abdel-Halim; Stewart, Alexandre F R; Narula, Jagat; Zink, Albert R; Finch, Caleb E; Michalik, David E; Thomas, Gregory S

    2014-05-01

    Case reports from Johan Czermak, Marc Ruffer, and others a century or more ago demonstrated ancient Egyptians had atherosclerosis three millennia ago. The Horus study team extended their findings, demonstrating that atherosclerosis was prevalent among 76 ancient Egyptian mummies and among 61 mummies from each of the ancient cultures of Peru, the American Southwest, and the Aleutian Islands. These findings challenge the assumption that atherosclerosis is a modern disease caused by present day risk factors. An extensive autopsy of an ancient Egyptian teenage male weaver named Nakht found that he was infected with four parasites: Schistosoma haematobium, Taenia species, Trichinella spiralis, and Plasmodium falciparum. Modern day patients with chronic inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, and human immunodeficiency virus experience premature atherosclerosis. Could the burden of chronic inflammatory disease have been a risk factor for atherosclerosis in these ancient cultures? The prevalence of atherosclerosis in four diverse ancient cultures is consistent with atherosclerosis being fundamental to aging. The impact of risk factors in modern times, and potentially in ancient times, suggests a strong gene-environmental interplay: human genes provide a vulnerability to atherosclerosis, the environment determines when and if atherosclerosis becomes manifest clinically. PMID:24582386

  18. Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases.

    PubMed

    Youssef, S A; Capucchio, M T; Rofina, J E; Chambers, J K; Uchida, K; Nakayama, H; Head, E

    2016-03-01

    According to the WHO, the proportion of people over 60 years is increasing and expected to reach 22% of total world's population in 2050. In parallel, recent animal demographic studies have shown that the life expectancy of pet dogs and cats is increasing. Brain aging is associated not only with molecular and morphological changes but also leads to different degrees of behavioral and cognitive dysfunction. Common age-related brain lesions in humans include brain atrophy, neuronal loss, amyloid plaques, cerebrovascular amyloid angiopathy, vascular mineralization, neurofibrillary tangles, meningeal osseous metaplasia, and accumulation of lipofuscin. In aging humans, the most common neurodegenerative disorder is Alzheimer's disease (AD), which progressively impairs cognition, behavior, and quality of life. Pathologic changes comparable to the lesions of AD are described in several other animal species, although their clinical significance and effect on cognitive function are poorly documented. This review describes the commonly reported age-associated neurologic lesions in domestic and laboratory animals and the relationship of these lesions to cognitive dysfunction. Also described are the comparative interspecies similarities and differences to AD and other human neurodegenerative diseases including Parkinson's disease and progressive supranuclear palsy, and the spontaneous and transgenic animal models of these diseases. PMID:26869150

  19. An Overview of the Work Progress Report. Manpower for the Human Services.

    ERIC Educational Resources Information Center

    Kassel, Myrna Bordelon

    This monograph is the first of a series summarizing the work progress of the Human Services Manpower Career Center, a special research and development project funded by the U. S. Department of Labor. During its first 2 years of operation, the Center has: (1) undertaken basic occupational research to identify the human services occupations in the…

  20. Physical mapping of human chromosome 16. Annual progress report

    SciTech Connect

    Sutherland, G.R.

    1992-08-01

    Project aims for the past year have been to refine the cytogenetic based physical map of human chromosome 16. This has been achieved by extending the panel of mouse/human hybrids of chromosome 16 to over sixty hybrids and mapping approximately 250 DNA makers. The high resolution of this physical map, with an average distance between breakpoints of less than 1.6 Mb, and the availability of at least one STS in the majority of these intervals, will be the basis for constructing extensive contigs of cloned DNA.

  1. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes.

    PubMed

    Gladyshev, Vadim N

    2016-08-01

    Different theories posit that aging is caused by molecular damage, genetic programs, continued development, hyperfunction, antagonistic pleiotropy alleles, mutations, trade-offs, incomplete repair, etc. Here, I discuss that these ideas can be conceptually unified as they capture particular facets of aging, while being incomplete. Their respective deleterious effects impact fitness at different levels of biological organization, adjusting progression through aging, rather than causing it. Living is associated with a myriad of deleterious processes, both random and deterministic, which are caused by imperfectness, exhibit cumulative properties, and represent the indirect effects of biological functions at all levels, from simple molecules to systems. From this, I derive the deleteriome, which encompasses cumulative deleterious age-related changes and represents the biological age. The organismal deleteriome consists of the deleteriomes of cells, organs, and systems, which change along roughly synchronized trajectories and may be assessed through biomarkers of aging. Aging is then a progressive decline in fitness due to the increasing deleteriome, adjusted by genetic, environmental, and stochastic processes. This model allows integration of diverse aging concepts, provides insights into the nature of aging, and suggests how lifespan may be adjusted during evolution and in experimental models. PMID:27060562

  2. [Multiplex mapping of human cDNAs]. Technical progress report

    SciTech Connect

    Nierman, W.C.

    1991-12-31

    J. Craig Venter, National Institute of Neurological Disorders and Stroke, has begun to identify genes expressed in the human brain by partially sequences cDNA clones. We are collaborating with the Venter group and using their sequence data to develop methods for rapid localization of newly identified cDNAs to human chromosomes. We are applying the ABI automated DNA sequencer to the analysis of fluorescently-tagged PCR products for assigning sequences to individual human chromosomes. The steps in our mapping protocol are (1) to design PCR primers from the Venter laboratory-generated sequence data, (2) to test the primers for specific amplification from human genomic DNA, (3) to use the primers for PCR amplification from a somatic cell hybrid cell mapping panel, (4) to determine the presence or absence of the specific amplification products from each cell line DNA by electrophoretic analysis using the ABI sequencer, and (5) to analyze the pattern of amplification results from the hybrid panel to identify the chromosomal origin of the cDNA sequence. We have demonstrated the principle by mapping 12 sequences or ``Expressed Sequence Tags`` (ESTs), providing primer sequence data for subsequent subchromosomal localizations. We will now concentrate on developing methodology to allow multiplexing the amplification reactions and analysis of the reaction products, to achieve a high throughput with a minimum allocation of resources. This project will generate a data set from which to evaluate strategies to identify functional primer sequences from cDNA sequence data.

  3. [Developing a physical map of human chromosome 22]. Progress report

    SciTech Connect

    Simon, M.I.

    1991-12-31

    We have developed bacterial F-factor based systems for cloning large fragments of human DNA in E. coli. In addition to large size, these systems are capable of maintaining human DNA with a high degree of stability. The cosmid size clones are called Fosmids and the clones containing larger inserts (100--200 kb) are called bacterial artificial chromosomes (BACs). The ultimate test of the effectiveness of cloning and mapping technology is the degree to which it can be efficiently applied to solve complex mapping problems. We, therefore, plan to use the large fragment cloning procedure as well as a variety of other approaches to generate a complete map of overlapping clones corresponding to human chromosome 22. We have thus far prepared two human chromosome 22 specific Fosmid libraries and we are in the process of constructing a chromosome 22 specific BAC library composed of fragments larger than 100 kb. We will further optimize the technology so that libraries of fragments larger than 200 kb can be readily prepared.

  4. Disentangling the Genetic Determinants of Human Aging: Biological Age as an Alternative to the Use of Survival Measures

    PubMed Central

    Karasik, David; Demissie, Serkalem; Cupples, L. Adrienne; Kiel, Douglas P.

    2005-01-01

    The choice of a phenotype is critical for the study of a complex genetically regulated process, such as aging. To date, most of the twin and family studies have focused on broad survival measures, primarily age at death or exceptional longevity. However, on the basis of recent studies of twins and families, biological age has also been shown to have a strong genetic component, with heritability estimates ranging from 27% to 57%. The aim of this review is twofold: first, to summarize growing consensus on reliable methods of biological age assessment, and second, to demonstrate validity of this phenotype for research in the genetics of aging in humans. PMID:15972604

  5. Effects of Caloric Restriction on Cardiovascular Aging in Non-human Primates and Humans

    PubMed Central

    Cruzen, Christina; Colman, Ricki J.

    2009-01-01

    Synopsis Approximately one in three Americans has some form of cardiovascular disease (CVD), accounting for one of every 2.8 deaths in the United States in 2004. Two of the major risk factors for CVD are advancing age and obesity. An intervention able to positively impact both aging and obesity, such as caloric restriction (CR), may prove extremely useful in the fight against CVD. CR is the only environmental or lifestyle intervention that has repeatedly been shown to increase maximum life span and to retard aging in laboratory rodents. In this article, we review evidence that CR in nonhuman primates and humans has a positive effect on risk factors for CVD. PMID:19944270

  6. Immune-inflammatory Dysregulation Modulates the Incidence of Progressive Fibrosis and Diastolic Stiffness in the Aging Heart

    PubMed Central

    Cieslik, Katarzyna A.; Taffet, George E.; Carlson, Signe; Hermosillo, Jesus; Trial, JoAnn; Entman, Mark L.

    2010-01-01

    Diastolic dysfunction in the aging heart is a grave condition that challenges the life and lifestyle of a growing segment of our population. This report seeks to examine the role and interrelationship of inflammatory dysregulation in interstitial myocardial fibrosis and progressive diastolic dysfunction in aging mice. We studied a population of C57BL/6 mice that developed progressive diastolic dysfunction over 30 months of life. This progressive dysfunction was associated with increasing infiltration of CD45+ fibroblasts of myeloid origin. In addition, increased rates of collagen expression as measured by cellular procollagen were apparent in the heart as a function of age. These cellular and functional changes were associated with progressive increases in mRNA for MCP-1 and IL-13 which correlated both temporally and quantitatively with changes in fibrosis and cellular procollagen levels. MCP-1 protein was also increased and found to be primarily in the venular endothelium. Protein assays also demonstrated elevation of IL-4 and IL-13 suggesting a shift to a Th2 phenotype in the aging heart. In vitro studies demonstrated that IL-13 markedly enhanced monocyte fibroblast transformation. Our results indicate that immunoinflammatory dysregulation in the aging heart induces progressive MCP-1 production and an increased shift to a Th2 phenotype paralleled by an associated increase in myocardial interstitial fibrosis, cellular collagen synthesis, and increased numbers of CD45+ myeloid-derived fibroblasts that contain procollagen. The temporal association and functional correlations suggests a causative relationship between age-dependent immunoinflammatory dysfunction, fibrosis and diastolic dysfunction. PMID:20974150

  7. Reprogramming of human cancer cells to pluripotency for models of cancer progression

    PubMed Central

    Kim, Jungsun; Zaret, Kenneth S

    2015-01-01

    The ability to study live cells as they progress through the stages of cancer provides the opportunity to discover dynamic networks underlying pathology, markers of early stages, and ways to assess therapeutics. Genetically engineered animal models of cancer, where it is possible to study the consequences of temporal-specific induction of oncogenes or deletion of tumor suppressors, have yielded major insights into cancer progression. Yet differences exist between animal and human cancers, such as in markers of progression and response to therapeutics. Thus, there is a need for human cell models of cancer progression. Most human cell models of cancer are based on tumor cell lines and xenografts of primary tumor cells that resemble the advanced tumor state, from which the cells were derived, and thus do not recapitulate disease progression. Yet a subset of cancer types have been reprogrammed to pluripotency or near-pluripotency by blastocyst injection, by somatic cell nuclear transfer and by induced pluripotent stem cell (iPS) technology. The reprogrammed cancer cells show that pluripotency can transiently dominate over the cancer phenotype. Diverse studies show that reprogrammed cancer cells can, in some cases, exhibit early-stage phenotypes reflective of only partial expression of the cancer genome. In one case, reprogrammed human pancreatic cancer cells have been shown to recapitulate stages of cancer progression, from early to late stages, thus providing a model for studying pancreatic cancer development in human cells where previously such could only be discerned from mouse models. We discuss these findings, the challenges in developing such models and their current limitations, and ways that iPS reprogramming may be enhanced to develop human cell models of cancer progression. PMID:25712212

  8. Progress Toward Effective Treatments for Human Photoreceptor Degenerations

    PubMed Central

    Stone, Edwin M.

    2015-01-01

    Mutations in several dozen genes have been shown to cause inherited photoreceptor degeneration in humans and it is likely that mutations in several dozen more will eventually be identified. Careful study of these genes has provided insight into the cellular and molecular mechanisms of human photoreceptor disease and has accelerated the development of a number of different classes of therapy including: nutritional supplementation, toxin avoidance, small- and large-molecule drugs, gene replacement, cell replacement, and even retinal prostheses. The retina is a very favorable system for the development of novel treatments for neurodegenerative disease because of its optical and physical accessibility as well as its highly ordered structure. With several forms of treatment for inherited retinal disease in or near clinical trial, one of the greatest remaining challenges is to educate clinicians in the appropriate use of genetic testing for identifying the individuals who will be most likely to benefit from each specific modality. PMID:19414246

  9. Family Economic Hardship and Progression of Poor Mental Health in Middle-aged Husbands and Wives

    PubMed Central

    Wickrama, K. A. S.; Surjadi, Florensia F.; Lorenz, Frederick O.; Conger, Rand D.; Walker, Catie

    2011-01-01

    Using prospective data from 370 middle-aged husbands and wives during a 12-year period, we investigated the intra-individual and dyadic influence of family economic hardship on the levels of depressive symptoms of husbands and wives over their middle years. The results suggest that family economic hardship during the early middle years contributes to subsequent increase in depressive symptoms of husbands and wives after controlling for family economic hardship in late middle years. Consistent with stress-process theory, economic hardship influences depressive symptoms directly and indirectly through its influence on self-esteem. The results also provided evidence for the scar hypothesis which suggests that depression predicts subsequent level of self-esteem and form a reciprocal process between depressive symptoms and self-esteem over time. In sum, for both husbands and wives, our findings showed that depressive symptoms progress over the middle years through a self-perpetuating reciprocal process between self-esteem and depression initiated by early family economic hardship and through cross-spouse influences involving self-esteem and depressive symptoms. PMID:22577243

  10. INCREASING SAVING BEHAVIOR THROUGH AGE-PROGRESSED RENDERINGS OF THE FUTURE SELF

    PubMed Central

    HERSHFIELD, HAL E.; GOLDSTEIN, DANIEL G.; SHARPE, WILLIAM F.; FOX, JESSE; YEYKELIS, LEO; CARSTENSEN, LAURA L.; BAILENSON, JEREMY N.

    2014-01-01

    Many people fail to save what they need to for retirement (Munnell, Webb, and Golub-Sass 2009). Research on excessive discounting of the future suggests that removing the lure of immediate rewards by pre-committing to decisions, or elaborating the value of future rewards can both make decisions more future-oriented. In this article, we explore a third and complementary route, one that deals not with present and future rewards, but with present and future selves. In line with thinkers who have suggested that people may fail, through a lack of belief or imagination, to identify with their future selves (Parfit 1971; Schelling 1984), we propose that allowing people to interact with age-progressed renderings of themselves will cause them to allocate more resources toward the future. In four studies, participants interacted with realistic computer renderings of their future selves using immersive virtual reality hardware and interactive decision aids. In all cases, those who interacted with virtual future selves exhibited an increased tendency to accept later monetary rewards over immediate ones. PMID:24634544

  11. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

    PubMed

    Hendrickson, Ronald C; Lee, Anita Y H; Song, Qinghua; Liaw, Andy; Wiener, Matt; Paweletz, Cloud P; Seeburger, Jeffrey L; Li, Jenny; Meng, Fanyu; Deyanova, Ekaterina G; Mazur, Matthew T; Settlage, Robert E; Zhao, Xuemei; Southwick, Katie; Du, Yi; Holder, Dan; Sachs, Jeffrey R; Laterza, Omar F; Dallob, Aimee; Chappell, Derek L; Snyder, Karen; Modur, Vijay; King, Elizabeth; Joachim, Catharine; Bondarenko, Andrey Y; Shearman, Mark; Soper, Keith A; Smith, A David; Potter, William Z; Koblan, Ken S; Sachs, Alan B; Yates, Nathan A

    2015-01-01

    Disease modifying treatments for Alzheimer's disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic. PMID:26270474

  12. Attenuated noradrenergic sensitivity during local cooling in aged human skin

    PubMed Central

    Thompson, Caitlin S; Holowatz, Lacy A; Kenney, W. Larry

    2005-01-01

    Reflex-mediated cutaneous vasoconstriction (VC) is impaired in older humans; however, it is unclear whether this blunted VC also occurs during local cooling, which mediates VC through different mechanisms. We tested the hypothesis that the sensitization of cutaneous vessels to noradrenaline (NA) during direct skin cooling seen in young skin is blunted in aged skin. In 11 young (18–30 years) and 11 older (62–76 years) men and women, skin blood flow was monitored at two forearm sites with laser Doppler (LD) flowmetry while local skin temperature was cooled and clamped at 24°C. Cutaneous vascular conductance (CVC; LD flux/mean arterial pressure) was expressed as percentage change from baseline (%ΔCVCbase). At one site, five doses of NA (10−10–10−2m) were sequentially infused via intradermal microdialysis during cooling while the other 24°C site served as control (Ringer solution + cooling). At control sites, VC due to cooling alone was similar in young versus older (−54 ± 5 versus −56 ± 3%ΔCVCbase, P= 0.46). In young, NA infusions induced additional dose-dependent VC (10−8, 10−6, 10−4 and 10−2m: −70 ± 2, −72 ± 3, −78 ± 3 and −79 ± 4%ΔCVCbase; P < 0.05 versus control). In older subjects, further VC did not occur until the highest infused dose of NA (10−2m: −70 ± 5%ΔCVCbase; P < 0.05 versus control). When cutaneous arterioles are sensitized to NA by direct cooling, young skin exhibits the capacity to further constrict to NA in a dose-dependent manner. However, older skin does not display enhanced VC capacity until treated with saturating doses of NA, possibly due to age-associated decrements in Ca2+ availability or α2C-adrenoceptor function. PMID:15705648

  13. ARSENIC AND HUMAN HEALTH: EPIDEMIOLOGIC PROGRESS AND PUBLIC HEALTH IMPLICATIONS

    PubMed Central

    Argos, Maria; Ahsan, Habibul; Graziano, Joseph H.

    2014-01-01

    Elevated concentrations of arsenic in groundwater pose a public health threat to millions of people worldwide, including severely affected populations in South and Southeast Asia. While arsenic is an established human carcinogen and has been associated with a multitude of health outcomes in epidemiologic studies, a mode of action has yet to be determined for some aspects of arsenic toxicity. Herein, we emphasize the role of recent genetic and molecular epidemiologic investigations of arsenic toxicity. Additionally, we discuss considerations for the public health impacts of arsenic exposure through drinking water with respect to primary and secondary prevention efforts. PMID:22962196

  14. Human Exploration Systems and Mobility Capability Roadmap Progress Review

    NASA Technical Reports Server (NTRS)

    Culbert, Chris; Taylor, Jeff

    2005-01-01

    Contents include the following: Capability Roadmap Team. Capability Description and Capability Breakdown Structure. Benefits of the Human Systems and Mobility Capability. Roadmap Process and Approach. Drivers and Assumptions for the whole team. Current State-of-the-Art, Assumptions and Requirements will be covered in the appropriate sections. Capability Presentations by Leads under Roadmap (Repeated for each capability under roadmap). Capability Description, Benefits, Current State-of-the-Art. Capability Requirements and Assumptions. Roadmap for Capability. Capability Readiness Level. Technology Readiness Level. Figures of Merit. Summary of Top Level Capability. Significant Technical Challenges. Summary and Forward Work.

  15. Individual and Societal Wisdom: Explaining the Paradox of Human Aging and High Well-Being.

    PubMed

    Jeste, Dilip V; Oswald, Andrew J

    2014-03-26

    Objective: Although human aging is characterized by loss of fertility and progressive decline in physical abilities, later life is associated with better psychological health and well-being. Furthermore, there has been an unprecedented increase in average lifespan over the past century without corresponding extensions of fertile and healthy age spans. We propose a possible explanation for these paradoxical phenomena. Method: We reviewed the relevant literature on aging, well-being, and wisdom. Results: An increase in specific components of individual wisdom in later life may make up for the loss of fertility as well as declining physical health. However, current data on the relationship between aging and individual wisdom are not consistent and do not explain increased longevity in the general population during the past century. We propose that greater societal wisdom (including compassion) may account for the notable increase in average lifespan over the last century. Data in older adults with serious mental illnesses are limited, but suggest that many of them too experience improved psychosocial functioning, although their longevity has not yet increased, suggesting persistent stigma against mental illness and inadequate societal compassion. Conclusions: The proposed construct of societal wisdom needs more investigation. Research should also focus on the reasons for discrepant findings related to age-associated changes in different components of individual wisdom. Studies of wisdom and well-being are warranted in older people with serious mental illnesses, along with campaigns to enhance societal compassion for these disenfranchised individuals. Finally, effective interventions to enhance wisdom need to be developed and tested. PMID:24670225

  16. Human face processing is tuned to sexual age preferences

    PubMed Central

    Ponseti, J.; Granert, O.; van Eimeren, T.; Jansen, O.; Wolff, S.; Beier, K.; Deuschl, G.; Bosinski, H.; Siebner, H.

    2014-01-01

    Human faces can motivate nurturing behaviour or sexual behaviour when adults see a child or an adult face, respectively. This suggests that face processing is tuned to detecting age cues of sexual maturity to stimulate the appropriate reproductive behaviour: either caretaking or mating. In paedophilia, sexual attraction is directed to sexually immature children. Therefore, we hypothesized that brain networks that normally are tuned to mature faces of the preferred gender show an abnormal tuning to sexual immature faces in paedophilia. Here, we use functional magnetic resonance imaging (fMRI) to test directly for the existence of a network which is tuned to face cues of sexual maturity. During fMRI, participants sexually attracted to either adults or children were exposed to various face images. In individuals attracted to adults, adult faces activated several brain regions significantly more than child faces. These brain regions comprised areas known to be implicated in face processing, and sexual processing, including occipital areas, the ventrolateral prefrontal cortex and, subcortically, the putamen and nucleus caudatus. The same regions were activated in paedophiles, but with a reversed preferential response pattern. PMID:24850896

  17. Human face processing is tuned to sexual age preferences.

    PubMed

    Ponseti, J; Granert, O; van Eimeren, T; Jansen, O; Wolff, S; Beier, K; Deuschl, G; Bosinski, H; Siebner, H

    2014-05-01

    Human faces can motivate nurturing behaviour or sexual behaviour when adults see a child or an adult face, respectively. This suggests that face processing is tuned to detecting age cues of sexual maturity to stimulate the appropriate reproductive behaviour: either caretaking or mating. In paedophilia, sexual attraction is directed to sexually immature children. Therefore, we hypothesized that brain networks that normally are tuned to mature faces of the preferred gender show an abnormal tuning to sexual immature faces in paedophilia. Here, we use functional magnetic resonance imaging (fMRI) to test directly for the existence of a network which is tuned to face cues of sexual maturity. During fMRI, participants sexually attracted to either adults or children were exposed to various face images. In individuals attracted to adults, adult faces activated several brain regions significantly more than child faces. These brain regions comprised areas known to be implicated in face processing, and sexual processing, including occipital areas, the ventrolateral prefrontal cortex and, subcortically, the putamen and nucleus caudatus. The same regions were activated in paedophiles, but with a reversed preferential response pattern. PMID:24850896

  18. Allotransplantation for patients age ≥40 years with non-Hodgkin lymphoma: encouraging progression-free survival.

    PubMed

    McClune, Brian L; Ahn, Kwang Woo; Wang, Hai-Lin; Antin, Joseph H; Artz, Andrew S; Cahn, Jean-Yves; Deol, Abhinav; Freytes, César O; Hamadani, Mehdi; Holmberg, Leona A; Jagasia, Madan H; Jakubowski, Ann A; Kharfan-Dabaja, Mohamed A; Lazarus, Hillard M; Miller, Alan M; Olsson, Richard; Pedersen, Tanya L; Pidala, Joseph; Pulsipher, Michael A; Rowe, Jacob M; Saber, Wael; van Besien, Koen W; Waller, Edmund K; Aljurf, Mahmoud D; Akpek, Görgun; Bacher, Ulrike; Chao, Nelson J; Chen, Yi-Bin; Cooper, Brenda W; Dehn, Jason; de Lima, Marcos J; Hsu, Jack W; Lewis, Ian D; Marks, David I; McGuirk, Joseph; Cairo, Mitchell S; Schouten, Harry C; Szer, Jeffrey; Ramanathan, Muthalagu; Savani, Bipin N; Seftel, Matthew; Socie, Gérard; Vij, Ravi; Warlick, Erica D; Weisdorf, Daniel J

    2014-07-01

    Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age ≥40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL. Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age ≥65; P = .0008). Fewer patients aged ≥65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age ≥65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age ≥65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age ≥55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age ≥55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL. PMID:24641829

  19. Nutritional interventions protect against age-related deficits in behavior: from animals to humans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aged rats show impaired performance on motor and cognitive tasks. Similar changes in behavior occur in humans with age, and the development of methods to retard or reverse these age-related neuronal and behavioral deficits could increase healthy aging and decrease health care costs. In the present s...

  20. Inverse correlation of genetic risk score with age at onset in bout-onset and progressive-onset multiple sclerosis.

    PubMed

    Sorosina, Melissa; Esposito, Federica; Guaschino, Clara; Clarelli, Ferdinando; Barizzone, Nadia; Osiceanu, Ana Maria; Brambilla, Paola; Mascia, Elisabetta; Cavalla, Paola; Gallo, Paolo; Martinelli, Vittorio; Leone, Maurizio; Comi, Giancarlo; D'Alfonso, Sandra; Martinelli Boneschi, Filippo

    2015-10-01

    We correlated the weighted genetic risk score measured using 107 established susceptibility variants for multiple sclerosis (MS) with the age at onset in bout-onset (BOMS, n=906) and progressive-onset MS Italian patients (PrMS) (n=544). We observed an opposite relationship in the two disease courses: a higher weighted genetic risk score was associated with an earlier age at onset in BOMS (rho= -0.1; p=5 × 10(-3)) and a later age at onset in PrMS cases (rho=0.07; p=0.15) (p of difference of regression=1.4 × 10(-2)). These findings suggest that established MS risk variants anticipate the onset of the inflammatory phase, while they have no impact on, or even delay, the onset of the progressive phase. PMID:25533292

  1. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression.

    PubMed

    Munawwar, Arshi; Singh, Sarman

    2016-01-01

    Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein-Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

  2. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression

    PubMed Central

    Munawwar, Arshi; Singh, Sarman

    2016-01-01

    Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein–Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

  3. Proteome-wide analysis reveals an age-associated cellular phenotype of in situ aged human fibroblasts

    PubMed Central

    Waldera-Lupa, Daniel M.; Kalfalah, Faiza; Florea, Ana-Maria; Sass, Steffen; Kruse, Fabian; Rieder, Vera; Tigges, Julia; Fritsche, Ellen; Krutmann, Jean; Busch, Hauke; Boerries, Melanie; Meyer, Helmut E.; Boege, Fritz; Theis, Fabian

    2014-01-01

    We analyzed an ex vivo model of in situ aged human dermal fibroblasts, obtained from 15 adult healthy donors from three different age groups using an unbiased quantitative proteome-wide approach applying label-free mass spectrometry. Thereby, we identified 2409 proteins, including 43 proteins with an age-associated abundance change. Most of the differentially abundant proteins have not been described in the context of fibroblasts’ aging before, but the deduced biological processes confirmed known hallmarks of aging and led to a consistent picture of eight biological categories involved in fibroblast aging, namely proteostasis, cell cycle and proliferation, development and differentiation, cell death, cell organization and cytoskeleton, response to stress, cell communication and signal transduction, as well as RNA metabolism and translation. The exhaustive analysis of protein and mRNA data revealed that 77% of the age-associated proteins were not linked to expression changes of the corresponding transcripts. This is in line with an associated miRNA study and led us to the conclusion that most of the age-associated alterations detected at the proteome level are likely caused post-transcriptionally rather than by differential gene expression. In summary, our findings led to the characterization of novel proteins potentially associated with fibroblast aging and revealed that primary cultures of in situ aged fibroblasts are characterized by moderate age-related proteomic changes comprising the multifactorial process of aging. PMID:25411231

  4. Accessing key steps of human tumor progression in vivo by using an avian embryo model

    NASA Astrophysics Data System (ADS)

    Hagedorn, Martin; Javerzat, Sophie; Gilges, Delphine; Meyre, Aurélie; de Lafarge, Benjamin; Eichmann, Anne; Bikfalvi, Andreas

    2005-02-01

    Experimental in vivo tumor models are essential for comprehending the dynamic process of human cancer progression, identifying therapeutic targets, and evaluating antitumor drugs. However, current rodent models are limited by high costs, long experimental duration, variability, restricted accessibility to the tumor, and major ethical concerns. To avoid these shortcomings, we investigated whether tumor growth on the chick chorio-allantoic membrane after human glioblastoma cell grafting would replicate characteristics of the human disease. Avascular tumors consistently formed within 2 days, then progressed through vascular endothelial growth factor receptor 2-dependent angiogenesis, associated with hemorrhage, necrosis, and peritumoral edema. Blocking of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor signaling pathways by using small-molecule receptor tyrosine kinase inhibitors abrogated tumor development. Gene regulation during the angiogenic switch was analyzed by oligonucleotide microarrays. Defined sample selection for gene profiling permitted identification of regulated genes whose functions are associated mainly with tumor vascularization and growth. Furthermore, expression of known tumor progression genes identified in the screen (IL-6 and cysteine-rich angiogenic inducer 61) as well as potential regulators (lumican and F-box-only 6) follow similar patterns in patient glioma. The model reliably simulates key features of human glioma growth in a few days and thus could considerably increase the speed and efficacy of research on human tumor progression and preclinical drug screening. angiogenesis | animal model alternatives | glioblastoma

  5. The transcriptional landscape of age in human peripheral blood

    PubMed Central

    Peters, Marjolein J.; Joehanes, Roby; Pilling, Luke C.; Schurmann, Claudia; Conneely, Karen N.; Powell, Joseph; Reinmaa, Eva; Sutphin, George L.; Zhernakova, Alexandra; Schramm, Katharina; Wilson, Yana A.; Kobes, Sayuko; Tukiainen, Taru; Nalls, Michael A.; Hernandez, Dena G.; Cookson, Mark R.; Gibbs, Raphael J.; Hardy, John; Ramasamy, Adaikalavan; Zonderman, Alan B.; Dillman, Allissa; Traynor, Bryan; Smith, Colin; Longo, Dan L.; Trabzuni, Daniah; Troncoso, Juan; van der Brug, Marcel; Weale, Michael E.; O'Brien, Richard; Johnson, Robert; Walker, Robert; Zielke, Ronald H.; Arepalli, Sampath; Ryten, Mina; Singleton, Andrew B.; Ramos, Yolande F.; Göring, Harald H. H.; Fornage, Myriam; Liu, Yongmei; Gharib, Sina A.; Stranger, Barbara E.; De Jager, Philip L.; Aviv, Abraham; Levy, Daniel; Murabito, Joanne M.; Munson, Peter J.; Huan, Tianxiao; Hofman, Albert; Uitterlinden, André G.; Rivadeneira, Fernando; van Rooij, Jeroen; Stolk, Lisette; Broer, Linda; Verbiest, Michael M. P. J.; Jhamai, Mila; Arp, Pascal; Metspalu, Andres; Tserel, Liina; Milani, Lili; Samani, Nilesh J.; Peterson, Pärt; Kasela, Silva; Codd, Veryan; Peters, Annette; Ward-Caviness, Cavin K.; Herder, Christian; Waldenberger, Melanie; Roden, Michael; Singmann, Paula; Zeilinger, Sonja; Illig, Thomas; Homuth, Georg; Grabe, Hans-Jörgen; Völzke, Henry; Steil, Leif; Kocher, Thomas; Murray, Anna; Melzer, David; Yaghootkar, Hanieh; Bandinelli, Stefania; Moses, Eric K.; Kent, Jack W.; Curran, Joanne E.; Johnson, Matthew P.; Williams-Blangero, Sarah; Westra, Harm-Jan; McRae, Allan F.; Smith, Jennifer A.; Kardia, Sharon L. R.; Hovatta, Iiris; Perola, Markus; Ripatti, Samuli; Salomaa, Veikko; Henders, Anjali K.; Martin, Nicholas G.; Smith, Alicia K.; Mehta, Divya; Binder, Elisabeth B.; Nylocks, K Maria; Kennedy, Elizabeth M.; Klengel, Torsten; Ding, Jingzhong; Suchy-Dicey, Astrid M.; Enquobahrie, Daniel A.; Brody, Jennifer; Rotter, Jerome I.; Chen, Yii-Der I.; Houwing-Duistermaat, Jeanine; Kloppenburg, Margreet; Slagboom, P. Eline; Helmer, Quinta; den Hollander, Wouter; Bean, Shannon; Raj, Towfique; Bakhshi, Noman; Wang, Qiao Ping; Oyston, Lisa J.; Psaty, Bruce M.; Tracy, Russell P.; Montgomery, Grant W.; Turner, Stephen T.; Blangero, John; Meulenbelt, Ingrid; Ressler, Kerry J.; Yang, Jian; Franke, Lude; Kettunen, Johannes; Visscher, Peter M.; Neely, G. Gregory; Korstanje, Ron; Hanson, Robert L.; Prokisch, Holger; Ferrucci, Luigi; Esko, Tonu; Teumer, Alexander; van Meurs, Joyce B. J.; Johnson, Andrew D.

    2015-01-01

    Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts. PMID:26490707

  6. The transcriptional landscape of age in human peripheral blood.

    PubMed

    Peters, Marjolein J; Joehanes, Roby; Pilling, Luke C; Schurmann, Claudia; Conneely, Karen N; Powell, Joseph; Reinmaa, Eva; Sutphin, George L; Zhernakova, Alexandra; Schramm, Katharina; Wilson, Yana A; Kobes, Sayuko; Tukiainen, Taru; Ramos, Yolande F; Göring, Harald H H; Fornage, Myriam; Liu, Yongmei; Gharib, Sina A; Stranger, Barbara E; De Jager, Philip L; Aviv, Abraham; Levy, Daniel; Murabito, Joanne M; Munson, Peter J; Huan, Tianxiao; Hofman, Albert; Uitterlinden, André G; Rivadeneira, Fernando; van Rooij, Jeroen; Stolk, Lisette; Broer, Linda; Verbiest, Michael M P J; Jhamai, Mila; Arp, Pascal; Metspalu, Andres; Tserel, Liina; Milani, Lili; Samani, Nilesh J; Peterson, Pärt; Kasela, Silva; Codd, Veryan; Peters, Annette; Ward-Caviness, Cavin K; Herder, Christian; Waldenberger, Melanie; Roden, Michael; Singmann, Paula; Zeilinger, Sonja; Illig, Thomas; Homuth, Georg; Grabe, Hans-Jörgen; Völzke, Henry; Steil, Leif; Kocher, Thomas; Murray, Anna; Melzer, David; Yaghootkar, Hanieh; Bandinelli, Stefania; Moses, Eric K; Kent, Jack W; Curran, Joanne E; Johnson, Matthew P; Williams-Blangero, Sarah; Westra, Harm-Jan; McRae, Allan F; Smith, Jennifer A; Kardia, Sharon L R; Hovatta, Iiris; Perola, Markus; Ripatti, Samuli; Salomaa, Veikko; Henders, Anjali K; Martin, Nicholas G; Smith, Alicia K; Mehta, Divya; Binder, Elisabeth B; Nylocks, K Maria; Kennedy, Elizabeth M; Klengel, Torsten; Ding, Jingzhong; Suchy-Dicey, Astrid M; Enquobahrie, Daniel A; Brody, Jennifer; Rotter, Jerome I; Chen, Yii-Der I; Houwing-Duistermaat, Jeanine; Kloppenburg, Margreet; Slagboom, P Eline; Helmer, Quinta; den Hollander, Wouter; Bean, Shannon; Raj, Towfique; Bakhshi, Noman; Wang, Qiao Ping; Oyston, Lisa J; Psaty, Bruce M; Tracy, Russell P; Montgomery, Grant W; Turner, Stephen T; Blangero, John; Meulenbelt, Ingrid; Ressler, Kerry J; Yang, Jian; Franke, Lude; Kettunen, Johannes; Visscher, Peter M; Neely, G Gregory; Korstanje, Ron; Hanson, Robert L; Prokisch, Holger; Ferrucci, Luigi; Esko, Tonu; Teumer, Alexander; van Meurs, Joyce B J; Johnson, Andrew D

    2015-01-01

    Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts. PMID:26490707

  7. [Development, human rights and woman's condition: a new age].

    PubMed

    Isaacs, S L

    1989-06-01

    After World War II (WWII) concern grew about the economic and social development of Third World countries. Most countries in Africa, Asia and the Middle East were European colonies while Latin America, even though independent was completely dominated by the US. These countries are characterized by: 1) a poor majority ruled by a small rich minority; 2) large rural populations migrating to the cities resulting in bottlenecks and unemployment; 3) bad health status with deteriorating nutritional states; 4) large families; 5) low levels of education (2/3 of the women in the world are illiterate and 90% live in 17 countries); 5) high levels of corruption in public positions; 6) governments ruled by a military dictator; 7) women in the lowest positions with limited legal rights. After WWII the Marshall Plan was instituted in developing countries (LDCs) to provide economic aid to development a model that used per capita income to measure a country's progress. During the 70's and 80's this model was questioned and more emphasis was put on the need for social and institutional development before investing in economic development. The World Bank and USAID have been promoting the role of the public sector, a strategy that has lowered inflation but has also affected the poor in many countries. For example, infant mortality in Brazil is higher now than 10 years ago. A wise development policy should recognize the need of LDCs to develop their own models while emphasizing agricultural development rather than industrial. Development is never accomplished until every citizen participates in their community. Improving the status of women is not only a human right but a high priority in achieving development. Women in LDCs only have partial rights--they cannot own land, nor inherit, and are not given any credit. Development is not only increasing the per capita income, it includes improving health, education, nutrition, and the quality of life of all its citizens. International law

  8. Five-Year Progression of Refractive Errors and Incidence of Myopia in School-Aged Children in Western China

    PubMed Central

    Zhou, Wen-Jun; Zhang, Yong-Ye; Li, Hua; Wu, Yu-Fei; Xu, Ji; Lv, Sha; Li, Ge; Liu, Shi-Chun; Song, Sheng-Fang

    2016-01-01

    Background To determine the change in refractive error and the incidence of myopia among school-aged children in the Yongchuan District of Chongqing City, Western China. Methods A population-based cross-sectional survey was initially conducted in 2006 among 3070 children aged 6 to 15 years. A longitudinal follow-up study was then conducted 5 years later between November 2011 and March 2012. Refractive error was measured under cycloplegia with autorefraction. Age, sex, and baseline refractive error were evaluated as risk factors for progression of refractive error and incidence of myopia. Results Longitudinal data were available for 1858 children (60.5%). The cumulative mean change in refractive error was −2.21 (standard deviation [SD], 1.87) diopters (D) for the entire study population, with an annual progression of refraction in a myopic direction of −0.43 D. Myopic progression of refractive error was associated with younger age, female sex, and higher myopic or hyperopic refractive error at baseline. The cumulative incidence of myopia, defined as a spherical equivalent refractive error of −0.50 D or more, among initial emmetropes and hyperopes was 54.9% (95% confidence interval [CI], 45.2%–63.5%), with an annual incidence of 10.6% (95% CI, 8.7%–13.1%). Myopia was found more likely to happen in female and older children. Conclusions In Western China, both myopic progression and incidence of myopia were higher than those of children from most other locations in China and from the European Caucasian population. Compared with a previous study in China, there was a relative increase in annual myopia progression and annual myopia incidence, a finding which is consistent with the increasing trend on prevalence of myopia in China. PMID:26875599

  9. Severity of Age-Related Macular Degeneration in 1 Eye and the Incidence and Progression of Age-Related Macular Degeneration in the Fellow Eye

    PubMed Central

    Gangnon, Ronald E.; Lee, Kristine E.; Klein, Barbara E. K.; Iyengar, Sudha K.; Sivakumaran, Theru A.; Klein, Ronald

    2014-01-01

    Importance Previous studies of the implications of age-related macular degeneration (AMD) severity in one eye on prognosis for the fellow eye have focused on incidence of neovascular AMD in the fellow eye of subjects with neovascular AMD in the other eye. It is unclear to what extent AMD severity in one eye impacts incidence, progression, and regression of AMD in its fellow eye across the entire range of AMD severity. Objective To investigate the impact of severity of AMD in one eye on incidence, progression, and regression of AMD in the fellow eye. Design, Setting and Participants The Beaver Dam Eye Study, a longitudinal population-based study of age-related eye diseases conducted in the city and township of Beaver Dam, Wisconsin. Examinations were performed every 5 years over a 20-year period (1988-1990 through 2008-2010). Study participants (N=4379) were aged 43 to 86 years at the baseline examination. At baseline and up to 4 subsequent examinations, retinal photographs were taken. Exposures Age, sex, and the Y402H polymorphism in the Complement Factor H gene on chromosome 1q; AMD severity in the fellow eye. Main Outcome Measures Incidence, progression, and regression of AMD assessed in retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System; mortality. Results More severe AMD in one eye was associated with increased incidence and progression of AMD in its fellow eye (Level 1 to 2: hazard ratio [HR] 4.90, 95% confidence interval [CI] 4.26-5.63; Level 2 to 3: HR 2.09, CI 1.42-3.06; Level 3 to 4: HR 2.38, CI 1.74-3.25; Level 4 to Level 5: HR 2.46, CI 1.65-3.66). Less severe AMD in one eye was associated with less progression of AMD in its fellow eye (Level 2 to 3: HR 0.42, CI 0.33-0.55; Level 3 to 4: HR 0.50, CI 0.34-0.83). We estimate that 51% of subjects who develop any AMD always maintain AMD severity states within 1 step of each other between eyes; 90% stay within 2 steps. Conclusions and Relevance Using multi-state models, we

  10. Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression.

    PubMed

    Lin, Jer-An; Wu, Chi-Hao; Lu, Chi-Cheng; Hsia, Shih-Min; Yen, Gow-Chin

    2016-08-01

    In recent years, glycative stress from exogenous or endogenous advanced glycation end products (AGEs) and highly reactive dicarbonyls has gained great attention for its putative effects on cancer development. AGEs are a group of compounds formed from the complex chemical reaction of reducing sugars with compounds containing an amino group. AGEs bind to and activate the receptor for AGEs (RAGE), which is a predominant modulator of inflammation-associated cancer, and AGEs induce reactive oxygen species that are an important regulator of the hallmarks of cancer. Dicarbonyls, which are formed during glycolysis, lipid oxidation, or protein degradation, include glyoxal, methylglyoxal, and 3-deoxyglucosone and are regarded as major precursors of AGEs. These dicarbonyls not only fuel the AGE pool in living organisms but also evoke carbonyl stress, which may contribute to the carbonylative damage of carbohydrates, lipids, proteins, or DNA. Carbonylative damage then leads to many lesions, some of which are implicated in the pathogenesis of cancer. In this review, studies regarding the effects of AGEs and dicarbonyls on cancer onset or progression are systematically discussed, and the utilization of AGE inhibitors and dicarbonyl scavengers in cancer therapy are noted. PMID:26774083

  11. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression.

    PubMed

    Sharma, Ankur; Yeow, Wen-Shuz; Ertel, Adam; Coleman, Ilsa; Clegg, Nigel; Thangavel, Chellappagounder; Morrissey, Colm; Zhang, Xiaotun; Comstock, Clay E S; Witkiewicz, Agnieszka K; Gomella, Leonard; Knudsen, Erik S; Nelson, Peter S; Knudsen, Karen E

    2010-12-01

    Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes. PMID:21099110

  12. PET Imaging of Tau Deposition in the Aging Human Brain.

    PubMed

    Schöll, Michael; Lockhart, Samuel N; Schonhaut, Daniel R; O'Neil, James P; Janabi, Mustafa; Ossenkoppele, Rik; Baker, Suzanne L; Vogel, Jacob W; Faria, Jamie; Schwimmer, Henry D; Rabinovici, Gil D; Jagust, William J

    2016-03-01

    Tau pathology is a hallmark of Alzheimer's disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition. PMID:26938442

  13. The promise of human embryonic stem cells in aging-associated diseases

    PubMed Central

    Yabut, Odessa; Bernstein, Harold S.

    2011-01-01

    Aging-associated diseases are often caused by progressive loss or dysfunction of cells that ultimately affect the overall function of tissues and organs. Successful treatment of these diseases could benefit from cell-based therapy that would regenerate lost cells or otherwise restore tissue function. Human embryonic stem cells (hESCs) promise to be an important therapeutic candidate in treating aging-associated diseases due to their unique capacity for self-renewal and pluripotency. To date, there are numerous hESC lines that have been developed and characterized. We will discuss how hESC lines are derived, their molecular and cellular properties, and how their ability to differentiate into all three embryonic germ layers is determined. We will also outline the methods currently employed to direct their differentiation into populations of tissue-specific, functional cells. Finally, we will highlight the general challenges that must be overcome and the strategies being developed to generate highly-purified hESC-derived cell populations that can safely be used for clinical applications. PMID:21566262

  14. (Mis)Understanding Human Beings: Theory, Value, and Progress in Education Research

    ERIC Educational Resources Information Center

    Hostetler, Karl

    2010-01-01

    There is renewed interest in what can be called an "experimentist" approach to education research. The claim is that if researchers would focus on experiments and "evidence-based" policies and practices, irreversible progress in education can be achieved. This experimentist approach cannot provide the understanding of knowledge and human beings…

  15. Normal aging in rats and pathological aging in human Alzheimer's disease decrease FAAH activity: modulation by cannabinoid agonists.

    PubMed

    Pascual, A C; Martín-Moreno, A M; Giusto, N M; de Ceballos, M L; Pasquaré, S J

    2014-12-01

    Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Aβ(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging. PMID:25456842

  16. Five-year incidence, progression and risk factors for age-related macular degeneration: The Age, Gene/Environment Susceptibility Study

    PubMed Central

    Jonasson, Fridbert; Fisher, Diana E.; Eiriksdottir, Gudny; Sigurdsson, Sigurdur; Klein, Ronald; Launer, Lenore J; Harris, Tamara; Gudnason, Vilmundur; Cotch, Mary Frances

    2014-01-01

    Objective To investigate the incidence and progression of age related m acular degeneration (AMD) and associated risk factors. Design Population-based prospective cohort study. Participants 2868 participants from the Age Gene/Environment Susceptibility-Reykjavik Study with retinal data at baseline and five-year follow-up. Methods Digital macular photographs were graded for presence of AMD. Participants completed a questionnaire and extensive clinical battery. Biomarkers were assessed. Risk factors for AMD were analyzed using multivariate regression analysis with odds ratios (ORs) and 95% confidence intervals (CIs). Main outcome measures AMD, defined as early or late. Results Among 2196 participants free of AMD at baseline, 14.9% developed incident AMD. In multivariate models, incident AMD was significantly associated with age (OR per year 1.14 (95% CI 1.11, 1.17)), current smoking (OR 2.07 (1.38, 3.11)), former smoking (OR 1.36 (1.04, 1.79)), plasma high-density lipoprotein (HDL) cholesterol level (OR 1.62 per mmol/L (1.19, 2.22)), and body mass index (BMI) (OR 1.04 per kg/m2 (1.01, 1.07)). Among 563 participants with early AMD at baseline, 22.7% progressed to late AMD (11.0% pure geographic atrophy (GA) and 11.7% exudative AMD). In multivariate analyses, age was significantly associated with progression to GA (OR 1.14 (1.07, 1.21)) and exudative AMD (OR 1.08 (1.01, 1.14)). Adjusting for age, female sex was associated with exudative AMD (OR 2.10 (1.10, 3.98)) and plasma HDL cholesterol with GA (OR 2.03 per mmol/L (1.02, 4.05)). Conclusion By age 85 years, 57.4% of participants had signs of AMD. Age, smoking, plasma HDL cholesterol, BMI and female sex are associated with AMD. Elevated HDL cholesterol is associated with GA development. PMID:24768241

  17. Characterization of Skin Aging-Associated Secreted Proteins (SAASP) Produced by Dermal Fibroblasts Isolated from Intrinsically Aged Human Skin.

    PubMed

    Waldera Lupa, Daniel M; Kalfalah, Faiza; Safferling, Kai; Boukamp, Petra; Poschmann, Gereon; Volpi, Elena; Götz-Rösch, Christine; Bernerd, Francoise; Haag, Laura; Huebenthal, Ulrike; Fritsche, Ellen; Boege, Fritz; Grabe, Niels; Tigges, Julia; Stühler, Kai; Krutmann, Jean

    2015-08-01

    Most molecular hallmarks of cellular senescence have been identified in studies of cells aged in vitro by driving them into replicative or stress-induced senescence. Comparatively, less is known about the characteristic features of cells that have aged in vivo. Here we provide a systematic molecular analysis of normal human dermal fibroblasts (NHDFs) that were isolated from intrinsically aged human skin of young versus middle aged versus old donors. Intrinsically aged NHDFs in culture exhibited more frequently nuclear foci positive for p53 binding protein 1 and promyelocytic leukemia protein reminiscent of 'DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS)'. Formation of such foci was neither accompanied by increased DNA double strand breaks, nor decreased cell viability, nor telomere shortening. However, it was associated with the development of a secretory phenotype, indicating incipient cell senescence. By quantitative analysis of the entire secretome present in conditioned cell culture supernatant, combined with a multiplex cytokine determination, we identified 998 proteins secreted by intrinsically aged NHDFs in culture. Seventy of these proteins exhibited an age-dependent secretion pattern and were accordingly denoted 'skin aging-associated secreted proteins (SAASP)'. Systematic comparison of SAASP with the classical senescence-associated secretory phenotype (SASP) revealed that matrix degradation as well as proinflammatory processes are common aspects of both conditions. However, secretion of 27 proteins involved in the biological processes of 'metabolism' and 'adherens junction interactions' was unique for NHDFs isolated from intrinsically aged skin. In conclusion, fibroblasts isolated from intrinsically aged skin exhibit some, but not all, molecular hallmarks of cellular senescence. Most importantly, they secrete a unique pattern of proteins that is distinct from the canonical SASP and might reflect specific processes of skin aging

  18. New 40Ar/39Ar Ages for Savai'i Island Reinstate Samoa as a Hotspot Trail with a Linear Age Progression

    NASA Astrophysics Data System (ADS)

    Koppers, A. A.; Russell, J. A.; Staudigel, H.; Hart, S. R.

    2006-12-01

    The volcanic islands and seamounts of the Samoan Archipelago have long been considered problematic in terms of the hotspot hypothesis. Existing K/Ar and 40Ar/39Ar measurements on subaerial samples from the Samoan islands have consistently given ages that are too young by several Myrs, conflicting with the expected linear age progression model. Previous data from the volcanic series and cones on Savai'i Island gave a range of ages between 0.2 and 2.1 Ma. This is in contrast to an age of 5.2 Ma that a Pacific plate motion of 7.1 cm/yr would predict for the onset of the shield building stage on Savai'i (Workman et al. 2004). The oldest shield ages for the islands of Upolu (2.7 My) and Tutuila (1.6 My) young eastward, toward the volcanically active Vailulu'u seamount that marks the current location of the Samoan hotspot (Hart et al. 2000; Staudigel et al. 2006). However, these ages are younger than predicted by the plate-speed model with 4.4 My and 2.7 My, respectively. The omnipresence of only young post-erosional volcanism on Savai'i has lead to extensive discussions on the origin of Samoan volcanism, and is often used as an argument against a possible hotspot and mantle plume origin. We present new 40Ar/39Ar data on volcanic samples from the deep flanks and rifts of Savai'i and a group of Samoan seamounts that were dredged during the ALIA Expedition. Twelve ages from eight different dredge locations confirm the predicted 7.1 cm/yr age progression for the Samoan hotspot. Three different volcanic samples from dredge ALIA-115, on the deepest portion of the SW flank of Savai'i Island, give indistinguishable ages (2σ confidence level) ranging from 4.99 to 5.21 Ma. In addition, a sample from dredge ALIA-128, on the NE flank of Savai'i, gives an age of 4.74 Ma. These results clearly demonstrate that the onset of the shield-building stage on Savai'i occurred much earlier than the oldest volcanics (2.1 Ma) sampled subaerially on the island. Sr-Nd-Pb isotopes and trace

  19. MALDI Imaging Mass Spectrometry Spatially Maps Age-Related Deamidation and Truncation of Human Lens Aquaporin-0

    PubMed Central

    Wenke, Jamie L.; Rose, Kristie L.; Spraggins, Jeffrey M.; Schey, Kevin L.

    2015-01-01

    Purpose To spatially map human lens Aquaporin-0 (AQP0) protein modifications, including lipidation, truncation, and deamidation, from birth through middle age using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS). Methods Human lens sections were water-washed to facilitate detection of membrane protein AQP0. We acquired MALDI images from eight human lenses ranging in age from 2 months to 63 years. In situ tryptic digestion was used to generate peptides of AQP0 and peptide images were acquired on a 15T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Peptide extracts were analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and database searched to identify peptides observed in MALDI imaging experiments. Results Unmodified, truncated, and fatty acid–acylated forms of AQP0 were detected in protein imaging experiments. Full-length AQP0 was fatty acid acylated in the core and cortex of young (2- and 4-month) lenses. Acylated and unmodified AQP0 were C-terminally truncated in older lens cores. Deamidated tryptic peptides (+0.9847 Da) were mass resolved from unmodified peptides by FTICR MS. Peptide images revealed differential localization of un-, singly-, and doubly-deamidated AQP0 C-terminal peptide (239–263). Deamidation was present at 4 months and increases with age. Liquid chromatography–MS/MS results indicated N246 undergoes deamidation more rapidly than N259. Conclusions Results indicated AQP0 fatty acid acylation and deamidation occur during early development. Progressive age-related AQP0 processing, including deamidation and truncation, was mapped in human lenses as a function of age. The localization of these modified AQP0 forms suggests where AQP0 functions may change throughout lens development and aging. PMID:26574799

  20. Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans.

    PubMed

    McGregor, Robin A; Poppitt, Sally D; Cameron-Smith, David

    2014-09-01

    Progressive age-related changes in skeletal muscle mass and composition, underpin decreases in muscle function, which can inturn lead to impaired mobility and quality of life in older adults. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression in skeletal muscle and are associated with aging. Accumulating evidence suggests that miRNAs play an important role in the age-related changes in skeletal muscle mass, composition and function. At the cellular level, miRNAs have been demonstrated to regulate muscle cell proliferation and differentiation. Furthermore, miRNAs are involved in the transitioning of muscle stem cells from a quiescent, to either an activated or senescence state. Evidence from animal and human studies has shown miRNAs are modulated in muscle atrophy and hypertrophy. In addition, miRNAs have been implicated in changes in muscle fiber composition, fat infiltration and insulin resistance. Both exercise and dietary interventions can combat age-related changes in muscle mass, composition and function, which may be mediated by miRNA modulation in skeletal muscle. Circulating miRNA species derived from myogenic cell populations represent potential biomarkers of aging muscle and the molecular responses to exercise or diet interventions, but larger validation studies are required. In future therapeutic approaches targeting miRNAs, either through exercise, diet or drugs may be able to slow down or prevent the age-related changes in skeletal muscle mass, composition, function, hence help maintain mobility and quality of life in old age. PMID:24833328

  1. Human Age Estimation Based on Locality and Ordinal Information.

    PubMed

    Li, Changsheng; Liu, Qingshan; Dong, Weishan; Zhu, Xiaobin; Liu, Jing; Lu, Hanqing

    2015-11-01

    In this paper, we propose a novel feature selection-based method for facial age estimation. The face aging is a typical temporal process, and facial images should have certain ordinal patterns in the aging feature space. From the geometrical perspective, a facial image can be usually seen as sampled from a low-dimensional manifold embedded in the original high-dimensional feature space. Thus, we first measure the energy of each feature in preserving the underlying local structure information and the ordinal information of the facial images, respectively, and then we intend to learn a low-dimensional aging representation that can maximally preserve both kinds of information. To further improve the performance, we try to eliminate the redundant local information and ordinal information as much as possible by minimizing nonlinear correlation and rank correlation among features. Finally, we formulate all these issues into a unified optimization problem, which is similar to linear discriminant analysis in format. Since it is expensive to collect the labeled facial aging images in practice, we extend the proposed supervised method to a semi-supervised learning mode including the semi-supervised feature selection method and the semi-supervised age prediction algorithm. Extensive experiments are conducted on the FACES dataset, the Images of Groups dataset, and the FG-NET aging dataset to show the power of the proposed algorithms, compared to the state-of-the-arts. PMID:26470062

  2. Molecular consequences of psychological stress in human aging.

    PubMed

    Moreno-Villanueva, M; Bürkle, A

    2015-08-01

    Psychological stress has often been described as a feeling of being overwhelmed by the necessity of constant adjustment to an individual's changing environment. Stress affects people of all ages, but the lives of the elderly may particularly be affected. Major changes can cause anxiety leading to feelings of insecurity and/or loss of self-esteem and depression. The cellular mechanisms underlying psychological stress are poorly understood. This review focuses on the physical and molecular consequences of psychological stress linked to aging processes and, in particular, how molecular changes induced by psychological stress can compromise healthy aging. PMID:25481270

  3. Being human in a global age of technology.

    PubMed

    Whelton, Beverly J B

    2016-01-01

    This philosophical enquiry considers the impact of a global world view and technology on the meaning of being human. The global vision increases our awareness of the common bond between all humans, while technology tends to separate us from an understanding of ourselves as human persons. We review some advances in connecting as community within our world, and many examples of technological changes. This review is not exhaustive. The focus is to understand enough changes to think through the possibility of healthcare professionals becoming cyborgs, human-machine units that are subsequently neither human and nor machine. It is seen that human technology interfaces are a different way of interacting but do not change what it is to be human in our rational capacities of providing meaningful speech and freely chosen actions. In the highly technical environment of the ICU, expert nurses work in harmony with both the technical equipment and the patient. We used Heidegger to consider the nature of equipment, and Descartes to explore unique human capacities. Aristotle, Wallace, Sokolowski, and Clarke provide a summary of humanity as substantial and relational. PMID:26608482

  4. Oxidative Stress, Aging and CNS disease in the Canine Model of Human Brain Aging

    PubMed Central

    Head, Elizabeth; Rofina, Jaime; Zicker, Steven

    2008-01-01

    SYNOPSIS Decline in cognitive functions that accompany aging in dogs may have a biological basis, and many of the disorders associated with aging in canines may be mitigated through dietary modifications that incorporate specific nutraceuticals. Based on previous research and the results of both laboratory and clinical studies – antioxidants may be one class of nutraceutical that provides benefits to aged dogs. Brains of aged dogs accumulate oxidative damage to proteins and lipids, which may lead to dysfunction of neuronal cells. The production of free radicals and lack of increase in compensatory antioxidant enzymes may lead to detrimental modifications to important macromolecules within neurons. Reducing oxidative damage through food ingredients rich in a broad spectrum of antioxidants significantly improves, or slows the decline of, learning and memory in aged dogs. However, determining all effective compounds and combinations, dosage ranges, as well as when to initiate intervention and long term effects constitute gaps in our current knowledge. PMID:18249248

  5. Baroreceptor reflex sensitivity in human neonates: the effect of postmenstrual age

    PubMed Central

    Andriessen, Peter; Oetomo, Sidarto Bambang; Peters, Chris; Vermeulen, Barbara; Wijn, Pieter FF; Blanco, Carlos E

    2005-01-01

    We performed a cross-sectional study in human infants to determine if indices of R–R interval variability, systolic blood pressure (SBP) variability, and baroreceptor reflex sensitivity change with postmenstrual age (PMA: gestational age + postnatal age). The electrocardiogram, arterial SBP and respiration were recorded in clinically stable infants (PMA, 28–42 weeks) in the quiet sleep state in the first days after birth. (Cross-)spectral analyses of R–R interval series and SBP series were performed to calculate the power of low-frequency (LF, indicating baroreceptor reflex activity, 0.04–0.15 Hz) and high-frequency (HF, indicating parasympathetic activity, individualized between the p-10 and p-90 values of respiratory frequency) fluctuations, and transfer function phase and gain. The mean R–R interval, and LF and HF spectral powers of R–R interval series increased with PMA. The mean SBP increased with PMA, but not the LF and HF spectral powers of SBP series. In the LF range, cross-spectral analysis showed high coherence values (> 0.5) with a consistent negative phase shift between R–R interval and SBP, indicating a ∼3 s lag in R–R interval changes in relation to SBP. Baroreceptor reflex sensitivity, calculated from LF transfer gain, increased significantly with PMA, from 5 (preterm) to 15 ms mmHg−1 (term). Baroreceptor reflex sensitivity correlated significantly with the (LF and) HF spectral powers of R–R interval series, but not with the LF and HF spectral powers of SBP series. The principal conclusions are that baroreceptor reflex sensitivity and spectral power in R–R interval series increase in parallel with PMA, suggesting a progressive vagal maturation with PMA. PMID:16051623

  6. Behavior analysis and the study of human aging

    PubMed Central

    Derenne, Adam; Baron, Alan

    2002-01-01

    As the population of older adults continues to rise, psychologists along with other behavioral and social scientists have shown increasing interest in this age group. Although behavior analysts have contributed to research on aging, the focus has been on applications that remedy age-related deficits, rather than a concern with aging as a developmental process. In particular, there has been little interest in the central theoretical questions that have guided gerontologists. How does behavior change with advancing years, and what are the sources of those changes? We consider the possibility that this neglect reflects the long-standing commitment of behavior analysts to variables that can be experimentally manipulated, a requirement that excludes the key variable—age itself. We review the options available to researchers and present strategies that minimize deviations from the traditional features of behavior-analytic designs. Our comments are predicated on the view that aging issues within contemporary society are far too important for behavior analysts to ignore. PMID:22478383

  7. Chronologic and actinically induced aging in human facial skin

    SciTech Connect

    Gilchrest, B.A.; Szabo, G.; Flynn, E.; Goldwyn, R.M.

    1983-06-01

    Clinical and histologic stigmata of aging are much more prominent in habitually sun-exposed skin than in sun-protected skin, but other possible manifestations of actinically induced aging are almost unexplored. We have examined the interrelation of chronologic and actinic aging using paired preauricular (sun-exposed) and postauricular (sun-protected) skin specimens. Keratinocyte cultures derived from sun-exposed skin consistently had a shorter in vitro lifespan but increased plating efficiency compared with cultures derived from adjacent sun-protected skin of the same individual, confirming a previous study of different paired body sites. Electron microscopic histologic sections revealed focal abnormalities of keratinocyte proliferation and alignment in vitro especially in those cultures derived from sun-exposed skin and decreased intercellular contact in stratified colonies at late passage, regardless of donor site. One-micron histologic sections of the original biopsy specimens revealed no striking site-related keratinocyte alterations, but sun-exposed specimens had fewer epidermal Langerhans cells (p less than 0.001), averaging approximately 50 percent the number in sun-protected skin, a possible exaggeration of the previously reported age-associated decrease in this cell population. These data suggest that sun exposure indeed accelerates aging by several criteria and that, regardless of mechanism, environmental factors may adversely affect the appearance and function of aging skin in ways amenable to experimental quantitation.

  8. An age-specific kinetic model of lead metabolism in humans.

    PubMed Central

    Leggett, R W

    1993-01-01

    Although considerable progress has been made in recent years in reducing human exposures to lead, the potential for high intake of this contaminant still exists in millions of homes and in many occupational settings. Moreover, there is growing evidence that levels of lead intake considered inconsequential just a few years ago can result in subtle, adverse health effects, particularly in children. Consequently, there have been increased efforts by health protection agencies to develop credible, versatile methods for relating levels of lead in environmental media to levels in blood and tissues of exposed humans of all ages. In a parallel effort motivated largely by the Chernobyl nuclear accident, the International Commission on Radiological Protection (ICRP) is assembling a set of age-specific biokinetic models for calculating radiation doses from environmentally important radionuclides, including radioisotopes of lead. This paper describes a new age-specific biokinetic model for lead originally developed for the ICRP but expanded to include additional features that are useful for consideration of lead as a chemical toxin. The model is developed within a generic, physiologically motivated framework designed to address a class of calciumlike elements. This framework provides a useful setting in which to synthesize experimental, occupational, and environmental data on lead and exploit common physiological properties of lead and the alkaline earth elements. The modular design is intended to allow researchers to modify specific parameter values or model components to address special problems in lead toxicology or to incorporate new information. Transport of lead between compartments is assumed to follow linear, first-order kinetics provided the concentration in red blood cells remains below a nonlinear threshold level, but a nonlinear relation between plasma lead and red blood cell lead is modeled for concentrations above that level. The model is shown to be consistent

  9. Evolution of Human Rights in the Age of Biotechnology.

    ERIC Educational Resources Information Center

    Hron, Benjamin

    1998-01-01

    Considers how biotechnology affects human-rights issues; in particular, the need for reexamining concerns about reproductive technology, the rights of indigenous peoples, and the rights of future generations. Maintains that the new areas for human-rights discussions, such as germ-line manipulation and genetic screening, are unprecedented concerns…

  10. Human gut microbiome viewed across age and geography

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, we characterized bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy child...

  11. Progressive squamous epithelial neoplasia in K14-human papillomavirus type 16 transgenic mice.

    PubMed Central

    Arbeit, J M; Münger, K; Howley, P M; Hanahan, D

    1994-01-01

    To model human papillomavirus-induced neoplastic progression, expression of the early region of human papillomavirus type 16 (HPV16) was targeted to the basal cells of the squamous epithelium in transgenic mice, using a human keratin 14 (K14) enhancer/promoter. Twenty-one transgenic founder mice were produced, and eight lines carrying either wild-type or mutant HPV16 early regions that did not express the E1 or E2 genes were established. As is characteristic of human cancers, the E6 and E7 genes remained intact in these mutants. The absence of E1 or E2 function did not influence the severity of the phenotype that eventually developed in the transgenic mice. Hyperplasia, papillomatosis, and dysplasia appeared at multiple epidermal and squamous mucosal sites, including ear and truncal skin, face, snout and eyelids, and anus. The ears were the most consistently affected site, with pathology being present in all lines with 100% penetrance. This phenotype also progressed through discernible stages. An initial mild hyperplasia was followed by hyperplasia, which further progressed to dysplasia and papillomatosis. During histopathological progression, there was an incremental increase in cellular DNA synthesis, determined by 5-bromo-2'-deoxyuridine incorporation, and a profound perturbation in keratinocyte terminal differentiation, as revealed by immunohistochemistry to K5, K14, and K10 and filaggrin. These K14-HPV16 transgenic mice present an opportunity to study the role of the HPV16 oncogenes in the neoplastic progression of squamous epithelium and provide a model with which to identify genetic and epigenetic factors necessary for carcinogenesis. Images PMID:7515971

  12. Correlation of chromosome patterns in human leukemic cells with exposure to chemicals and/or radiation. Progress report, July 1992--August 1993

    SciTech Connect

    Rowley, J.D.

    1993-09-01

    Progress in identification of chromosomal transformations associated with leukemogenesis is described. In particular progress in DNA cloning of chromosomal break points in human cancer patients is described.

  13. Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options.

    PubMed

    Vermeij, Wilbert P; Hoeijmakers, Jan H J; Pothof, Joris

    2016-01-01

    Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology. PMID:26514200

  14. Effects of age and expertise on tactile learning in humans.

    PubMed

    Reuter, Eva-Maria; Voelcker-Rehage, Claudia; Vieluf, Solveig; Godde, Ben

    2014-08-01

    Repetitive tactile stimulation is a well-established tool for inducing somatosensory cortical plasticity and changes in tactile perception. Previous studies have suggested that baseline performance determines the amount of stimulation-induced learning differently in specific populations. Older adults with lower baseline performance than young adults, but also experts, with higher baseline performance than non-experts of the same age, have been found to profit most from such interventions. This begs the question of how age-related and expertise-related differences in tactile learning are reflected in neurophysiological correlates. In two experiments, we investigated how tactile learning depends on age (experiment 1) and expertise (experiment 2). We assessed tactile spatial and temporal discrimination accuracy and event-related potentials (ERPs) in 57 persons of different age and expertise groups before and after a 30-min tactile stimulation intervention. The intervention increased accuracy in temporal (found in experiment 1) and spatial (found in experiment 2) discrimination. Experts improved more than non-experts in spatial discrimination. Lower baseline performance was associated with higher learning gain in experts and non-experts. After the intervention, P300 latencies were reduced in young adults and amplitudes were increased in late middle-aged adults in the temporal discrimination task. Experts showed a steeper P300 parietal-to-frontal gradient after the stimulation. We demonstrated that tactile stimulation partially reverses the age-related decline in late middle-aged adults and increases processing speed in young adults. We further showed that learning gain depends on baseline performance in both non-experts and experts. In experts, however, the upper limit for learning seems to be shifted to a higher level. PMID:24863287

  15. The Membrane Attack Complex in Aging Human Choriocapillaris

    PubMed Central

    Mullins, Robert F.; Schoo, Desi P.; Sohn, Elliott H.; Flamme-Wiese, Miles J.; Workamelahu, Grefachew; Johnston, Rebecca M.; Wang, Kai; Tucker, Budd A.; Stone, Edwin M.

    2015-01-01

    Age-related macular degeneration (AMD) is a common disease that can result in severe visual impairment. Abnormal regulation of the complement system has been implicated in its pathogenesis, and CFH polymorphisms contribute substantially to risk. How these polymorphisms exert their effects is poorly understood. We performed enzyme-linked immunosorbent assay (ELISA) analysis on young, aged, and AMD choroids to determine the abundance of the membrane attack complex (MAC) and performed immunofluorescence studies on eyes from 117 donors to evaluate the MAC in aging, early AMD, and advanced AMD. Morphometric studies were performed on eyes with high- or low-risk CFH genotypes. ELISA confirmed that MAC increases significantly with aging and with AMD. MAC was localized to Bruch’s membrane and the choriocapillaris and was detectable at low levels as early as 5 years of age. Hard drusen were labeled with anti-MAC antibody, but large or confluent drusen and basal deposits were generally unlabeled. Labeling of retinal pigment epithelium was observed in some cases of advanced AMD, but not in early disease. Eyes homozygous for the high-risk CFH genotype had thinner choroids than low-risk homozygotes (P < 0.05). These findings suggest that increased complement activation in AMD and in high-risk genotypes can lead to loss of endothelial cells in early AMD. Treatments to protect the choriocapillaris in early AMD are needed. PMID:25204844

  16. Sepsis in Old Age: Review of Human and Animal Studies

    PubMed Central

    Starr, Marlene E; Saito, Hiroshi

    2014-01-01

    Sepsis is a serious problem among the geriatric population as its incidence and mortality rates dramatically increase with advanced age. Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy that rescues elderly patients with severe sepsis. Recognition of this problem is relatively low as compared to other age-associated diseases. The disparity between clinical and basic studies is a problem, and this is likely due, in part, to the fact that most laboratory animals used for sepsis research are not old while the majority of sepsis cases occur in the geriatric population. The objective of this article is to review recent epidemiological studies and clinical observations, and compare these with findings from basic laboratory studies which have used aged animals in experimental sepsis. PMID:24729938

  17. Epigenomic maintenance through dietary intervention can facilitate DNA repair process to slow down the progress of premature aging.

    PubMed

    Ghosh, Shampa; Sinha, Jitendra Kumar; Raghunath, Manchala

    2016-09-01

    DNA damage caused by various sources remains one of the most researched topics in the area of aging and neurodegeneration. Increased DNA damage causes premature aging. Aging is plastic and is characterised by the decline in the ability of a cell/organism to maintain genomic stability. Lifespan can be modulated by various interventions like calorie restriction, a balanced diet of macro and micronutrients or supplementation with nutrients/nutrient formulations such as Amalaki rasayana, docosahexaenoic acid, resveratrol, curcumin, etc. Increased levels of DNA damage in the form of double stranded and single stranded breaks are associated with decreased longevity in animal models like WNIN/Ob obese rats. Erroneous DNA repair can result in accumulation of DNA damage products, which in turn result in premature aging disorders such as Hutchinson-Gilford progeria syndrome. Epigenomic studies of the aging process have opened a completely new arena for research and development of drugs and therapeutic agents. We propose here that agents or interventions that can maintain epigenomic stability and facilitate the DNA repair process can slow down the progress of premature aging, if not completely prevent it. © 2016 IUBMB Life, 68(9):717-721, 2016. PMID:27364681

  18. Ageing and colony-forming efficiency of human hair follicle keratinocytes.

    PubMed

    Lecardonnel, Jennifer; Deshayes, Nathalie; Genty, Gaïanne; Parent, Nathalie; Bernard, Bruno A; Rathman-Josserand, Michelle; Paris, Maryline

    2013-09-01

    The decline of tissue regenerative potential of skin and hair is a hallmark of physiological ageing and may be associated with age-related changes in tissue-specific stem cells and/or their environment. Human hair follicles (hHF) contain keratinocytes having the property of stem cells such as clonogenic potential. Growth capacity of hHF keratinocytes shows that most of the colony-forming cells are classified as holoclones, meroclones or paraclones when analysed in a clonal assay (Cell, Volume 76, page 1063). Despite the well-known impact of ageing on human hair growth, little is known about changes in hHF keratinocyte clonogenic potential with age. This study aimed at assessing the clone-forming efficiency (CFE) of hHF keratinocytes from three age groups of human donors. It demonstrates that ageing affects hHF keratinocyte CFE. PMID:23947676

  19. Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes

    PubMed Central

    Berman, Albert E.; Leontieva, Olga V.; Natarajan, Venkatesh; McCubrey, James A.; Demidenko, Zoya N.; Nikiforov, Mikhail A.

    2012-01-01

    It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the “hyperfunction theory”, which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin). These pathways consist of different enzymes, mostly kinases, but also phosphatases, deacetylases, GTPases, and some other molecules that cause overactivation of normal cellular functions. Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age-related diseases. As was emphasized by the author of the “hyperfunction model”, many (or actually all) of them also play roles in cancer. So these “participants” in pro-aging signaling pathways are actually very well acquainted to cancer researchers. A cancer-related journal such as Oncotarget is the perfect place for publication of such experimental studies, reviews and perspectives, as it can bridge the gap between cancer and aging researchers. PMID:23455653

  20. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    SciTech Connect

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  1. Effects of age, dietary, and behavioral enrichment on brain mitochondria in a canine model of human aging.

    PubMed

    Head, E; Nukala, V N; Fenoglio, K A; Muggenburg, B A; Cotman, C W; Sullivan, P G

    2009-11-01

    Dogs develop cognitive decline and a progressive accumulation of oxidative damage. In a previous longitudinal study, we demonstrated that aged dogs treated with either an antioxidant diet or with behavioral enrichment show cognitive improvement. The antioxidant diet included cellular antioxidants (vitamins E and C, fruits and vegetables) and mitochondrial cofactors (lipoic acid and carnitine). Behavioral enrichment consisted of physical exercise, social enrichment, and cognitive training. We hypothesized that the antioxidant treatment improved neuronal function through increased mitochondrial function. Thus, we measured reactive oxygen species (ROS) production and bioenergetics in mitochondria isolated from young, aged, and treated aged animals. Aged canine brain mitochondria show significant increases in ROS production and a reduction in NADH-linked respiration. Mitochondrial function (ROS and NADH-linked respiration) was improved selectively in aged dogs treated with an antioxidant diet. In contrast, behavioral enrichment had no effect on any mitochondrial parameters. These results suggest that an antioxidant diet improves cognition by maintaining mitochondrial homeostasis, which may be an independent molecular pathway not engaged by behavioral enrichment. PMID:19703441

  2. Paternal Age and Numerical Chromosome Abnormalities in Human Spermatozoa.

    PubMed

    Donate, Anna; Estop, Anna M; Giraldo, Jesús; Templado, Cristina

    2016-01-01

    This study explores the relationship between numerical chromosome abnormalities in sperm and age in healthy men. We performed FISH in the spermatozoa of 10 donors from the general population: 5 men younger than 40 years of age and 5 fertile men older than 60 years of age. For each chromosome, 1,000 sperm nuclei were analyzed, with a total of 15,000 sperm nuclei for each donor. We used a single sperm sample per donor, thus minimizing intra-donor variability and optimizing consistent analysis. FISH with a TelVysion assay, which provides data on aneuploidy of 19 chromosomes, was used in order to gain a more genome-wide perspective of the level of aneuploidy. Aneuploidy and diploidy rates observed in the younger and older groups were compared. There were no significant differences in the incidence of autosomal disomy, sex chromosome disomy, total chromosome disomy, diploidy, nor total numerical abnormalities between younger and older men. This work confirms that aneuploidy of the sex chromosomes is more common than that of autosomes and that this does not change with age. Our results suggest that some probe combinations have a tendency to indicate higher levels of diploidy, thus potentially affecting FISH results and highlighting the limitations of FISH. PMID:27322585

  3. Age and Sex Differences in Interaction with a Human Infant.

    ERIC Educational Resources Information Center

    Blakemore, Judith E. O.

    1981-01-01

    Examines sex differences in vocalizations and play behaviors displayed toward an infant by preschoolers, preadolescents, and adults. Preschoolers showed less interaction than older subjects. Males talked and played less with the baby than did females at all ages; however, among adult subjects, no sex-role effects were found. (Author/RH)

  4. Temporal changes of mechanical signals and extracellular composition in human intervertebral disc during degenerative progression

    PubMed Central

    Zhu, Qiaoqiao; Gao, Xin; Gu, Weiyong

    2014-01-01

    In this study, a three-dimensional finite element model was used to investigate the changes in tissue composition and mechanical signals within human lumbar intervertebral disc during the degenerative progression. This model was developed based on the cell-activity coupled mechano-electrochemical mixture theory. The disc degeneration was simulated by lowering nutrition levels at disc boundaries, and the temporal and spatial distributions of the fixed charge density, water content, fluid pressure, Von Mises stress, and disc deformation were analyzed. Results showed that fixed charge density, fluid pressure, and water content decreased significantly in the nucleus pulposus (NP) and the inner to middle annulus fibrosus (AF) regions of the degenerative disc. It was found that, with degenerative progression, the Von Mises stress (relative to that at healthy state) increased within the disc, with a larger increase in the outer AF region. Both the disc volume and height decreased with the degenerative progression. The predicted results of fluid pressure change in the NP were consistent with experimental findings in the literature. The knowledge of the variations of temporal and spatial distributions of composition and mechanical signals within the human IVDs provide a better understanding of the progression of disc degeneration. PMID:25305690

  5. Progressive post-yield behavior of human cortical bone in shear

    PubMed Central

    Dong, Xuanliang N.; Luo, Qing; Wang, Xiaodu

    2012-01-01

    Bone fragility depends on its post-yield behavior since most of energy dissipation in bone occurs during the post-yield deformation. Previous studies have investigated the progressive changes in the post-yield behavior of human cortical bone in tension and compression using a novel progressive loading scheme. However, little is known regarding the progressive changes in the post-yield behavior of bone in shear. The objective of this short study was to address this issue by testing bone specimens in an inclined double notch shear configuration using the progressive loading protocol. The results of this study indicated that the shear modulus of bone decreased with respect to the applied strain, and the rate of degradation was about 50% less than those previously observed in compression and tension tests. In addition, a quasi-linear relationship between the plastic and applied strains was observed in shear mode, which is similar to those previously reported in tension and compression tests. However, the viscous responses of bone (i.e. relaxation time constants and stress magnitude) demonstrated slight differences in shear compared with those observed in tension and compression tests. Nonetheless, the results of this study suggest that the intrinsic mechanism of plastic deformation of human cortical bone may be independent of loading modes. PMID:23219946

  6. From Oxford to Hawaii Ecophysiological Barriers Limit Human Progression in Ten Sport Monuments

    PubMed Central

    Desgorces, François-Denis; Berthelot, Geoffroy; El Helou, Nour; Thibault, Valérie; Guillaume, Marion; Tafflet, Muriel; Hermine, Olivier; Toussaint, Jean-François

    2008-01-01

    In order to understand the determinants and trends of human performance evolution, we analyzed ten outdoor events among the oldest and most popular in sports history. Best performances of the Oxford-Cambridge boat race (since 1836), the channel crossing in swimming (1875), the hour cycling record (1893), the Elfstedentocht speed skating race (1909), the cross country ski Vasaloppet (1922), the speed ski record (1930), the Streif down-hill in Kitzbühel (1947), the eastward and westward sailing transatlantic records (1960) and the triathlon Hawaii ironman (1978) all follow a similar evolutive pattern, best described through a piecewise exponential decaying model (r2 = 0.95±0.07). The oldest events present highest progression curvature during their early phase. Performance asymptotic limits predicted from the model may be achieved in fourty years (2049±32 y). Prolonged progression may be anticipated in disciplines which further rely on technology such as sailing and cycling. Human progression in outdoor sports tends to asymptotic limits depending on physiological and environmental parameters and may temporarily benefit from further technological progresses. PMID:18985149

  7. Human choice in "counterintuitive" situations: fixed- versus progressive-ratio schedules.

    PubMed Central

    Wanchisen, B A; Tatham, T A; Hineline, P N

    1992-01-01

    College undergraduates were given repeated opportunities to choose between a fixed-ratio and a progressive-ratio schedule of reinforcement. Completions of a progressive-ratio schedule produced points (exchangeable for money) and incremented that response requirement by 20 responses with each consecutive choice. In the reset condition, completion of a fixed ratio produced the same number of points and also reset the progressive ratio back to its initial value. In the no-reset condition, the progressive ratio continued to increase by increments of 20 throughout the session with each successive selection of this schedule, irrespective of fixed-ratio choices. Subjects' schedule choices were sensitive to parametric manipulations of the size of the fixed-ratio schedule and were consistent with predictions made on the basis of minimizing the number of responses emitted per point earned, which is a principle of most optimality theories. Also, the present results suggest that if data from human performances are to be compared with results for other species, humans should be exposed to schedules of reinforcement for long periods of time, as is commonly done with nonhuman subjects. PMID:1645102

  8. Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model

    PubMed Central

    Fan, Xingjun; Reneker, Lixing W.; Obrenovich, Mark E.; Strauch, Christopher; Cheng, Rongzhu; Jarvis, Simon M.; Ortwerth, Beryl J.; Monnier, Vincent M.

    2006-01-01

    Senile cataracts are associated with progressive oxidation, fragmentation, cross-linking, insolubilization, and yellow pigmentation of lens crystallins. We hypothesized that the Maillard reaction, which leads browning and aroma development during the baking of foods, would occur between the lens proteins and the highly reactive oxidation products of vitamin C. To test this hypothesis, we engineered a mouse that selectively overexpresses the human vitamin C transporter SVCT2 in the lens. Consequently, lenticular levels of vitamin C and its oxidation products were 5- to 15-fold elevated, resulting in a highly compressed aging process and accelerated formation of several protein-bound advanced Maillard reaction products identical with those of aging human lens proteins. These data strongly implicate vitamin C in lens crystallin aging and may serve as a model for protein aging in other tissues particularly rich in vitamin C, such as the hippocampal neurons and the adrenal gland. The hSVCT2 mouse is expected to facilitate the search for drugs that inhibit damage by vitamin C oxidation products. PMID:17075057

  9. Canonical Wnt/β-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance.

    PubMed

    Watson, Adrienne L; Rahrmann, Eric P; Moriarity, Branden S; Choi, Kwangmin; Conboy, Caitlin B; Greeley, Andrew D; Halfond, Amanda L; Anderson, Leah K; Wahl, Brian R; Keng, Vincent W; Rizzardi, Anthony E; Forster, Colleen L; Collins, Margaret H; Sarver, Aaron L; Wallace, Margaret R; Schmechel, Stephen C; Ratner, Nancy; Largaespada, David A

    2013-06-01

    Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors. PMID:23535903

  10. Lower expression of Nrdp1 in human glioma contributes tumor progression by reducing apoptosis.

    PubMed

    Shi, Hengliang; Du, Jin; Wang, Lei; Zheng, Bao; Gong, Hui; Wu, Yuxuan; Tang, Yuan; Gao, Yong; Yu, Rutong

    2014-10-01

    Ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) plays important roles in multiple physiological process because it can ubiquitinate various substrates such as ErbB3, BRUCE, MyD88, C/EBPβ, and Parkin, and so forth. In addition to the physiological function, it was also found to be involved in tumor progression. It has been shown that loss of Nrdp1 enhances breast cancer cell growth. Up to now, the role of Nrdp1 in glioma has not been elucidated. Here, we reported that Nrdp1 as well as cleaved caspase 3 was lower expressed in human glioma tissues comparing with the nontumorous. And then we found that the expression of Nrdp1 and cleaved caspase 3 was increased in the treatment of Temozolomide (TMZ), a drug for glioma chemotherapy. Further investigation indicated that transient transfection of Nrdp1 significantly promoted cell apoptosis by aggravating the degradation of BRUCE and activation of caspase 3. In addition, overexpression of Nrdp1 augmented TMZ induced apoptosis by evaluating the degradation of BRUCE and the activation of caspase 3, while silencing of Nrdp1 reduced the sensitivity to the TMZ by inhibiting the degradation of BRUCE and the activation of caspase 3 in human glioma cells. These observations show that Nrdp1 is a pro-apoptotic protein in human glioma and lower expression of Nrdp1 in human glioma may promote tumor progression by reducing apoptosis, suggesting that Nrdp1 may be an important regulator in the development of human glioma. PMID:25355637

  11. Effect of aging on muscle mitochondrial substrate utilization in humans

    PubMed Central

    Petersen, Kitt Falk; Morino, Katsutaro; Alves, Tiago C.; Kibbey, Richard G.; Dufour, Sylvie; Sono, Saki; Yoo, Peter S.; Cline, Gary W.; Shulman, Gerald I.

    2015-01-01

    Previous studies have implicated age-associated reductions in mitochondrial oxidative phosphorylation activity in skeletal muscle as a predisposing factor for intramyocellular lipid (IMCL) accumulation and muscle insulin resistance (IR) in the elderly. To further investigate potential alterations in muscle mitochondrial function associated with aging, we assessed basal and insulin-stimulated rates of muscle pyruvate dehydrogenase (VPDH) flux relative to citrate synthase flux (VCS) in healthy lean, elderly subjects and healthy young body mass index- and activity-matched subjects. VPDH/VCS flux was assessed from the 13C incorporation from of infused [1-13C] glucose into glutamate [4-13C] relative to alanine [3-13C] assessed by LC-tandem MS in muscle biopsies. Insulin-stimulated rates of muscle glucose uptake were reduced by 25% (P < 0.01) in the elderly subjects and were associated with ∼70% (P < 0.04) increase in IMCL, assessed by 1H magnetic resonance spectroscopy. Basal VPDH/VCS fluxes were similar between the groups (young: 0.20 ± 0.03; elderly: 0.14 ± 0.03) and increased approximately threefold in the young subjects following insulin stimulation. However, this increase was severely blunted in the elderly subjects (young: 0.55 ± 0.04; elderly: 0.18 ± 0.02, P = 0.0002) and was associated with an ∼40% (P = 0.004) reduction in insulin activation of Akt. These results provide new insights into acquired mitochondrial abnormalities associated with aging and demonstrate that age-associated reductions in muscle mitochondrial function and increased IMCL are associated with a marked inability of mitochondria to switch from lipid to glucose oxidation during insulin stimulation. PMID:26305973

  12. Interacting Socially with Human Hands at 24 Months of Age

    ERIC Educational Resources Information Center

    Slaughter, Virginia; Nielsen, Mark; Enchelmaier, Petrina

    2008-01-01

    This experiment explored whether or not 2-year-olds would engage in synchronic imitation with human hands. Sixty-four 24-month-old infants participated. In a test of synchronic imitation, infants were given a toy while a model simultaneously performed novel actions on an identical toy. Infants were randomly assigned to 1 of 4 model conditions: a…

  13. A review of the equine age-related changes in the immune system: comparisons between human and equine aging, with focus on lung-specific immune-aging.

    PubMed

    Hansen, S; Baptiste, K E; Fjeldborg, J; Horohov, D W

    2015-03-01

    The equine aging process involves many changes to the immune system that may be related to genetics, the level of nutrition, the environment and/or an underlying subclinical disease. Geriatric horses defined as horses above the age of 20, exhibit a decline in body condition, muscle tone and general well-being. It is not known whether these changes contribute to decreased immune function or are the result of declining immune function. Geriatric years are characterized by increased susceptibility to infections and a reduced antibody response to vaccination as a result of changes in the immune system. Humans and horses share many of these age-related changes, with only a few differences. Thus, inflamm-aging and immunosenescence are well-described phenomena in both human and equine research, particularly in relation to the peripheral blood and especially the T-cell compartment. However, the lung is faced with unique challenges because of its constant interaction with the external environment and thus may not share similarities to peripheral blood when considering age-related changes in immune function. Indeed, recent studies have shown discrepancies in cytokine mRNA and protein expression between the peripheral blood and bronchoalveolar lavage immune cells. These results provide important evidence that age-related immune changes or 'dys-functions' are organ-specific. PMID:25497559

  14. Employing biomarkers of healthy ageing for leveraging genetic studies into human longevity.

    PubMed

    Deelen, Joris; van den Akker, Erik B; Trompet, Stella; van Heemst, Diana; Mooijaart, Simon P; Slagboom, P Eline; Beekman, Marian

    2016-09-01

    Genetic studies have thus far identified a limited number of loci associated with human longevity by applying age at death or survival up to advanced ages as phenotype. As an alternative approach, one could first try to identify biomarkers of healthy ageing and the genetic variants associated with these traits and subsequently determine the association of these variants with human longevity. In the present study, we used this approach by testing whether the 35 baseline serum parameters measured in the Leiden Longevity Study (LLS) meet the proposed criteria for a biomarker of healthy ageing. The LLS consists of 421 families with long-lived siblings of European descent, who were recruited together with their offspring and the spouses of the offspring (controls). To test the four criteria for a biomarker of healthy ageing in the LLS, we determined the association of the serum parameters with chronological age, familial longevity, general practitioner-reported general health, and mortality. Out of the 35 serum parameters, we identified glucose, insulin, and triglycerides as biomarkers of healthy ageing, meeting all four criteria in the LLS. We subsequently showed that the genetic variants previously associated with these parameters are significantly enriched in the largest genome-wide association study for human longevity. In conclusion, we showed that biomarkers of healthy ageing can be used to leverage genetic studies into human longevity. We identified several genetic variants influencing the variation in glucose, insulin and triglycerides that contribute to human longevity. PMID:27374409

  15. Predicting human age using regional morphometry and inter-regional morphological similarity

    NASA Astrophysics Data System (ADS)

    Wang, Xun-Heng; Li, Lihua

    2016-03-01

    The goal of this study is predicting human age using neuro-metrics derived from structural MRI, as well as investigating the relationships between age and predictive neuro-metrics. To this end, a cohort of healthy subjects were recruited from 1000 Functional Connectomes Project. The ages of the participations were ranging from 7 to 83 (36.17+/-20.46). The structural MRI for each subject was preprocessed using FreeSurfer, resulting in regional cortical thickness, mean curvature, regional volume and regional surface area for 148 anatomical parcellations. The individual age was predicted from the combination of regional and inter-regional neuro-metrics. The prediction accuracy is r = 0.835, p < 0.00001, evaluated by Pearson correlation coefficient between predicted ages and actual ages. Moreover, the LASSO linear regression also found certain predictive features, most of which were inter-regional features. The turning-point of the developmental trajectories in human brain was around 40 years old based on regional cortical thickness. In conclusion, structural MRI could be potential biomarkers for the aging in human brain. The human age could be successfully predicted from the combination of regional morphometry and inter-regional morphological similarity. The inter-regional measures could be beneficial to investigating human brain connectome.

  16. Antioxidant-enriched diet does not delay the progression of age-related hearing loss.

    PubMed

    Sha, Su-Hua; Kanicki, Ariane; Halsey, Karin; Wearne, Kimberly Anne; Schacht, Jochen

    2012-05-01

    Oxidative stress has been linked to noise- and drug-induced as well as age-related hearing loss. Antioxidants can attenuate the decline of cochlear structure and function after exposure to noise or drugs, but it is debated as to whether they can protect from age-related hearing loss. In a long-term longitudinal study, 10-month-old female CBA/J mice were placed on either a control or antioxidant-enriched diet and monitored through 24 months of age. Supplementation with vitamins A, C, and E, L-carnitine, and α-lipoic acid significantly increased the antioxidant capacity of inner ear tissues. However, by 24 months of age, the magnitude of hearing loss was equal between the two groups. Likewise, there were no significant differences in hair cell loss or degeneration of spiral ganglion cells. We conclude that dietary manipulations can alter cochlear antioxidant capacity but do not ameliorate age-related sensorineural hearing loss in the CBA/J mouse. PMID:22154190

  17. ADAM15 Is Functionally Associated with the Metastatic Progression of Human Bladder Cancer

    PubMed Central

    Rubin, John R.; Hayward, Alexandra; Cates, Angelica L.; Day, Kathleen C.; El-Sawy, Layla; Kunju, L. Priya; Daignault, Stephanie; Lee, Cheryl T.; Liebert, Monica; Hussain, Maha; Day, Mark L.

    2016-01-01

    ADAM15 is a member of a family of catalytically active disintegrin membrane metalloproteinases that function as molecular signaling switches, shed membrane bound growth factors and/or cleave and inactivate cell adhesion molecules. Aberrant metalloproteinase function of ADAM15 may contribute to tumor progression through the release of growth factors or disruption of cell adhesion. In this study, we utilized human bladder cancer tissues and cell lines to evaluate the expression and function of ADAM15 in the progression of human bladder cancer. Examination of genome and transcriptome databases revealed that ADAM15 ranked in the top 5% of amplified genes and its mRNA was significantly overexpressed in invasive and metastatic bladder cancer compared to noninvasive disease. Immunostaining of a bladder tumor tissue array designed to evaluate disease progression revealed increased ADAM15 immunoreactivity associated with increasing cancer stage and exhibited significantly stronger staining in metastatic samples. About half of the invasive tumors and the majority of the metastatic cases exhibited high ADAM15 staining index, while all low grade and noninvasive cases exhibited negative or low staining. The knockdown of ADAM15 mRNA expression significantly inhibited bladder tumor cell migration and reduced the invasive capacity of bladder tumor cells through MatrigelTM and monolayers of vascular endothelium. The knockdown of ADAM15 in a human xenograft model of bladder cancer inhibited tumor growth by 45% compared to controls. Structural modeling of the catalytic domain led to the design of a novel ADAM15-specific sulfonamide inhibitor that demonstrated bioactivity and significantly reduced the viability of bladder cancer cells in vitro and in human bladder cancer xenografts. Taken together, the results revealed an undescribed role of ADAM15 in the invasion of human bladder cancer and suggested that the ADAM15 catalytic domain may represent a viable therapeutic target in

  18. Assessing Progress towards Public Health, Human Rights, and International Development Goals Using Frontier Analysis.

    PubMed

    Luh, Jeanne; Cronk, Ryan; Bartram, Jamie

    2016-01-01

    Indicators to measure progress towards achieving public health, human rights, and international development targets, such as 100% access to improved drinking water or zero maternal mortality ratio, generally focus on status (i.e., level of attainment or coverage) or trends in status (i.e., rates of change). However, these indicators do not account for different levels of development that countries experience, thus making it difficult to compare progress between countries. We describe a recently developed new use of frontier analysis and apply this method to calculate country performance indices in three areas: maternal mortality ratio, poverty headcount ratio, and primary school completion rate. Frontier analysis is used to identify the maximum achievable rates of change, defined by the historically best-performing countries, as a function of coverage level. Performance indices are calculated by comparing a country's rate of change against the maximum achievable rate at the same coverage level. A country's performance can be positive or negative, corresponding to progression or regression, respectively. The calculated performance indices allow countries to be compared against each other regardless of whether they have only begun to make progress or whether they have almost achieved the target. This paper is the first to use frontier analysis to determine the maximum achievable rates as a function of coverage level and to calculate performance indices for public health, human rights, and international development indicators. The method can be applied to multiple fields and settings, for example health targets such as cessation in smoking or specific vaccine immunizations, and offers both a new approach to analyze existing data and a new data source for consideration when assessing progress achieved. PMID:26812524

  19. Assessing Progress towards Public Health, Human Rights, and International Development Goals Using Frontier Analysis

    PubMed Central

    Luh, Jeanne; Cronk, Ryan; Bartram, Jamie

    2016-01-01

    Indicators to measure progress towards achieving public health, human rights, and international development targets, such as 100% access to improved drinking water or zero maternal mortality ratio, generally focus on status (i.e., level of attainment or coverage) or trends in status (i.e., rates of change). However, these indicators do not account for different levels of development that countries experience, thus making it difficult to compare progress between countries. We describe a recently developed new use of frontier analysis and apply this method to calculate country performance indices in three areas: maternal mortality ratio, poverty headcount ratio, and primary school completion rate. Frontier analysis is used to identify the maximum achievable rates of change, defined by the historically best-performing countries, as a function of coverage level. Performance indices are calculated by comparing a country’s rate of change against the maximum achievable rate at the same coverage level. A country’s performance can be positive or negative, corresponding to progression or regression, respectively. The calculated performance indices allow countries to be compared against each other regardless of whether they have only begun to make progress or whether they have almost achieved the target. This paper is the first to use frontier analysis to determine the maximum achievable rates as a function of coverage level and to calculate performance indices for public health, human rights, and international development indicators. The method can be applied to multiple fields and settings, for example health targets such as cessation in smoking or specific vaccine immunizations, and offers both a new approach to analyze existing data and a new data source for consideration when assessing progress achieved. PMID:26812524

  20. Human computers: the first pioneers of the information age.

    PubMed

    Grier, D A

    2001-03-01

    Before computers were machines, they were people. They were men and women, young and old, well educated and common. They were the workers who convinced scientists that large-scale calculation had value. Long before Presper Eckert and John Mauchly built the ENIAC at the Moore School of Electronics, Philadelphia, or Maurice Wilkes designed the EDSAC for Manchester University, human computers had created the discipline of computation. They developed numerical methodologies and proved them on practical problems. These human computers were not savants or calculating geniuses. Some knew little more than basic arithmetic. A few were near equals of the scientists they served and, in a different time or place, might have become practicing scientists had they not been barred from a scientific career by their class, education, gender or ethnicity. PMID:11314458

  1. Mapping trabecular disconnection "hotspots" in aged human spine and hip.

    PubMed

    Aaron, Jean E; Shore, Patricia A; Itoda, Mizuo; Morrison, Rory J M; Hartopp, Andrew; Hensor, Elizabeth M A; Hordon, Lesley D

    2015-09-01

    Trabecular bone disconnection is an independent factor in age-related skeletal failure where real termini (ReTm; rare in youth) may cause weakness disproportionate to tissue loss, yet their structural contribution at vulnerable locations remains uncertain. ReTm (previously recorded at the iliac crest) were mapped in "normal" aged vertebral bodies (T11-L5 autopsy; 20 females, 10 males) and corresponding proximal femora (autopsy; 10 females). Results were compared with biomechanically failed femora from orthopaedic subjects aged >58 yr (osteoporosis OP, 10 females; osteoarthritis OA, 10 females). A novel direct 2D/3D histological method was applied to large, thick (300 μm) slices superficially silver-stained to separate ReTm (unstained) from apparent termini (planar artefacts, brown). Light microscope field co-ordinates enabled ReTm mapping and statistical testing relative to i) sex, ii) tissue sector and iii) slicing plane. In men ReTm populations were small and random while in women they were large and sector-specific. In vertebrae they clustered anterior/superior being rare posterior/inferior; in the femoral head they concentrated distal/superior and also near the fovea, being fewer distal/inferior. A distribution polarity was evident with 100% more ReTm observed transversely (i.e., on tensile-related cross struts) than longitudinally (i.e., on compression-related vertical struts). Their numbers rose in OP (BV/TV<14%, microCT) and in OA (BV/TV>14%), remaining polarised and sector-specific in OP only. Comparative experimentation by marrow elution of an OP animal model demonstrated "floating segments" as a possible outcome. Conclusions were supported statistically that trabecular disconnection "hotspots" at vulnerable locations are sex- and sector-specific, mainly transaxial, and subject to disease modulation. PMID:25874446

  2. Functional Changes in the Human Auditory Cortex in Ageing

    PubMed Central

    Profant, Oliver; Tintěra, Jaroslav; Balogová, Zuzana; Ibrahim, Ibrahim; Jilek, Milan; Syka, Josef

    2015-01-01

    Hearing loss, presbycusis, is one of the most common sensory declines in the ageing population. Presbycusis is characterised by a deterioration in the processing of temporal sound features as well as a decline in speech perception, thus indicating a possible central component. With the aim to explore the central component of presbycusis, we studied the function of the auditory cortex by functional MRI in two groups of elderly subjects (>65 years) and compared the results with young subjects (age-related changes at the level of the auditory cortex. The fMRI showed only minimal activation in response to the 8 kHz stimulation, despite the fact that all subjects heard the stimulus. Both elderly groups showed greater activation in response to acoustical stimuli in the temporal lobes in comparison with young subjects. In addition, activation in the right temporal lobe was more expressed than in the left temporal lobe in both elderly groups, whereas in the young control subjects (YC) leftward lateralization was present. No statistically significant differences in activation of the auditory cortex were found between the MP and EP groups. The greater extent of cortical activation in elderly subjects in comparison with young subjects, with an asymmetry towards the right side, may serve as a compensatory mechanism for the impaired processing of auditory information appearing as a consequence of ageing. PMID:25734519

  3. AGE-RELATED GENE EXPRESSION CHANGES IN HUMAN SKIN FIBROBLASTS INDUCED BY MMS

    EPA Science Inventory

    Age-Related Gene Expression Changes In Human Skin Fibroblasts Induced By methyl methanesulfonate. Geremy W. Knapp, Alan H. Tennant, and Russell D. Owen. Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, U. S. Environmental Prote...

  4. Effects of Aging and Anatomic Location on Gene Expression in Human Retina

    PubMed Central

    Cai, Hui; Fields, Mark A.; Hoshino, Risa; Priore, Lucian V. Del

    2012-01-01

    Objective: To determine the effects of age and topographic location on gene expression in human neural retina. Methods: Macular and peripheral neural retina RNA was isolated from human donor eyes for DNA microarray and quantitative RT-PCR analyses. Results: Total RNA integrity from human donors was preserved. Hierarchical clustering analysis demonstrates that the gene expression profiles of young, old, macula, and peripheral retina cluster into four distinct groups. Genes which are highly expressed in macular, peripheral, young, or old retina were identified, including inhibitors of Wnt Signaling Pathway (DKK1, FZD10, and SFRP2) which are preferably expressed in the periphery. Conclusion: The transcriptome of the human retina is affected by age and topographic location. Wnt pathway inhibitors in the periphery may maintain peripheral retinal cells in an undifferentiated state. Understanding the effects of age and topographic location on gene expression may lead to the development of new therapeutic interventions for age-related eye diseases. PMID:22666212

  5. Reduced DNA methylation patterning and transcriptional connectivity define human skin aging.

    PubMed

    Bormann, Felix; Rodríguez-Paredes, Manuel; Hagemann, Sabine; Manchanda, Himanshu; Kristof, Boris; Gutekunst, Julian; Raddatz, Günter; Haas, Rainer; Terstegen, Lara; Wenck, Horst; Kaderali, Lars; Winnefeld, Marc; Lyko, Frank

    2016-06-01

    Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age-related changes in DNA methylation at the genome scale have been termed 'epigenetic drift', but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age-related epigenetic changes because of its substantial cell-type homogeneity and its well-known age-related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array-based profiling of 450 000 methylation marks in various age groups. Data analysis confirmed that age-related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovered an age-related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome. PMID:27004597

  6. Quantification of regional differences in aortic stiffness in the aging human

    PubMed Central

    Roccabianca, S.; Figueroa, C.A.; Tellides, G.; Humphrey, J.D.

    2013-01-01

    There has been a growing awareness over the past decade that stiffening of the aorta, and its attendant effects on hemodynamics, is both an indicator and initiator of diverse cardiovascular, neurovascular, and renovascular diseases. Although different clinical metrics of arterial stiffness have been proposed and found useful in particular situations, there remains a need to understand better the complex interactions between evolving aortic stiffness and the hemodynamics. Computational fluid–solid-interaction (FSI) models are amongst the most promising means to understand such interactions for one can parametrically examine effects of regional variations in material properties and arterial geometry on local and systemic blood pressure and flow. Such models will not only increase our understanding, they will also serve as important steps towards the development of fluid–solid-growth (FSG) models that can further examine interactions between the evolving wall mechanics and hemodynamics that lead to arterial adaptations or disease progression over long periods. In this paper, we present a consistent quantification and comparison of regional nonlinear biaxial mechanical properties of the human aorta based on 19 data sets available in the literature and we calculate associated values of linearized stiffness over the cardiac cycle that are useful for initial large-scale FSI and FSG simulations. It is shown, however, that there is considerable variability amongst the available data and consequently that there is a pressing need for more standardized biaxial testing of the human aorta to collect data as a function of both location and age, particularly for young healthy individuals who serve as essential controls. PMID:23499251

  7. Privacy and human behavior in the age of information.

    PubMed

    Acquisti, Alessandro; Brandimarte, Laura; Loewenstein, George

    2015-01-30

    This Review summarizes and draws connections between diverse streams of empirical research on privacy behavior. We use three themes to connect insights from social and behavioral sciences: people's uncertainty about the consequences of privacy-related behaviors and their own preferences over those consequences; the context-dependence of people's concern, or lack thereof, about privacy; and the degree to which privacy concerns are malleable—manipulable by commercial and governmental interests. Organizing our discussion by these themes, we offer observations concerning the role of public policy in the protection of privacy in the information age. PMID:25635091

  8. Effects of Aging on Genioglossus Motor Units in Humans

    PubMed Central

    Saboisky, Julian P.; Stashuk, Daniel W.; Hamilton-Wright, Andrew; Trinder, John; Nandedkar, Sanjeev; Malhotra, Atul

    2014-01-01

    The genioglossus is a major upper airway dilator muscle thought to be important in obstructive sleep apnea pathogenesis. Aging is a risk factor for obstructive sleep apnea although the mechanisms are unclear and the effects of aging on motor unit remodeled in the genioglossus remains unknown. To assess possible changes associated with aging we compared quantitative parameters related to motor unit potential morphology derived from EMG signals in a sample of older (n = 11; >55 years) versus younger (n = 29; <55 years) adults. All data were recorded during quiet breathing with the subjects awake. Diagnostic sleep studies (Apnea Hypopnea Index) confirmed the presence or absence of obstructive sleep apnea. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which estimated a MUP template from each extracted motor unit potential train (MUPT) for both the selective concentric needle and concentric needle macro (CNMACRO) recorded EMG signals. 2074 MUPTs from 40 subjects (mean±95% CI; older AHI 19.6±9.9 events/hr versus younger AHI 30.1±6.1 events/hr) were extracted. MUPs detected in older adults were 32% longer in duration (14.7±0.5 ms versus 11.1±0.2 ms; P  =  0.05), with similar amplitudes (395.2±25.1 µV versus 394.6±13.7 µV). Amplitudes of CNMACRO MUPs detected in older adults were larger by 22% (62.7±6.5 µV versus 51.3±3.0 µV; P<0.05), with areas 24% larger (160.6±18.6 µV.ms versus 130.0±7.4 µV.ms; P<0.05) than those detected in younger adults. These results confirm that remodeled motor units are present in the genioglossus muscle of individuals above 55 years, which may have implications for OSA pathogenesis and aging related upper airway collapsibility. PMID:25111799

  9. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease.

    PubMed

    Lake, April D; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D; Lu, Zhenqiang; Lehman-McKeeman, Lois D; Cherrington, Nathan J

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the 'classical' (neutral) and 'alternative' (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. PMID:23391614

  10. Analysis and significance of the malignant 'eclipse' during the progression of primary cutaneous human melanomas.

    PubMed

    Kerbel, R S; Kobayashi, H; Graham, C H; Lu, C

    1996-04-01

    Why is it that primary melanomas which are less than 0.76 mm in thickness are almost always curable by surgery whereas thicker lesions are associated with a worse prognosis? Put in another way, why is it that such small increases in tumor thickness beyond 0.76 mm are often associated with the eventual formation of distant metastases and death? Part of the answer lies in the dramatic qualitative changes which can accompany small increases in the size of primary human melanomas. Thus, primary melanomas less than 0.76 mm in thickness usually contain very low proportions of metastatically competent tumor cells, whereas slightly thicker lesions can contain very high proportions of such cells, resulting from a selective growth advantage of the latter in the dermal mesenchyme. This overgrowth process is akin to a 'malignant eclipse' phenomenon (by analogy with a solar eclipse). We have been studying the causes of the malignant eclipse in melanoma, for which there are at least four possibilities: 1) an increase in autocrine, mitogenic growth factors by melanoma cells; 2) a decreased rate of apoptosis in the same population; 3) an acquired resistance to paracrine growth inhibitory factors; and 4) an increased ability to induce an angiogenic response. Evidence exists for all four possibilities. Our experimental approach to studying this problem has relied heavily on the use of cell lines obtained from early stage radial growth phase or vertical growth phase lesions which have a clinical-like inability to grow progressively in nude mice, and variants obtained from such lines which are aggressively tumorigenic. Using such paired lines, and other experimental systems, we have obtained evidence that shows early stage melanoma cell lines may be deficient in inducing angiogenesis, are highly sensitive to the growth inhibitory effects of a plethora of cytokines, including transforming growth factor beta, interleukin-6, and oncostatin M, and are more sensitive to undergoing

  11. Progress in Research on Aging in the Behavioral and Social Sciences.

    ERIC Educational Resources Information Center

    Birren, James E.

    1980-01-01

    Proposes a biobehavioral view of research on aging which suggests that behavior depends upon the limits set by genetic heritage, the modifications and reinforcements of physical and social environments, and the self-concept achieved through the integration of past life experiences. (Author/SS)

  12. Family Economic Hardship and Progression of Poor Mental Health in Middle-Aged Husbands and Wives

    ERIC Educational Resources Information Center

    Wickrama, K. A. S.; Surjadi, Florensia F.; Lorenz, Frederick O.; Conger, Rand D.; O'Neal, Catherine Walker

    2012-01-01

    Using prospective data from 370 middle-aged husbands and wives during a 12-year period, we investigated the intra-individual and dyadic influence of family economic hardship on the levels of depressive symptoms of husbands and wives over their middle years. The results suggest that family economic hardship during the early middle years contributes…

  13. Oxidation of a potassium channel causes progressive sensory function loss during ageing

    PubMed Central

    Cai, Shi-Qing; Sesti, Federico

    2009-01-01

    A central question is whether potassium (K+) channels, which are key regulators of neuronal excitability, are targets of reactive oxygen species (ROS) and whether these interactions have a role in the mechanisms underlying neurodegeneration. Here, we show that oxidation of K+ channel KVS-1 during ageing causes sensory function loss in Caenorhabditis elegans, and that protection of this channel from oxidation preserves neuronal function. Chemotaxis, a function controlled by KVS-1, was significantly impaired in worms exposed to oxidizing agents, but only moderately affected in worms harboring an oxidation-resistant KVS-1 mutant (C113S). In ageing C113S transgenic worms, the effects of free radical accumulation were significantly attenuated compared to wild type. Electrophysiological analyses showed that both ROS accumulation during ageing, or acute exposure to oxidizing agents, acted primarily to alter the excitability of the neurons that mediate chemotaxis. Together, these findings establish a pivotal role for ROS-mediated oxidation of voltage-gated K+ channels in sensorial decline during ageing in invertebrates. PMID:19330004

  14. Effects of Age on Na+,K+-ATPase Expression in Human and Rodent Skeletal Muscle

    PubMed Central

    Wyckelsma, Victoria L.; McKenna, Michael J.

    2016-01-01

    The maintenance of transmembrane Na+ and K+ concentration gradients and membrane potential is vital for the production of force in skeletal muscle. In aging an inability to maintain ion regulation and membrane potential would have adverse consequences on the capacity for performing repeated muscle contractions, which are critical for everyday activities and functional independence. This short review focusses on the effects of aging on one major and vital component affecting muscle Na+ and K+ concentrations, membrane potential and excitability in skeletal muscle, the Na+,K+-ATPase (Na+,K+-pump, NKA) protein. The review examines the effects of age on NKA in both human and rodent models and highlights a distant lack of research in NKA with aging. In rodents, the muscle NKA measured by [3H]ouabain binding site content, declines with advanced age from peak values in early life. In human skeletal muscle, however, there appears to be no age effect on [3H]ouabain binding site content in physically active older adults between 55 and 76 years compared to those aged between 18 and 30 years of age. Analysis of the NKA isoforms reveal differential changes with age in fiber-types in both rat and humans. The data show considerable disparities, suggesting different regulation of NKA isoforms between rodents and humans. Finally we review the importance of physical activity on NKA content in older humans. Findings suggest that physical activity levels of an individual may have a greater effect on regulating the NKA content in skeletal muscle rather than aging per se, at least up until 80 years of age. PMID:27531982

  15. Effects of Age on Na(+),K(+)-ATPase Expression in Human and Rodent Skeletal Muscle.

    PubMed

    Wyckelsma, Victoria L; McKenna, Michael J

    2016-01-01

    The maintenance of transmembrane Na(+) and K(+) concentration gradients and membrane potential is vital for the production of force in skeletal muscle. In aging an inability to maintain ion regulation and membrane potential would have adverse consequences on the capacity for performing repeated muscle contractions, which are critical for everyday activities and functional independence. This short review focusses on the effects of aging on one major and vital component affecting muscle Na(+) and K(+) concentrations, membrane potential and excitability in skeletal muscle, the Na(+),K(+)-ATPase (Na(+),K(+)-pump, NKA) protein. The review examines the effects of age on NKA in both human and rodent models and highlights a distant lack of research in NKA with aging. In rodents, the muscle NKA measured by [(3)H]ouabain binding site content, declines with advanced age from peak values in early life. In human skeletal muscle, however, there appears to be no age effect on [(3)H]ouabain binding site content in physically active older adults between 55 and 76 years compared to those aged between 18 and 30 years of age. Analysis of the NKA isoforms reveal differential changes with age in fiber-types in both rat and humans. The data show considerable disparities, suggesting different regulation of NKA isoforms between rodents and humans. Finally we review the importance of physical activity on NKA content in older humans. Findings suggest that physical activity levels of an individual may have a greater effect on regulating the NKA content in skeletal muscle rather than aging per se, at least up until 80 years of age. PMID:27531982

  16. Actuarial aging rate is not constant within the human life span.

    PubMed

    Ekonomov, A L; Rudd, C L; Lomakin, A J

    1989-01-01

    It is often believed that the mortality intensity in the modern human population undergoes an exponential growth after 40 years, i.e. the actuarial aging rate is regarded to be constant after 40 years. To check this assumption we have calculated local aging rate values for 13 age ranges (within the interval of 30-92 years) for the male and female population of 48 states of the US (1969-1971). It was found that generally the male aging rate is not constant but lowers monotonically with time, while for females the aging rate has a pronounced approximately-shaped character with a minimum in the range of 45-60 years and a maximum within the range of 70-80 years. The results obtained are a warning to those who boldly use Gompertz or Gompertz-Makeham formulas when describing human aging on the population level. PMID:2792778

  17. Atherosclerosis in ancient humans, accelerated aging syndromes and normal aging: is lamin a protein a common link?

    PubMed

    Miyamoto, Michael I; Djabali, Karima; Gordon, Leslie B

    2014-06-01

    Imaging studies of ancient human mummies have demonstrated the presence of vascular calcification that is consistent with the presence of atherosclerosis. These findings have stimulated interest in the underlying biological processes that might impart to humans an inherent predisposition to the development of atherosclerosis. Clues to these processes may possibly be found in accelerated aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare disorder characterized by premature aging phenotypes, including very aggressive forms of atherosclerosis, occurring in childhood. The genetic defect in HGPS eventuates in the production of a mutant form of the nuclear structural protein lamin A, called progerin, which is thought to interfere with normal nuclear functioning. Progerin appears to be expressed in vascular cells, resulting in vessel wall cell loss and replacement by fibrous tissue, reducing vessel compliance and promoting calcification, leading to the vascular dysfunction and atherosclerosis seen in HGPS. Interestingly, vascular progerin is detectable in lower levels, in an age-related manner, in the general population, providing the basis for further study of the potential role of abnormal forms of lamin A in the atherosclerotic process of normal aging. PMID:25667091

  18. Progression of multiple behavioral deficits with various ages of onset in a murine model of Hurler syndrome.

    PubMed

    Pan, Dao; Sciascia, Anthony; Vorhees, Charles V; Williams, Michael T

    2008-01-10

    Mucopolysaccharidosis type I (MPS I) is one of the most common lysosomal storage diseases with progressive neurological dysfunction. To characterize the chronological behavioral profiles and identify the onset of functional deficits in a MPS I mouse model (IDUA(-/-)), we evaluated anxiety, locomotor behavior, startle, spatial learning and memory with mice at 2, 4, 6 and 8 months of age. In automated open-field test, IDUA(-/-) mice showed hypoactivity as early as 2 months of age and altered anxiety starting from 6 months of age during the initial exploratory phase, even though normal habituation was observed at all ages. In the marble-burying task, the anxiety-like compulsive behavior was normal in IDUA(-/-) mice at almost all tested ages, but significantly reduced in 8-month old male IDUA(-/-) mice which coincided with the rapid death of IDUA(-/-) males starting from 7 months of age. In the Morris water maze, IDUA(-/-) mice exhibited impaired proficient learning only at 4 months of age during the acquisition phase. Spatial memory deficits were observed in IDUA(-/-) mice during both 1 and 7 days probe trials at 4 and 8 months of age. The IDUA(-/-) mice performed normally in a novel object recognition task at younger ages until 8 months old when reduced visual cognitive memory retention was noted in the IDUA(-/-) mice. In addition, 8-month-old IDUA(-/-) mice failed to habituate to repeated open-field exposure, suggesting deficits in non-aversive and non-associative memory. In acoustic startle assessment, significantly more non-responders were found in IDUA(-/-) mice, but normal performance was seen in those that did show a response. These results presented a temporal evaluation of phenotypic behavioral dysfunctions in IDUA(-/-) mice from adolescence to maturity, indicating the impairments, with different ages of onset, in locomotor and anxiety-like compulsive behaviors, spatial learning and memory, visual recognition and short-term non-associative memory retention

  19. Deep biomarkers of human aging: Application of deep neural networks to biomarker development

    PubMed Central

    Putin, Evgeny; Mamoshina, Polina; Aliper, Alexander; Korzinkin, Mikhail; Moskalev, Alexey; Kolosov, Alexey; Ostrovskiy, Alexander; Cantor, Charles; Vijg, Jan; Zhavoronkov, Alex

    2016-01-01

    One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. The best performing DNN in the ensemble demonstrated 81.5 % epsilon-accuracy r = 0.90 with R2 = 0.80 and MAE = 6.07 years in predicting chronological age within a 10 year frame, while the entire ensemble achieved 83.5% epsilon-accuracy r = 0.91 with R2 = 0.82 and MAE = 5.55 years. The ensemble also identified the 5 most important markers for predicting human chronological age: albumin, glucose, alkaline phosphatase, urea and erythrocytes. To allow for public testing and evaluate real-life performance of the predictor, we developed an online system available at http://www.aging.ai. The ensemble approach may facilitate integration of multi-modal data linked to chronological age and sex that may lead to simple, minimally invasive, and affordable methods of tracking integrated biomarkers of aging in humans and performing cross-species feature importance analysis. PMID:27191382

  20. Deep biomarkers of human aging: Application of deep neural networks to biomarker development.

    PubMed

    Putin, Evgeny; Mamoshina, Polina; Aliper, Alexander; Korzinkin, Mikhail; Moskalev, Alexey; Kolosov, Alexey; Ostrovskiy, Alexander; Cantor, Charles; Vijg, Jan; Zhavoronkov, Alex

    2016-05-01

    One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. The best performing DNN in the ensemble demonstrated 81.5 % epsilon-accuracy r = 0.90 with R(2) = 0.80 and MAE = 6.07 years in predicting chronological age within a 10 year frame, while the entire ensemble achieved 83.5% epsilon-accuracy r = 0.91 with R(2) = 0.82 and MAE = 5.55 years. The ensemble also identified the 5 most important markers for predicting human chronological age: albumin, glucose, alkaline phosphatase, urea and erythrocytes. To allow for public testing and evaluate real-life performance of the predictor, we developed an online system available at http://www.aging.ai. The ensemble approach may facilitate integration of multi-modal data linked to chronological age and sex that may lead to simple, minimally invasive, and affordable methods of tracking integrated biomarkers of aging in humans and performing cross-species feature importance analysis. PMID:27191382

  1. On the Increasing Fragility of Human Teeth with Age: ADeep-Ultraviolet Resonance Raman Study

    SciTech Connect

    Ager III, J.W.; Nalla, R.K.; Balooch, G.; Kim, G.; Pugach, M.; Habelitz, S.; Marshall, G.W.; Kinney, J.H.; Ritchie, R.O.

    2006-07-14

    Ultraviolet resonance Raman spectroscopy (UVRRS) using 244nm excitation was used to investigate the impact of aging on humandentin. The intensity of a spectroscopic feature from the peptide bondsin the collagen increases with tissue age, similar to a finding reportedpreviously for human cortical bone.

  2. Ion channel genes and human neurological disease: Recent progress, prospects, and challenges

    PubMed Central

    Cooper, Edward C.; Jan, Lily Yeh

    1999-01-01

    What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are “paroxysmal disorders” whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism. PMID:10220366

  3. Three-dimensional cultures modeling premalignant progression of human breast epithelial cells: role of cysteine cathepsins.

    PubMed

    Mullins, Stefanie R; Sameni, Mansoureth; Blum, Galia; Bogyo, Matthew; Sloane, Bonnie F; Moin, Kamiar

    2012-12-01

    The expression of the cysteine protease cathepsin B is increased in early stages of human breast cancer.To assess the potential role of cathepsin B in premalignant progression of breast epithelial cells, we employed a 3D reconstituted basement membrane overlay culture model of MCF10A human breast epithelial cells and isogenic variants that replicate the in vivo phenotypes of hyper plasia(MCF10AneoT) and atypical hyperplasia (MCF10AT1). MCF10A cells developed into polarized acinar structures with central lumens. In contrast, MCF10AneoT and MCF10AT1 cells form larger structures in which the lumens are filled with cells. CA074Me, a cell-permeable inhibitor selective for the cysteine cathepsins B and L,reduced proliferation and increased apoptosis of MCF10A, MCF10AneoT and MCF10AT1 cells in 3D culture. We detected active cysteine cathepsins in the isogenic MCF10 variants in 3D culture with GB111, a cell-permeable activity based probe, and established differential inhibition of cathepsin B in our 3D cultures. We conclude that cathepsin B promotes proliferation and premalignant progression of breast epithelial cells. These findings are consistent with studies by others showing that deletion of cathepsin B in the transgenic MMTV-PyMT mice, a murine model that is predisposed to development of mammary cancer, reduces malignant progression. PMID:23667900

  4. Primary age-related tauopathy (PART): a common pathology associated with human aging.

    PubMed

    Crary, John F; Trojanowski, John Q; Schneider, Julie A; Abisambra, Jose F; Abner, Erin L; Alafuzoff, Irina; Arnold, Steven E; Attems, Johannes; Beach, Thomas G; Bigio, Eileen H; Cairns, Nigel J; Dickson, Dennis W; Gearing, Marla; Grinberg, Lea T; Hof, Patrick R; Hyman, Bradley T; Jellinger, Kurt; Jicha, Gregory A; Kovacs, Gabor G; Knopman, David S; Kofler, Julia; Kukull, Walter A; Mackenzie, Ian R; Masliah, Eliezer; McKee, Ann; Montine, Thomas J; Murray, Melissa E; Neltner, Janna H; Santa-Maria, Ismael; Seeley, William W; Serrano-Pozo, Alberto; Shelanski, Michael L; Stein, Thor; Takao, Masaki; Thal, Dietmar R; Toledo, Jonathan B; Troncoso, Juan C; Vonsattel, Jean Paul; White, Charles L; Wisniewski, Thomas; Woltjer, Randall L; Yamada, Masahito; Nelson, Peter T

    2014-12-01

    We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed. PMID:25348064

  5. Isothermal aging effects on extex-tetryl mixtures. Progress report, October 1971--December 1971

    SciTech Connect

    Clink, G.L.

    1998-12-31

    An isothermal aging study of a 50/50 weight mixture of Extex (80% PETN, 20% Sylgard) and Tetryl (2,4,6-trinitrophenylmethylnitramine) was undertaken to determine its stability at elevated storage temperatures (60 and 100 C) for extended periods (100 days), to simulate long storage. The original components and mixture, along with the isothermal residues underwent various analyses including infrared spectral and differential thermal analyses, weight loss monitoring at selected intervals up to 100 days, and photomicrography.

  6. Temporal lobe in human aging: A quantitative protein profiling study of samples from Chinese Human Brain Bank.

    PubMed

    Xu, Benhong; Xiong, Feng; Tian, Rui; Zhan, Shaohua; Gao, Yanpan; Qiu, Wenying; Wang, Renzhi; Ge, Wei; Ma, Chao

    2016-01-01

    The temporal lobe is a portion of the cerebral cortex with critical functionality. The age-related protein profile changes in the human temporal lobe have not been previously studied. This 4-plex tandem mass tag labeled proteomic study was performed on samples of temporal lobe from Chinese donors. Tissue samples were assigned to four age groups: Group A (the young, age: 34±13 years); Group B (the elderly, 62±5 years); Group C (the aged, 84±4 years) and Group D (the old, 95±1 years). Pooled samples from the different groups were subjected to proteomics and bioinformatics analysis to identify age-related changes in protein expression and associated pathways. We isolated 5072 proteins, and found that 67 proteins were downregulated and 109 proteins were upregulated in one or more groups during the aging process. Western blotting assays were performed to verify the proteomic results. Bioinformatic analysis identified proteins involved in neuronal degeneration, including proteins involved in neuronal firing, myelin sheath damage, and cell structure stability. We also observed the accumulation of extracellular matrix and lysosomal proteins which imply the occurrence of fibrosis and autophagy. Our results suggest a series of changes across a wide range of proteins in the human temporal lobe that may relate to aging and age-related neurodegenerative disorders. PMID:26631761

  7. Serum Levels of Toxic AGEs (TAGE) May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases.

    PubMed

    Takeuchi, Masayoshi

    2016-01-01

    Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE)), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer's disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD. PMID:27338481

  8. Serum Levels of Toxic AGEs (TAGE) May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases

    PubMed Central

    Takeuchi, Masayoshi

    2016-01-01

    Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE)), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer’s disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD. PMID:27338481

  9. Changes in cardiovascular health score and atherosclerosis progression in middle-aged and older persons in China: a cohort study

    PubMed Central

    Gao, Jingsheng; Bao, Minghui; Liu, Yan; Shi, Jihong; Huang, Zhe; Xing, Aijun; Wang, Yang; An, Shasha; Cai, Jun; Wu, Shouling; Yang, Xinchun

    2015-01-01

    Objectives The American Heart Association (AHA) proposed a definition of 4 cardiovascular health behaviours and 3 health factors. On the basis of the 7 metrics, the cardiovascular health score (CHS) was used to estimate individual-level changes in cardiovascular health status. The aim of this study was to investigate whether changes in CHS (⊿CHS) at different time-points are associated with atherosclerosis progression in middle-aged and older persons. Design Prospective cohort study in China. Settings We defined 8 groups (≤−4, −3, −2, −1, 0, 1, 2 and ≥3) according to ⊿CHS. The impact of ⊿CHS on the change of brachial–ankle pulse wave velocity (⊿baPWV) and atherosclerosis progression was analysed. Participants A total of 3951 individuals met the inclusion criteria (≥40 years old; no history of stroke, transient ischaemic attack or myocardial infarction) and had complete information. Results ⊿baPWV decreased gradually (126.46±355.91, 78.4±343.81, 69.6±316.27, 49.59±287.57, 57.07±261.17, 40.45±264.27, 37.45±283.26 and 21.66±264.17 cm/s, respectively) with increasing ⊿CHS (p for trend<0.05). Multivariate linear regression analysis suggested a negative relationship between these 2 variables, which persisted after adjustment for other risk factors. Each increase in CHS was associated with a reduced baPWV for 15.22 cm/s (B value −15.22, p<0.001). Conclusions ⊿CHS were negatively related to ⊿baPWV, which proved to be an independent predictor of the progression of atherosclerosis in middle-aged and older persons. Trial registration number Kailuan study (ChiCTR-TNC-11001489). PMID:26310397

  10. Lack of age-related clinical progression in PGC-1α-deficient mice - implications for mitochondrial encephalopathies.

    PubMed

    Szalardy, Levente; Molnar, Mate; Torok, Rita; Zadori, Denes; Kovacs, Gabor G; Vecsei, Laszlo; Klivenyi, Peter

    2016-10-15

    Impaired peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) function has been demonstrated in several neurodegenerative diseases, and murine whole-body knockouts of PGC-1α have been considered as models for Huntington's disease. Recent neuropathological studies, however, rather propose these animals to be morphological models of mitochondrial encephalopathies, with special reminiscence of Kearns-Sayre syndrome. PGC-1α-deficient animals have already been subjected to behavioral assessments; however, the contradictory findings and the paucity of data assessing long-term progression necessitated further examinations. This study provides a comprehensive neurological phenotypic profiling of full-length-(FL-)PGC-1α-deficient mice in a broad age spectrum, with special focus on previously controversial findings, the issue of long-term phenotypic progression, the histopathological assessment of previously non-characterized tissues of potential clinicopathological relevance, and the gene expression profile of novel brain-specific isoforms of PGC-1α. Our findings demonstrate moderate hypomotility with signs of gait and trunk ataxia in addition to severe impairments in coordination and muscle strength in FL-PGC-1α-deficient mice, phenotypic features consistent of a mitochondrial disease. Intriguingly, however, these early alterations did not progress with age, the understanding of which may unveil mechanisms of potential therapeutic relevance, as discussed. The observed phenotype did not associate with retinal or spinal cord alterations, and was accompanied by mild myopathic changes. Based on these, FL-PGC-1α-deficient mice can be regarded not only as morphological but behavioral models of mitochondrial encephalopathies, with an important temporal limitation that has now been clarified. The mechanisms capable of halting a potentially lethal phenotype are to be unveiled, as they may hold therapeutic value for mitochondrial diseases. PMID

  11. Canine ceroid lipofuscinosis, a model for ageing of the human isocortex.

    PubMed

    Braak, H; Braak, E; Strenge, H; Koppang, N

    1984-01-01

    In canine ceroid lipofuscinosis (one case studied), isocortical layer IIIab pyramidal cells develop spindle-shaped enlargements of their proximal axon filled with lipopigment, a feature that can be observed in juvenile and adult type of human neuronal ceroid lipofuscinosis and in normal ageing of the human isocortex as well. PMID:6479601

  12. Human cognition and mobility in aging: a model for berry fruit interventions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Changes in motor function in aging, in both animals and humans, include decrements in balance, strength, and coordination, even in the absence of specific movement disorders such as Parkinson’s disease. In humans, these alterations can increase fall risk, often leading to injury and premature nursin...

  13. SEM analysis of red blood cells in aged human bloodstains.

    PubMed

    Hortolà, P

    1992-08-01

    Mammal red blood cells (RBC) in bloodstains have been previously detected by light microscopy on stone tools from as early as 100,000 +/- 25,000 years ago. In order to evaluate the degree of morphological preservation of erythrocytes in bloodstains, an accidental human blood smear on white chert and several experimental bloodstains on hard substrates (the same stone-white chert; another type of stone-graywacke; a non-stone support-stainless steel), were stored in a room, in non-sterile and fluctuating conditions, for lengths of time ranging from 3 to 18 months. Afterwards, the specimens were coated with gold and examined by a Cambridge Stereoscan 120 scanning electron microscope. Results revealed a high preservation of RBC integrity, with the maintenance of several discocytary shapes, a low tendency to echinocytosis and a frequent appearance of a moon-like erythrocytary shape in the thinner areas of the bloodstains. PMID:1398371

  14. Emergence of fractal geometry on the surface of human cervical epithelial cells during progression towards cancer

    NASA Astrophysics Data System (ADS)

    Dokukin, M. E.; Guz, N. V.; Woodworth, C. D.; Sokolov, I.

    2015-03-01

    Despite considerable advances in understanding the molecular nature of cancer, many biophysical aspects of malignant development are still unclear. Here we study physical alterations of the surface of human cervical epithelial cells during stepwise in vitro development of cancer (from normal to immortal (premalignant), to malignant). We use atomic force microscopy to demonstrate that development of cancer is associated with emergence of simple fractal geometry on the cell surface. Contrary to the previously expected correlation between cancer and fractals, we find that fractal geometry occurs only at a limited period of development when immortal cells become cancerous; further cancer progression demonstrates deviation from fractal. Because of the connection between fractal behaviour and chaos (or far from equilibrium behaviour), these results suggest that chaotic behaviour coincides with the cancer transformation of the immortalization stage of cancer development, whereas further cancer progression recovers determinism of processes responsible for cell surface formation.

  15. Emerging of fractal geometry on surface of human cervical epithelial cells during progression towards cancer

    PubMed Central

    Dokukin, M. E.; Guz, N. V.; Woodworth, C.D.; Sokolov, I.

    2015-01-01

    Despite considerable advances in understanding the molecular nature of cancer, many biophysical aspects of malignant development are still unclear. Here we study physical alterations of the surface of human cervical epithelial cells during stepwise in vitro development of cancer (from normal to immortal (premalignant), to malignant). We use atomic force microscopy to demonstrate that development of cancer is associated with emergence of simple fractal geometry on the cell surface. Contrary to the previously expected correlation between cancer and fractals, we find that fractal geometry occurs only at a limited period of development when immortal cells become cancerous; further cancer progression demonstrates deviation from fractal. Because of the connection between fractal behaviour and chaos (or far from equilibrium behaviour), these results suggest that chaotic behaviour coincides with the cancer transformation of the immortalization stage of cancer development, whereas further cancer progression recovers determinism of processes responsible for cell surface formation. PMID:25844044

  16. Up-regulation of microRNA-15b correlates with unfavorable prognosis and malignant progression of human glioma

    PubMed Central

    Pang, Chao; Guan, Yanlei; Zhao, Kai; Chen, Ling; Bao, Yijun; Cui, Run; Li, Guangyu; Wang, Yunjie

    2015-01-01

    Recent studies have demonstrated that microRNA-15b (miR-15b) regulates cell cycle progression, proliferationnd apoptosis in glioma cells by targeting Cyclins. However, the clinical significance of miR-15b in human glioma remains unclear. Therefore, the aim of this study was to investigate the significance of miR-15b expression in diagnosis, prognosis and malignant progression of glioma. Quantitative real-time reverse transcriptive-PCR (qRT-PCR) was performed to examine miR-15b expression levels in 76 glioma tissues (13 grade II, 13 grade III and 50 grade IV gliomas) and seven glioma cell lines, as well as 10 non-neoplastic brain tissues and human astrocyte as control. MiR-15b showed significant increased expression in high-grade gliomas (P ≤ 0.001) and glioma cells (fold change 2.8-7.6) relative to non-neoplastic brains and astrocyte, respectively. Additionally, high miR-15b expression was significantly associated with advanced WHO grade (P ≤ 0.001), advanced patient age (P ≤ 0.001) and low Karnofsky performance score (KPS, P ≤ 0.001). Furthermore, Kaplan-Meier survival analysis and Cox regression analysis showed that patients with high miR-15b expression had significantly poor overall survival rate (P ≤ 0.001) and miR-15b expression was an independent prognosis-predicting factor for glioma patients (P ≤ 0.001; risk ratio = 5.6), respectively. Moreover, miR-15b expression was examined in seven independent patients with primary grade II or III gliomas that spontaneously progressed to grade III or IV gliomas. Statistically significant higher expression (P = 0.01) in the recurrent tumor compared with the corresponding primary tumor was observed in all of the seven patients. Our results suggest that miR-15b may be a prognostic predictor and be involved in malignant progression of glioma. PMID:26191187

  17. Exogenous fatty acid binding protein 4 promotes human prostate cancer cell progression.

    PubMed

    Uehara, Hisanori; Takahashi, Tetsuyuki; Oha, Mina; Ogawa, Hirohisa; Izumi, Keisuke

    2014-12-01

    Epidemiologic studies have found that obesity is associated with malignant grade and mortality in prostate cancer. Several adipokines have been implicated as putative mediating factors between obesity and prostate cancer. Fatty acid binding protein 4 (FABP4), a member of the cytoplasmic fatty acid binding protein multigene family, was recently identified as a novel adipokine. Although FABP4 is released from adipocytes and mean circulating concentrations of FABP4 are linked with obesity, effects of exogenous FABP4 on prostate cancer progression are unclear. In this study, we examined the effects of exogenous FABP4 on human prostate cancer cell progression. FABP4 treatment promoted serum-induced prostate cancer cell invasion in vitro. Furthermore, oleic acid promoted prostate cancer cell invasion only if FABP4 was present in the medium. These promoting effects were reduced by FABP4 inhibitor, which inhibits FABP4 binding to fatty acids. Immunostaining for FABP4 showed that exogenous FABP4 was taken up into DU145 cells in three-dimensional culture. In mice, treatment with FABP4 inhibitor reduced the subcutaneous growth and lung metastasis of prostate cancer cells. Immunohistochemical analysis showed that the number of apoptotic cells, positive for cleaved caspase-3 and cleaved PARP, was increased in subcutaneous tumors of FABP4 inhibitor-treated mice, as compared with control mice. These results suggest that exogenous FABP4 might promote human prostate cancer cell progression by binding with fatty acids. Additionally, exogenous FABP4 activated the PI3K/Akt pathway, independently of binding to fatty acids. Thus, FABP4 might be a key molecule to understand the mechanisms underlying the obesity-prostate cancer progression link. PMID:24740818

  18. Metrics for the Human Proteome Project 2015: Progress on the Human Proteome and Guidelines for High-Confidence Protein Identification.

    PubMed

    Omenn, Gilbert S; Lane, Lydie; Lundberg, Emma K; Beavis, Ronald C; Nesvizhskii, Alexey I; Deutsch, Eric W

    2015-09-01

    Remarkable progress continues on the annotation of the proteins identified in the Human Proteome and on finding credible proteomic evidence for the expression of "missing proteins". Missing proteins are those with no previous protein-level evidence or insufficient evidence to make a confident identification upon reanalysis in PeptideAtlas and curation in neXtProt. Enhanced with several major new data sets published in 2014, the human proteome presented as neXtProt, version 2014-09-19, has 16,491 unique confident proteins (PE level 1), up from 13,664 at 2012-12 and 15,646 at 2013-09. That leaves 2948 missing proteins from genes classified having protein existence level PE 2, 3, or 4, as well as 616 dubious proteins at PE 5. Here, we document the progress of the HPP and discuss the importance of assessing the quality of evidence, confirming automated findings and considering alternative protein matches for spectra and peptides. We provide guidelines for proteomics investigators to apply in reporting newly identified proteins. PMID:26155816

  19. Key role of human leukocyte antigen in modulating human immunodeficiency virus progression: An overview of the possible applications.

    PubMed

    Grifoni, Alba; Montesano, Carla; Colizzi, Vittorio; Amicosante, Massimo

    2015-05-12

    Host and viral factors deeply influence the human immunodeficiency virus (HIV) disease progression. Among them human leukocyte antigen (HLA) locus plays a key role at different levels. In fact, genes of the HLA locus have shown the peculiar capability to modulate both innate and adaptive immune responses. In particular, HLA class I molecules are recognized by CD8(+) T-cells and natural killers (NK) cells towards the interaction with T cell receptor (TCR) and Killer Immunoglobulin Receptor (KIR) 3DL1 respectively. Polymorphisms within the different HLA alleles generate structural changes in HLA class I peptide-binding pockets. Amino acid changes in the peptide-binding pocket lead to the presentation of a different set of peptides to T and NK cells. This review summarizes the role of HLA in HIV progression toward acquired immunodeficiency disease syndrome and its receptors. Recently, many studies have been focused on determining the HLA binding-peptides. The novel use of immune-informatics tools, from the prediction of the HLA-bound peptides to the modification of the HLA-receptor complexes, is considered. A better knowledge of HLA peptide presentation and recognition are allowing new strategies for immune response manipulation to be applied against HIV virus. PMID:25964877

  20. Primary age-related tauopathy (PART): a common pathology associated with human aging

    PubMed Central

    Crary, John F.; Trojanowski, John Q.; Schneider, Julie A.; Abisambra, Jose F.; Abner, Erin L.; Alafuzoff, Irina; Arnold, Steven E.; Attems, Johannes; Beach, Thomas G.; Bigio, Eileen H.; Cairns, Nigel J.; Dickson, Dennis W.; Gearing, Marla; Grinberg, Lea T.; Hof, Patrick R.; Hyman, Bradley T.; Jellinger, Kurt; Jicha, Gregory A.; Kovacs, Gabor G.; Knopman, David S.; Kofler, Julia; Kukull, Walter A.; Mackenzie, Ian R.; Masliah, Eliezer; McKee, Ann; Montine, Thomas J.; Murray, Melissa E.; Neltner, Janna H.; Santa-Maria, Ismael; Seeley, William W.; Serrano-Pozo, Alberto; Shelanski, Michael L.; Stein, Thor; Takao, Masaki; Thal, Dietmar R.; Toledo, Jonathan B.; Troncoso, Juan C.; Vonsattel, Jean Paul; White, Charles L.; Wisniewski, Thomas; Woltjer, Randall L.; Yamada, Masahito; Nelson, Peter T.

    2014-01-01

    We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFT) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFT are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed. PMID:25348064

  1. Human Cpr (Cell Cycle Progression Restoration) Genes Impart a Far(-) Phenotype on Yeast Cells

    PubMed Central

    Edwards, M. C.; Liegeois, N.; Horecka, J.; DePinho, R. A.; Sprague-Jr., G. F.; Tyers, M.; Elledge, S. J.

    1997-01-01

    Regulated cell cycle progression depends on the proper integration of growth control pathways with the basic cell cycle machinery. While many of the central molecules such as cyclins, CDKs, and CKIs are known, and many of the kinases and phosphatases that modify the CDKs have been identified, little is known about the additional layers of regulation that impinge upon these molecules. To identify new regulators of cell proliferation, we have selected for human and yeast cDNAs that when overexpressed were capable of specifically overcoming G(1) arrest signals from the cell cycle branch of the mating pheromone pathway, while still maintaining the integrity of the transcriptional induction branch. We have identified 13 human CPR (cell cycle progression restoration) genes and 11 yeast OPY (overproduction-induced pheromone-resistant yeast) genes that specifically block the G(1) arrest by mating pheromone. The CPR genes represent a variety of biochemical functions including a new cyclin, a tumor suppressor binding protein, chaperones, transcription factors, translation factors, RNA-binding proteins, as well as novel proteins. Several CPR genes require individual CLNs to promote pheromone resistance and those that require CLN3 increase the basal levels of Cln3 protein. Moreover, several of the yeast OPY genes have overlapping functions with the human CPR genes, indicating a possible conservation of roles. PMID:9383053

  2. Stratum corneum acidification is impaired in moderately aged human and murine skin.

    PubMed

    Choi, Eung-Ho; Man, Mao-Qiang; Xu, Pu; Xin, Shujun; Liu, Zhili; Crumrine, Debra A; Jiang, Yan J; Fluhr, Joachim W; Feingold, Kenneth R; Elias, Peter M; Mauro, Theodora M

    2007-12-01

    Aged skin commonly is afflicted by inflammatory skin diseases or xerosis/eczema that could be triggered or exacerbated by impaired epidermal permeability barrier homeostasis. This defect is linked to reduced epidermal lipid synthesis in humans and in mice of advanced age (i.e., >75 years in human or >18-24 months in mice). We now report that barrier defects in moderately aged humans (50-80 years) or analogously aged mice (12-15 months) are linked instead to defective stratum corneum (SC) acidity. In moderately aged mouse epidermis, we find that abnormal acidification, in turn, is linked to decreased Na+/H+ antiporter (NHE1) expression. Decreased NHE1 levels lead to increased SC pH, which results in defective lipid processing and delayed maturation of lamellar membranes, due to suboptimal activation of the pH-sensitive essential, lipid-processing enzyme, beta-glucocerebrosidase. Conversely, impaired SC integrity in moderately aged mice is due to increased pH-dependent activation of serine proteases, leading to premature degradation of corneodesmosomes. These abnormalities were normalized by exogenously acidifying the SC, suggesting a basis for the well-known acidification therapies that are widely used to treat the pathologic xerosis/eczema seen in moderately aged humans. PMID:17554364

  3. Photoprotective and anti-skin-aging effects of eicosapentaenoic acid in human skin in vivo.

    PubMed

    Kim, Hyeon Ho; Cho, Soyun; Lee, Serah; Kim, Kyu Han; Cho, Kwang Hyun; Eun, Hee Chul; Chung, Jin Ho

    2006-05-01

    Skin aging can be attributed to photoaging (extrinsic) and chronological (intrinsic) aging. Photoaging and intrinsic aging are induced by damage to human skin attributable to repeated exposure to ultraviolet (UV) irradiation and to the passage of time, respectively. In our previous report, eicosapentaenoic acid (EPA) was found to inhibit UV-induced matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Therefore, we investigated the effects of EPA on UV-induced skin damage and intrinsic aging by applying EPA topically to young and aged human skin, respectively. By immunohistochemical analysis and Western blotting, we found that topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease induced by UV light. It was also found that EPA attenuated UV-induced MMP-1 and MMP-9 expression by inhibiting UV-induced c-Jun phosphorylation, which is closely related to UV-induced activator protein-1 activation, and by inhibiting JNK and p38 activation. EPA also inhibited UV-induced cyclooxygenase-2 (COX-2) expression without altering COX-1 expression. Moreover, it was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. Together, these results demonstrate that topical EPA has potential as an anti-skin-aging agent. PMID:16467281

  4. Similarly Strong Purifying Selection Acts on Human Disease Genes of All Evolutionary Ages

    PubMed Central

    Cai, James J.; Borenstein, Elhanan; Chen, Rong

    2009-01-01

    A number of studies have showed that recently created genes differ from the genes created in deep evolutionary past in many aspects. Here, we determined the age of emergence and propensity for gene loss (PGL) of all human protein–coding genes and compared disease genes with non-disease genes in terms of their evolutionary rate, strength of purifying selection, mRNA expression, and genetic redundancy. The older and the less prone to loss, non-disease genes have been evolving 1.5- to 3-fold slower between humans and chimps than young non-disease genes, whereas Mendelian disease genes have been evolving very slowly regardless of their ages and PGL. Complex disease genes showed an intermediate pattern. Disease genes also have higher mRNA expression heterogeneity across multiple tissues than non-disease genes regardless of age and PGL. Young and middle-aged disease genes have fewer similar paralogs as non-disease genes of the same age. We reasoned that genes were more likely to be involved in human disease if they were under a strong functional constraint, expressed heterogeneously across tissues, and lacked genetic redundancy. Young human genes that have been evolving under strong constraint between humans and chimps might also be enriched for genes that encode important primate or even human-specific functions. PMID:20333184

  5. Developmental Progression of the Coronary Vasculature in Human Embryos and Fetuses.

    PubMed

    Tomanek, Robert J

    2016-01-01

    Although considerable advances in our understanding of mammalian and avian embryonic coronary development have occurred during the last decade, our current knowledge of this topic in humans is limited. Accordingly, the aim of this study was to determine if the development of the human coronary vasculature in humans is like that of other mammals and avians. The data document a progression of events involving mesenchymal cell-containing villi from the proepicardium, establishment of blood islands and a capillary network. The major finding of the study is direct evidence that the capillary plexus associated with spindle cells and erythroblasts invades the base of the aorta to form coronary ostia. A role for the dorsal mesocardium is also indicated by the finding that cells from this region are continuous with the aorta and pulmonary artery. The development of the tunica media of the coronary arteries follows the same base-apex progression as in other species, with the development of branches occurring late in the embryonic period. The fetal period is characterized by 1) growth and a numerical increase in the smallest arterial branches, veins, and venules, 2) innervation of arteries, and 3) inclusion of elastic fibers in the tunica media of the coronary arteries and development of the tunica adventitia. In conclusion, the data demonstrate that the development of the coronary system in humans is similar to that of other mammalian and avian species, and for the first time documents that the formation of the ostia and coronary stems in humans occurs by ingrowth of a vascular plexus and associated cells from the epicardium. PMID:26475042

  6. Role of growth factors in the human endometrium during aging.

    PubMed

    Leone, M; Costantini, C; Gallo, G; Voci, A; Massajoli, M; Messeni Leone, M; de Cecco, L

    1993-01-01

    The aim of this study was to investigate the possible role of epidermal growth factor (EGF) and of insulin-like growth factor-I (IGF-I) in physiological and pathological changes of the endometrial tissue during aging. Thirty-four patients undergoing hysterectomy were divided into three groups: (A) premenopausal women with regular menses, (B) pre-menopausal women with irregular bleeding and (C) post-menopausal women. Endometrial samples were collected after the removal of uterus and were used for immunohistochemical evaluation of EGF, EGF receptor (EGFr) and IGF-I and also for Northern blot analysis of IGF-I gene expression. Plasma levels of 17 beta-oestradiol (E2), D4-androstenedione (D4-A) and oestrone (E1) were also assayed. The immunohistochemical scores (HSCORES) for EGF, EGFr and IGF-I were significantly higher in groups A and B than in group C. Independently from the menstrual history, significantly higher HSCORES of EGF, EGFr and IGF-I were present in hyperplastic endometrium than in those which were proliferative and atrophic. Moreover, IGF-I mRNA expression was observed in all pre-menopausal women, whereas only 1 post-menopausal women with hyperplastic endometrium showed detectable RNA encoding for IGF-I. Higher levels of D4-A were also significantly correlated (P < 0.05) with higher HSCORES of EGF, EGFr and IGF-I. Our results suggest that the above mentioned growth factors could act as mediators of oestrogens on the endometrial functional activity. PMID:7679182

  7. Analysis of cancer genomes reveals basic features of human aging and its role in cancer development.

    PubMed

    Podolskiy, Dmitriy I; Lobanov, Alexei V; Kryukov, Gregory V; Gladyshev, Vadim N

    2016-01-01

    Somatic mutations have long been implicated in aging and disease, but their impact on fitness and function is difficult to assess. Here by analysing human cancer genomes we identify mutational patterns associated with aging. Our analyses suggest that age-associated mutation load and burden double approximately every 8 years, similar to the all-cause mortality doubling time. This analysis further reveals variance in the rate of aging among different human tissues, for example, slightly accelerated aging of the reproductive system. Age-adjusted mutation load and burden correlate with the corresponding cancer incidence and precede it on average by 15 years, pointing to pre-clinical cancer development times. Behaviour of mutation load also exhibits gender differences and late-life reversals, explaining some gender-specific and late-life patterns in cancer incidence rates. Overall, this study characterizes some features of human aging and offers a mechanism for age being a risk factor for the onset of cancer. PMID:27515585

  8. Age-Infusion Approach to Derive Injury Risk Curves for Dummies from Human Cadaver Tests

    PubMed Central

    Yoganandan, Narayan; Banerjee, Anjishnu; Pintar, Frank A.

    2015-01-01

    Injury criteria and risk curves are needed for anthropomorphic test devices (dummies) to assess injuries for improving human safety. The present state of knowledge is based on using injury outcomes and biomechanical metrics from post-mortem human subject (PMHS) and mechanical records from dummy tests. Data from these models are combined to develop dummy injury assessment risk curves (IARCs)/dummy injury assessment risk values (IARVs). This simple substitution approach involves duplicating dummy metrics for PMHS tested under similar conditions and pairing with PMHS injury outcomes. It does not directly account for the age of each specimen tested in the PMHS group. Current substitution methods for injury risk assessments use age as a covariate and dummy metrics (e.g., accelerations) are not modified so that age can be directly included in the model. The age-infusion methodology presented in this perspective article accommodates for an annual rate factor that modifies the dummy injury risk assessment responses to account for the age of the PMHS that the injury data were based on. The annual rate factor is determined using human injury risk curves. The dummy metrics are modulated based on individual PMHS age and rate factor, thus “infusing” age into the dummy data. Using PMHS injuries and accelerations from side-impact experiments, matched-pair dummy tests, and logistic regression techniques, the methodology demonstrates the process of age-infusion to derive the IARCs and IARVs. PMID:26697422

  9. Analysis of cancer genomes reveals basic features of human aging and its role in cancer development

    PubMed Central

    Podolskiy, Dmitriy I.; Lobanov, Alexei V.; Kryukov, Gregory V.; Gladyshev, Vadim N.

    2016-01-01

    Somatic mutations have long been implicated in aging and disease, but their impact on fitness and function is difficult to assess. Here by analysing human cancer genomes we identify mutational patterns associated with aging. Our analyses suggest that age-associated mutation load and burden double approximately every 8 years, similar to the all-cause mortality doubling time. This analysis further reveals variance in the rate of aging among different human tissues, for example, slightly accelerated aging of the reproductive system. Age-adjusted mutation load and burden correlate with the corresponding cancer incidence and precede it on average by 15 years, pointing to pre-clinical cancer development times. Behaviour of mutation load also exhibits gender differences and late-life reversals, explaining some gender-specific and late-life patterns in cancer incidence rates. Overall, this study characterizes some features of human aging and offers a mechanism for age being a risk factor for the onset of cancer. PMID:27515585

  10. Genetic determination of telomere size in humans: A twin study of three age groups

    SciTech Connect

    Slagboom, P.E.; Droog, S.; Boomsma, D.I.

    1994-11-01

    Reduction of telomere length has been postulated to be a casual factor in cellular aging. Human telomeres terminate in tandemly arranged repeat arrays consisting of the (TTAGGG) motif. The length of these arrays in cells from human mitotic tissues is inversely related to the age of the donor, indicating telomere reduction with age. In addition to telemore length differences between different age cohorts, considerable variation is present among individuals of the same age. To investigate whether this variation can be ascribed to genetic influences, we have measured the size of terminal restriction fragments (TRFs) in HaeIII-digested genomic DNA from 123 human MZ and DZ twin pairs 2-95 years of age. The average rate of telomere shortening was 31 bp/year, which is similar to that observed by others. Statistical analysis in 115 pairs 2-63 years of age indicates a 78% heritability for mean TRF length in this age cohort. The individual differences in mean TRF length in blood, therefore, seem to a large extent to be genetically determined. 24 refs., 4 figs., 2 tabs.

  11. The effect of plant aging on equipment qualification and human performance issues related to license renewal

    SciTech Connect

    Gunther, W.E.; Higgins, J.C.; Aggarwal, S.K.

    1991-12-31

    The aging of nuclear power plants is one of the most important issues facing the nuclear industry worldwide. Aging encompasses as forms of degradation to nuclear power plant components, systems, and structures that result from exposure to environmental conditions or from operational stresses. Both the degradation from aging and actions taken to address the aging, such as increased maintenance and testing, can significantly impact human performance in the plant. Research into the causes and effects of aging as obtained through the assessment of operating experience and testing have raised questions regarding the adequacy of existing industry standards for addressing the concerns raised by this research. This paper discusses these issues, with particular emphasis in the area of equipment qualification and human performance.

  12. The effect of plant aging on equipment qualification and human performance issues related to license renewal

    SciTech Connect

    Gunther, W.E.; Higgins, J.C. ); Aggarwal, S.K. )

    1991-01-01

    The aging of nuclear power plants is one of the most important issues facing the nuclear industry worldwide. Aging encompasses as forms of degradation to nuclear power plant components, systems, and structures that result from exposure to environmental conditions or from operational stresses. Both the degradation from aging and actions taken to address the aging, such as increased maintenance and testing, can significantly impact human performance in the plant. Research into the causes and effects of aging as obtained through the assessment of operating experience and testing have raised questions regarding the adequacy of existing industry standards for addressing the concerns raised by this research. This paper discusses these issues, with particular emphasis in the area of equipment qualification and human performance.

  13. Orientation dependence of progressive post-yield behavior of human cortical bone in compression

    PubMed Central

    Dong, Xuanliang N.; Acuna, Rae L.; Luo, Qing; Wang, Xiaodu

    2013-01-01

    Identifying the underlying mechanisms of energy dissipation during post-yield deformation of bone is critical in understanding bone fragility fractures. However, the orientation-dependence of post-yield properties of bone is still poorly understood. Thus, the objective of this study was to determine the effect of loading direction on the evolution of post-yield behavior of bone using a progressive loading protocol. To do so, cylindrical compressive bone samples were prepared each in the longitudinal, circumferential and radial directions, from the mid-shaft of cadaveric femurs procured from eight middle-aged male donors (51.5 ± 3.3 years old). These specimens were tested in compression in a progressive loading scheme. The results exhibited that the elastic modulus, yield stress, and energy dissipation were significantly greater in the longitudinal direction than in the transverse (circumferential and radial) directions. However, no significant differences were observed in the yield strain as well as in the successive plastic strain with respect to the increasing applied strain among the three orientations. These results suggest that the initiation and progression of plastic strain are independent of loading orientations, thus implying that the underlying mechanism of plastic behavior of bone in compression is similar in all the orientations. PMID:22995144

  14. Effects of aging on nitrergic neurons in human striatum and subthalamic nucleus.

    PubMed

    Santos-Lobato, Bruno Lopes dos; Del-Bel, Elaine Aparecida; Pittella, José Eymard Homem; Tumas, Vitor

    2015-09-01

    Nitric oxide (NO) is a major neurotransmitter associated with motor control in basal ganglia. Movement disorders, as essential tremor and Parkinson's disease, are more prevalent on aged individuals. We investigated the effects of aging on neuronal density and diameter/area of nitrergic neurons in samples of striatum (caudate and putamen) and subthalamic nucleus of 20 human brains from normal subjects, stained by histochemistry for NADPH-diaphorase and immunohistochemistry for neuronal NO synthase. Our data showed aging does not modify the neuronal density and size of nitrergic neurons in striatum and subthalamic nucleus. These findings suggest a lack of association between aging and morphologic changes on nitrergic neurons. PMID:26352497

  15. Allotransplantation for patients age 40 years and greater with non-Hodgkin Lymphoma (NHL): encouraging progression-free survival

    PubMed Central

    McClune, Brian L.; Ahn, Kwang Woo; Wang, Hai-Lin; Antin, Joseph H.; Artz, Andrew S.; Cahn, Jean-Yves; Deol, Abhinav; Freytes, César O.; Hamadani, Mehdi; Holmberg, Leona A.; Jagasia, Madan H.; Jakubowski, Ann A.; Kharfan-Dabaja, Mohamed A.; Lazarus, Hillard M.; Miller, Alan M.; Olsson, Richard; Pedersen, Tanya L.; Pidala, Joseph; Pulsipher, Michael A.; Rowe, Jacob M.; Saber, Wael; van Besien, Koen W.; Waller, Edmund K.; Aljurf, Mahmoud D.; Akpek, Görgun; Bacher, Ulrike; Chao, Nelson J.; Chen, Yi-Bin; Cooper, Brenda W.; Dehn, Jason; de Lima, Marcos J.; Hsu, Jack W.; Lewis, Ian D.; Marks, David I.; McGuirk, Joseph; Cairo, Mitchell S.; Schouten, Harry C.; Szer, Jeffrey; Ramanathan, Muthalagu; Savani, Bipin N.; Seftel, Matthew; Socie, Gérard; Vij, Ravi; Warlick, Erica D.; Weisdorf, Daniel J.

    2014-01-01

    Non-Hodgkin lymphomas (NHL) disproportionately affect older patients who uncommonly receive allogeneic hematopoietic cell transplantation (HCT). We analyzed CIBMTR data on 1248 patients ≥40 years receiving reduced-intensity conditioning (RIC) or non-myeloablative (NMA) HCT for aggressive (n=668) and indolent (n=580) NHL. Aggressive lymphoma was more frequent in the oldest cohort [(age 40–54) 49% vs. (55–64) 57% vs. (≥65) 67% p=0.0008]; fewer patients ≥65 had prior autografting [26% vs. 24% vs. 9%; p=0.002)]. Rates of relapse, acute and chronic GVHD and non-relapse mortality (NRM) at one year were similar [22%, 95% confidence interval (CI) 19–26%; 27%, 95% CI 23–31%; 34%, 95% CI 24–44%]. Progression-free (PFS) and overall (OS) survival at 3 years was slightly lower in older cohorts [OS:54%, 95% CI 50–58%; 40%, 95% CI 36–44%; 39%, 95% CI 28–50%; p<0.0001]. Multivariate analysis revealed no significant effect of age on acute or chronic GVHD or relapse. Age ≥55 years, Karnofsky performance status <80, and HLA-mismatch adversely impacted NRM, PFS, and OS. Disease status at HCT, but not histologic subtype, worsened NRM, relapse, PFS and OS. Even for patients ≥55 years, OS still approached 40% at 3 years suggesting HCT effects long-term remissions and remains underutilized in qualified older patients with NHL. PMID:24641829

  16. Towards Synthesis and Usage of Actinide-Bearing REE Phosphate age Standards: A Progress Report

    NASA Astrophysics Data System (ADS)

    Pyle, J. M.; Cherniak, D. J.

    2006-05-01

    Electron microprobe (EMP) dates result from a concentration-time unit conversion, so use of a concentration- based (rather than isotope-ratio based) fictive age standard is warranted. This observation has motivated our mineral synthesis program, aimed at producing actinide-doped REE phosphate EMP dating standards that meet the following criteria: 1) known concentrations of U, Th, and Pb; 2) homogeneous intragrain distribution of all components; 3) of suitable size, either as a single-crystal or polycrystalline sintered ceramic. Single-crystal synthesis of actinide-doped LaPO4 by flux-growth methods results in disproportionation of lanthanide and flux, alkali, and actinide components into phosphate and oxide phases, respectively, and flux- growth methods were abandoned. Actinide-doped La phosphate is successfully prepared by high-T annealing and hydrothermal processing of microcrystalline phosphate; both homogeneity and charge-balance of (Ca, Th, Pb)-bearing LaPO4 increase with increasing solvent acidity during cold-seal hydrothermal synthesis. A combination of pressing and high-T (1400° C) sintering transforms fine-grained (0.1-10 μm) run- products to ceramic pellets with 90-95% theoretical density. Our most recent runs focused on a target composition of La80(CaTh)17(CaU)2(PbTh)1PO4 processed with 6% 2M HCl at 820° C, 0.75 kbar for 1 week. The run products are 0.1-2 μm crystals identified by XRD as La-actinide phosphate solid solution. 2 μm grains (N=16) give a composition (mean±2 sd) of La79.77(1.26)(CaTh)17.87(1.00)(CaU)1.53(0.42)(PbTh)0.82(0.09)PO4. Th (8.07-9.13 wt. %) is homogeneous at the level of analytical precision, and the Pb concentration range (3500-4350 ppm) is restricted relative to untreated precipitate. Uranium concentration values are more variable (6500-10000 ppm). This run yields a fictive age of 702±4 Ma (mean±2 se), compared to the fictive age of 794 Ma for the target composition.

  17. Aging and DNA damage in humans: a meta-analysis study

    PubMed Central

    Soares, Jorge Pinto; Cortinhas, António; Bento, Teresa; Leitão, José Carlos; Collins, Andrew R.; Gaivã, Isabel; Mota, Maria Paula

    2014-01-01

    Age-related DNA damage is regarded as one of the possible explanations of aging. Although a generalized idea about the accumulation of DNA damage with age exists, results found in the literature are inconsistent. To better understand the question of age-related DNA damage in humans and to identify possible moderator variables, a meta-analysis was conducted. Electronic databases and bibliographies for studies published since 2004 were searched. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for age-related DNA damage were calculated in a random-effects model. A total of 76 correlations from 36 studies with 4676 participants were included. Based on our analysis, a correlation between age and DNA damage was found (r = 0.230, p = 0.000; 95% confidence interval = 0.111 - 0.342). The test for heterogeneity of variance indicates that the study´s results are significantly high (Q (75) = 1754.831, p = 0.000). Moderator variables such as smoking habits, technique used, and the tissue/sample analyzed, are shown to influence age-related DNA damage (p=0.026; p=0.000; p=0.000, respectively). Nevertheless, sex did not show any influence on this relation (p=0.114). In conclusion, this meta-analysis showed an association between age and DNA damage in humans. It was also found that smoking habits, the technique used, and tissue/sample analyzed, are important moderator variables in age-related DNA damage. PMID:25140379

  18. Rejuvenation of Gene Expression Pattern of Aged Human Skin by Broadband Light Treatment: A Pilot Study

    PubMed Central

    Chang, Anne Lynn S; Bitter, Patrick H; Qu, Kun; Lin, Meihong; Rapicavoli, Nicole A; Chang, Howard Y

    2013-01-01

    Studies in model organisms suggest that aged cells can be functionally rejuvenated, but whether this concept applies to human skin is unclear. Here we apply 3′-end sequencing for expression quantification (“3-seq”) to discover the gene expression program associated with human photoaging and intrinsic skin aging (collectively termed “skin aging”), and the impact of broadband light (BBL) treatment. We find that skin aging was associated with a significantly altered expression level of 2,265 coding and noncoding RNAs, of which 1,293 became “rejuvenated” after BBL treatment; i.e., they became more similar to their expression level in youthful skin. Rejuvenated genes (RGs) included several known key regulators of organismal longevity and their proximal long noncoding RNAs. Skin aging is not associated with systematic changes in 3′-end mRNA processing. Hence, BBL treatment can restore gene expression pattern of photoaged and intrinsically aged human skin to resemble young skin. In addition, our data reveal, to our knowledge, a previously unreported set of targets that may lead to new insights into the human skin aging process. PMID:22931923

  19. The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research.

    PubMed

    Milman, Sofiya; Huffman, Derek M; Barzilai, Nir

    2016-06-14

    Mutations resulting in reduced signaling of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis are associated with increased life- and healthspan across model organisms. Similar findings have been noted in human cohorts with functional mutations in the somatotropic axis, suggesting that this pathway may also be relevant to human aging and protection from age-related diseases. While epidemiological data indicate that low circulating IGF-1 level may protect aging populations from cancer, results remain inconclusive regarding most other diseases. We propose that studies in humans and animals need to consider differences in sex, pathway function, organs, and time-specific effects of GH/IGF-1 signaling in order to better define the role of the somatotropic axis in aging. Agents that modulate signaling of the GH/IGF-1 pathway are available for human use, but before they can be implemented in clinical studies that target aging and age-related diseases, researchers need to address the challenges discussed in this Review. PMID:27304500

  20. Recombinant Human Bone Morphogenetic Protein-2 in Development and Progression of Oral Squamous Cell Carcinoma.

    PubMed

    Zaid, Khaled Waleed; Chantiri, Mansour; Bassit, Ghassan

    2016-01-01

    Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor-β superfamily, regulate many cellular activities including cell migration, differentiation, adhesion, proliferation and apoptosis. Use of recombinant human bone morphogenic protein?2 (rhBMP?2) in oral and maxillofacial surgery has seen a tremendous increase. Due to its role in many cellular pathways, the influence of this protein on carcinogenesis in different organs has been intensively studied over the past decade. BMPs also have been detected to have a role in the development and progression of many tumors, particularly disease-specific bone metastasis. In oral squamous cell carcinoma - the tumor type accounting for more than 90% of head and neck malignancies- aberrations of both BMP expression and associated signaling pathways have a certain relation with the development and progression of the disease by regulating a range of biological functions in the altered cells. In the current review, we discuss the influence of BMPs -especially rhBMP-2- in the development and progression of oral squamous cell carcinoma. PMID:27039814

  1. Magnetic Shielding Accelerates the Proliferation of Human Neuroblastoma Cell by Promoting G1-Phase Progression

    PubMed Central

    Liu, Ying; Bartlett, Perry F.; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  2. Location of several putative genes possibly involved in human breast cancer progression.

    PubMed

    Driouch, K; Briffod, M; Bièche, I; Champème, M H; Lidereau, R

    1998-05-15

    Cancer is a genetic disease resulting from an accumulation of genetic abnormalities in various regulatory genes. Most studies on genetic alterations in human breast cancer have involved primary tumors. The possible involvement of specific tumor suppressor genes in the later stages of cancer progression is poorly documented. We investigated allelic losses associated with breast cancer progression by analyzing 55 polymorphic markers on 11 autosomal chromosomes in a series of 49 relapses (23 local recurrences and 26 distant metastases). All of the loss of heterozygosity (LOH) regions reported in primary breast tumors were frequent in both series of relapses. These results suggest that the allelic losses that are common to the different series of samples occur very early during tumor progression. This study points to candidate metastasis-related genes targeted by LOH on chromosome arms 3p21.3, 16q22.2-23.2, and, possibly, 7q31 but provides no clear evidence of LOH affecting previously described metastasis-related genes such as NME1, MTS1, and TSG101. PMID:9605747

  3. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

    PubMed Central

    Chattopadhyay, Koushik

    2011-01-01

    Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals. PMID:22345983

  4. Magnetic shielding accelerates the proliferation of human neuroblastoma cell by promoting G1-phase progression.

    PubMed

    Mo, Wei-chuan; Zhang, Zi-jian; Liu, Ying; Bartlett, Perry F; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  5. Polarization sensitive changes in the human macula associated with normal aging and age-related macular degeneration

    NASA Astrophysics Data System (ADS)

    VanNasdale, Dean Allan, Jr.

    2011-12-01

    The human macula occupies a relatively small, but crucial retinal area, as it is the location responsible for our most acute spatial vision and best color discrimination. Localizing important landmarks in the retina is difficult even in normal eyes where morphological inter-individual variability is high. This becomes even more challenging in the presence of sight-threatening pathology. With respect to the human macula, there remains a significant gap in the understanding of normal structure and function. Even less is known about the pathological mechanisms that occur in sight-threatening diseases including age-related macular degeneration. Because relatively little is known about normal aging changes, it is also difficult to differentiate those changes from changes associated with retinal disease. To better understand normal and pathological changes in the macula, imaging techniques using specific optical signatures are required. Structural features in the macula can be distinguished based on their intrinsic properties using specific light/tissue interactions. Because of the high degree of structural regularity in the macula, polarization sensitive imaging is potentially a useful tool for evaluating the morphology and integrity of the cellular architecture for both normal individuals and those affected by disease. In our investigations, we used polarization sensitive imaging to determining normal landmarks that are important clinically and for research investigations. We found that precision and accuracy in localizing the central macula was greatly improved through the use of polarization sensitive imaging. We also found that specific polarization alterations can be used to demonstrate systematic changes as a function of age, disproportionately affecting the central macular region. When evaluating patients with age-related macular degeneration, we found that precision and accuracy of localizing the central macula was also improved, even when significant pathology

  6. Australia's oldest human remains: age of the Lake Mungo 3 skeleton.

    PubMed

    Thorne, A; Grün, R; Mortimer, G; Spooner, N A; Simpson, J J; McCulloch, M; Taylor, L; Curnoe, D

    1999-06-01

    We have carried out a comprehensive ESR and U-series dating study on the Lake Mungo 3 (LM3) human skeleton. The isotopic Th/U and Pa/U ratios indicate that some minor uranium mobilization may have occurred in the past. Taking such effects into account, the best age estimate for the human skeleton is obtained through the combination of U-series and ESR analyses yielding 62,000+/-6000 years. This age is in close agreement with OSL age estimates on the sediment into which the skeleton was buried of 61,000+/-2000 years. Furthermore, we obtained a U-series age of 81,000+/-21,000 years for the calcitic matrix that was precipitated on the bones after burial. All age results are considerably older than the previously assumed age of LM3 and demonstrate the necessity for directly dating hominid remains. We conclude that the Lake Mungo 3 burial documents the earliest known human presence on the Australian continent. The age implies that people who were skeletally within the range of the present Australian indigenous population colonized the continent during or before oxygen isotope stage 4 (57,000-71,000 years). PMID:10330330

  7. Aging and immunosenescence in invertebrates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Most contemporary research into aging is driven by interest in the human aging process and in interventions that attenuate the normal and pathophysiological effects of aging, or senescence. Operationally, senescence is the progressive, inevitable breakdown of the organism. Among the changes associat...

  8. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress

    PubMed Central

    ZHANG, Xiao-Liang; PANG, Wei; HU, Xin-Tian; LI, Jia-Li; YAO, Yong-Gang; ZHENG, Yong-Tang

    2014-01-01

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China’s growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China’s life sciences and pharmaceutical industry, and enhance China’s position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

  9. Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

    PubMed

    Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

    2014-11-18

    Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China. PMID:25465081

  10. Molecular features of a human rhabdomyosarcoma cell line with spontaneous metastatic progression

    PubMed Central

    Scholl, F A; Betts, D R; Niggli, F K; Schäfer, B W

    2000-01-01

    A novel human cell line was established from a primary botryoid rhabdomyosarcoma. Reverse transcription polymerase chain reaction investigations of this cell line, called RUCH-2, demonstrated expression of the regulatory factors PAX3, Myf3 and Myf5. After 3.5 months in culture, cells underwent a crisis after which Myf3 and Myf5 could no longer be detected, whereas PAX3 expression remained constant over the entire period. Karyotype analysis revealed breakpoints in regions similar to previously described alterations in primary rhabdomyosarcoma tumour samples. Interestingly, cells progressed to a metastatic phenotype, as observed by enhanced invasiveness in vitro and tumour growth in nude mice in vivo. On the molecular level, microarray analysis before and after progression identified extensive changes in the composition of the extracellular matrix. As expected, down-regulation of tissue inhibitors of metalloproteinases and up-regulation of matrix metalloproteinases were observed. Extensive down-regulation of several death receptors of the tumour necrosis factor family suggests that these cells might have an altered response to appropriate apoptotic stimuli. The RUCH-2 cell line represents a cellular model to study multistep tumorigenesis in human rhabdomyosarcoma, allowing molecular comparison of tumorigenic versus metastatic cancer cells. © 2000 Cancer Research Campaign PMID:10735512

  11. An improved syngeneic orthotopic murine model of human breast cancer progression.

    PubMed

    Rashid, Omar M; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-10-01

    Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous (OP) injection in the area of the nipple, or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. ODV produced less variable-sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development . PMID:25200444

  12. Progression and inflammation of human myeloid leukemia induced by ambient PM2.5 exposure.

    PubMed

    Jin, Xiao-Ting; Chen, Mei-Lan; Li, Rui-Jin; An, Quan; Song, Li; Zhao, Yi; Xiao, Hong; Cheng, Long; Li, Zhuo-Yu

    2016-08-01

    PM2.5 (aerodynamic diameter ≤2.5 μm) has been a dominating and ubiquitous air pollutant and has become a global concern. Emerging evidences suggest a positive correlation between PM2.5 and leukemia, but the underlying molecular mechanisms remain unclear and need to be elucidated. Here, we assessed the impacts of PM2.5 on the progression and inflammation of human myeloid leukemia at lower environmental doses and explored the possible pathway. We showed that PM2.5 exposure significantly induced the leukemia cell growth and enhanced the release of inflammatory mediators in both in vitro and in vivo models. Additionally, NF-κB p65 and p-STAT3 were activated in PM2.5-treated leukemia cells, with a concomitant increase in both ROS formation and NADPH oxidase expressions. Strikingly, the supplement of inhibitors, including NAC (ROS), PDTC (NF-κB), or WP1066 (STAT3), contributed to a decline in leukemia cell growth. Furthermore, enhanced expressions of inflammatory cytokines were attenuated by the addition of NAC or PDTC, but not affected by WP1066. This study demonstrates that PM2.5 promotes leukemia progression, identifies a potential intervention target, and provides further understanding of the detrimental effect of PM2.5 exposure on human health. PMID:26486797

  13. The information age as a work in progress: Implications for technical communicators

    SciTech Connect

    Preecs, B.L.

    1992-07-01

    The commercial media system in the United States is in the midst of radical, even revolutionary changes. Cable television companies are vying with telephone companies to provide advanced communications and information services to both homes and businesses. Recent decisions by the Federal Communications Commission to allow television networks to buy cable television systems create the possibility of bypassing local television stations. Computer companies are planning joint ventures with entertainment companies. The publishing, broadcasting, advertising, communications, and information-services businesses are converging into one universal, digital, interactive industry with annual revenues exceeding $120 billion. The same technology-driven changes also affect government. State and local governments are experimenting with delivering some government services electronically. While early experiments focus on easily delivered services, such as auto licenses, more complex applications are underway, such as creating information networks for economic development or converting property and utility records into computerized maps. The Information Age has arrived, and the implications for Society for Technical Communication (STC) members can hardly be overstated. Technical communicators will face changes in the way they work and how their work is distributed.

  14. Disrupted progression of the intestinal microbiota with age in children with cystic fibrosis

    PubMed Central

    Nielsen, Shaun; Needham, Bronwen; Leach, Steven T.; Day, Andrew S.; Jaffe, Adam; Thomas, Torsten; Ooi, Chee Y.

    2016-01-01

    Cystic fibrosis (CF) is a genetic disorder that leads to formation of thick epithelial secretions in affected organs. Chronic microbial infections associated with thick mucus secretions are the hallmarks of lung disease in CF. Despite similar conditions existing in the gastrointestinal tract, it is much less studied. We therefore examined the microbial communities within the gastrointestinal tract of children with and without CF (either pancreatic sufficient or insufficient) across a range of childhood ages (0.87–17 years). We observed a substantial reduction in the richness and diversity of gut bacteria associated with CF from early childhood (2 years) until late adolescence (17 years). A number of bacteria that establish themselves in the gut of healthy children were unable to do so in children with CF. In contrast, a few bacteria dominated the gut microbiota in children with CF and are unlikely to be beneficial for the metabolic function of the gut. A functioning pancreas (pancreatic sufficient) under a CF lifestyle showed little effect on microbial communities. Our results argue that any attempts to rectify the loss of bacterial diversity and provide normal bacterial function in the gut of CF patients should be conducted no later than early childhood. PMID:27143104

  15. Disrupted progression of the intestinal microbiota with age in children with cystic fibrosis.

    PubMed

    Nielsen, Shaun; Needham, Bronwen; Leach, Steven T; Day, Andrew S; Jaffe, Adam; Thomas, Torsten; Ooi, Chee Y

    2016-01-01

    Cystic fibrosis (CF) is a genetic disorder that leads to formation of thick epithelial secretions in affected organs. Chronic microbial infections associated with thick mucus secretions are the hallmarks of lung disease in CF. Despite similar conditions existing in the gastrointestinal tract, it is much less studied. We therefore examined the microbial communities within the gastrointestinal tract of children with and without CF (either pancreatic sufficient or insufficient) across a range of childhood ages (0.87-17 years). We observed a substantial reduction in the richness and diversity of gut bacteria associated with CF from early childhood (2 years) until late adolescence (17 years). A number of bacteria that establish themselves in the gut of healthy children were unable to do so in children with CF. In contrast, a few bacteria dominated the gut microbiota in children with CF and are unlikely to be beneficial for the metabolic function of the gut. A functioning pancreas (pancreatic sufficient) under a CF lifestyle showed little effect on microbial communities. Our results argue that any attempts to rectify the loss of bacterial diversity and provide normal bacterial function in the gut of CF patients should be conducted no later than early childhood. PMID:27143104

  16. Structural Aging Program technical progress for period, January 1, 1992--December 31, 1992

    SciTech Connect

    Naus, D.J.; Oland, C.B.

    1993-07-01

    The Structural Aging (SAG) Program is conducted for the Nuclear Regulatory Commission (NRC) by the Oak Ridge National Laboratory (ORNL). The program has the overall objective of preparing an expandable handbook or report which will provide potential structural safety issues and acceptance criteria for use by the NRC in nuclear power plant evaluations of continued service. Initial focus of the program is on concrete and concrete-related materials which comprise safety-related (Category I) structures in light-water reactor facilities. The SAG Program is organized into four tasks: Task S.1 -- Program Management, Task S.2 -- Materials Property Data Base, Task S.3 -- Structural Component Assessment/Repair Technology, and Task S.4 -- Quantitative Methodology for Continued Service Determinations. In meeting the individual objectives of these tasks resources are drawn from ORNL with subcontract support from universities and other research laboratories. This report provides an overview of principal developments in each of the four program tasks from January 1, 1992 to December 31, 1992. Planned activities under each of these tasks are also presented.

  17. Secreted proteome profiling in human RPE cell cultures derived from donors with age related macular degeneration and age matched healthy donors.

    PubMed

    An, Eunkyung; Lu, Xiaoning; Flippin, Jessica; Devaney, Joseph M; Halligan, Brian; Hoffman, Eric P; Hoffman, Eric; Strunnikova, Nataly; Csaky, Karl; Hathout, Yetrib

    2006-10-01

    Age-related macular degeneration (AMD) is characterized by progressive loss of central vision, which is attributed to abnormal accumulation of macular deposits called "drusen" at the interface between the basal surface of the retinal pigment epithelium (RPE) and Bruch's membrane. In the most severe cases, drusen deposits are accompanied by the growth of new blood vessels that breach the RPE layer and invade photoreceptors. In this study, we hypothesized that RPE secreted proteins are responsible for drusen formation and choroidal neovascularization. We used stable isotope labeling by amino acids in cell culture (SILAC) in combination with LC-MS/MS analysis and ZoomQuant quantification to assess differential protein secretion by RPE cell cultures prepared from human autopsy eyes of AMD donors (diagnosed by histological examinations of the macula and genotyped for the Y402H-complement factor H variant) and age-matched healthy control donors. In general, RPE cells were found to secrete a variety of extracellular matrix proteins, complement factors, and protease inhibitors that have been reported to be major constituents of drusen (hallmark deposits in AMD). Interestingly, RPE cells from AMD donors secreted 2 to 3-fold more galectin 3 binding protein, fibronectin, clusterin, matrix metalloproteinase-2 and pigment epithelium derived factor than RPE cells from age-matched healthy donors. Conversely, secreted protein acidic and rich in cysteine (SPARC) was found to be down regulated by 2-fold in AMD RPE cells versus healthy RPE cells. Ingenuity pathway analysis grouped these differentially secreted proteins into two groups; those involved in tissue development and angiogenesis and those involved in complement regulation and protein aggregation such as clusterin. Overall, these data strongly suggest that RPE cells are involved in the biogenesis of drusen and the pathology of AMD. PMID:17022631

  18. Diverse Roles of Growth Hormone and Insulin-Like Growth Factor-1 in Mammalian Aging: Progress and Controversies

    PubMed Central

    Csiszar, Anna; de Cabo, Raphael; Ferrucci, Luigi; Ungvari, Zoltan

    2012-01-01

    Because the initial reports demonstrating that circulating growth hormone and insulin-like growth factor-1 decrease with age in laboratory animals and humans, there have been numerous studies related to the importance of these hormones for healthy aging. Nevertheless, the role of these potent anabolic hormones in the genesis of the aging phenotype remains controversial. In this chapter, we review the studies demonstrating the beneficial and deleterious effects of growth hormone and insulin-like growth factor-1 deficiency and explore their effects on specific tissues and pathology as well as their potentially unique effects early during development. Based on this review, we conclude that the perceived contradictory roles of growth hormone and insulin-like growth factor-1 in the genesis of the aging phenotype should not be interpreted as a controversy on whether growth hormone or insulin-like growth factor-1 increases or decreases life span but rather as an opportunity to explore the complex roles of these hormones during specific stages of the life span. PMID:22522510

  19. Chondrocyte number and proteoglycan synthesis in the aging and osteoarthritic human articular cartilage

    PubMed Central

    Bobacz, K; Erlacher, L; Smolen, J; Soleiman, A; Graninger, W

    2004-01-01

    Objective: To correlate the number of chondrocytes in healthy and osteoarthritic human articular cartilage with age, and to evaluate the influence of donor age on total proteoglycan synthesis. Methods: Chondrocytes were isolated from human articular cartilage derived from hip joints with and without osteoarthritic lesions. The cell number was normalised to cartilage sample wet weight. In addition, the influence of age on chondrocyte numbers was assessed histomorphometrically. Chondrocytes were grown as monolayer cultures for seven days in a chemically defined serum-free basal medium. Total proteoglycan synthesis was measured by [35S]sulphate incorporation into newly synthesised macromolecules. Results: Chondrocyte numbers in healthy cartilage decreased significantly with advancing age (r = –0.69, p<0.0001). In contrast to healthy specimens, chondrocyte numbers were decreased in osteoarthritic cartilage irrespective of and unrelated to age, and differed markedly, by an average of 38%, from the cell numbers found in healthy individuals (p<0.0001). Regarding synthesis of matrix macromolecules, no dependence on patients' age, either in healthy or in osteoarthritic specimens, could be observed. Conclusions: Under the experimental conditions employed, chondrocytes from healthy and osteoarthritic joints synthesised comparable amounts of cartilage macromolecules, independent of age or underlying osteoarthritic disease. Thus the decrease in chondrocyte number in aging and osteoarthritic joints could be a crucial factor in limiting tissue replenishment. PMID:15547085

  20. Comprehensive Analysis of Maillard Protein Modifications in Human Lenses: Effect of Age and Cataract

    PubMed Central

    Smuda, Mareen; Henning, Christian; Raghavan, Cibin T.; Johar, Kaid; Vasavada, Abhay R.; Nagaraj, Ram H.; Glomb, Marcus A.

    2015-01-01

    In human lens proteins, advanced glycation endproducts (AGEs) originate from the reaction of glycating agents, e.g., vitamin C and glucose. AGEs have been considered to play a significant role in lens aging and cataract formation. Although several AGEs have been detected in the human lens, the contribution of individual glycating agents to their formation remains unclear. A highly sensitive liquid chromatography–tandem mass spectrometry multimethod was developed that allowed us to quantitate 21 protein modifications in normal and cataractous lenses, respectively. N6-Carboxymethyl lysine, N6-carboxyethyl lysine, N7-carboxyethyl arginine, methylglyoxal hydroimidazolone 1, and N6-lactoyl lysine were found to be the major Maillard protein modifications among these AGEs. The novel vitamin C specific amide AGEs, N6-xylonyl and N6-lyxonyl lysine, but also AGEs from glyoxal were detected, albeit in minor quantities. Among the 21 modifications, AGEs from the Amadori product (derived from the reaction of glucose and lysine) and methylglyoxal were dominant. PMID:25849437

  1. Aging Shapes the Population-Mean and -Dispersion of Gene Expression in Human Brains

    PubMed Central

    Brinkmeyer-Langford, Candice L.; Guan, Jinting; Ji, Guoli; Cai, James J.

    2016-01-01

    Human aging is associated with cognitive decline and an increased risk of neurodegenerative disease. Our objective for this study was to evaluate potential relationships between age and variation in gene expression across different regions of the brain. We analyzed the Genotype-Tissue Expression (GTEx) data from 54 to 101 tissue samples across 13 brain regions in post-mortem donors of European descent aged between 20 and 70 years at death. After accounting for the effects of covariates and hidden confounding factors, we identified 1446 protein-coding genes whose expression in one or more brain regions is correlated with chronological age at a false discovery rate of 5%. These genes are involved in various biological processes including apoptosis, mRNA splicing, amino acid biosynthesis, and neurotransmitter transport. The distribution of these genes among brain regions is uneven, suggesting variable regional responses to aging. We also found that the aging response of many genes, e.g., TP37 and C1QA, depends on individuals' genotypic backgrounds. Finally, using dispersion-specific analysis, we identified genes such as IL7R, MS4A4E, and TERF1/TERF2 whose expressions are differentially dispersed by aging, i.e., variances differ between age groups. Our results demonstrate that age-related gene expression is brain region-specific, genotype-dependent, and associated with both mean and dispersion changes. Our findings provide a foundation for more sophisticated gene expression modeling in the studies of age-related neurodegenerative diseases. PMID:27536236

  2. AGEs in human lens capsule promote the TGFβ2-mediated EMT of lens epithelial cells: implications for age-associated fibrosis.

    PubMed

    Raghavan, Cibin T; Smuda, Mareen; Smith, Andrew J O; Howell, Scott; Smith, Dawn G; Singh, Annapurna; Gupta, Pankaj; Glomb, Marcus A; Wormstone, Ian Michael; Nagaraj, Ram H

    2016-06-01

    Proteins in basement membrane (BM) are long-lived and accumulate chemical modifications during aging; advanced glycation endproduct (AGE) formation is one such modification. The human lens capsule is a BM secreted by lens epithelial cells. In this study, we have investigated the effect of aging and cataracts on the AGE levels in the human lens capsule and determined their role in the epithelial-to-mesenchymal transition (EMT) of lens epithelial cells. EMT occurs during posterior capsule opacification (PCO), also known as secondary cataract formation. We found age-dependent increases in several AGEs and significantly higher levels in cataractous lens capsules than in normal lens capsules measured by LC-MS/MS. The TGFβ2-mediated upregulation of the mRNA levels (by qPCR) of EMT-associated proteins was significantly enhanced in cells cultured on AGE-modified BM and human lens capsule compared with those on unmodified proteins. Such responses were also observed for TGFβ1. In the human capsular bag model of PCO, the AGE content of the capsule proteins was correlated with the synthesis of TGFβ2-mediated α-smooth muscle actin (αSMA). Taken together, our data imply that AGEs in the lens capsule promote the TGFβ2-mediated fibrosis of lens epithelial cells during PCO and suggest that AGEs in BMs could have a broader role in aging and diabetes-associated fibrosis. PMID:26853893

  3. Progress and Challenges in Developing Metabolic Footprints from Diet in Human Gut Microbial Cometabolism12

    PubMed Central

    Duffy, Linda C; Raiten, Daniel J; Hubbard, Van S; Starke-Reed, Pamela

    2015-01-01

    Homo sapiens harbor trillions of microbes, whose microbial metagenome (collective genome of a microbial community) using omic validation interrogation tools is estimated to be at least 100-fold that of human cells, which comprise 23,000 genes. This article highlights some of the current progress and open questions in nutrition-related areas of microbiome research. It also underscores the metabolic capabilities of microbial fermentation on nutritional substrates that require further mechanistic understanding and systems biology approaches of studying functional interactions between diet composition, gut microbiota, and host metabolism. Questions surrounding bacterial fermentation and degradation of dietary constituents (particularly by Firmicutes and Bacteroidetes) and deciphering how microbial encoding of enzymes and derived metabolites affect recovery of dietary energy by the host are more complex than previously thought. Moreover, it is essential to understand to what extent the intestinal microbiota is subject to dietary control and to integrate these data with functional metabolic signatures and biomarkers. Many lines of research have demonstrated the significant role of the gut microbiota in human physiology and disease. Probiotic and prebiotic products are proliferating in the market in response to consumer demand, and the science and technology around these products are progressing rapidly. With high-throughput molecular technologies driving the science, studying the bidirectional interactions of host-microbial cometabolism, epithelial cell maturation, shaping of innate immune development, normal vs. dysfunctional nutrient absorption and processing, and the complex signaling pathways involved is now possible. Substantiating the safety and mechanisms of action of probiotic/prebiotic formulations is critical. Beneficial modulation of the human microbiota by using these nutritional and biotherapeutic strategies holds considerable promise as next

  4. Progress and challenges in developing metabolic footprints from diet in human gut microbial cometabolism.

    PubMed

    Duffy, Linda C; Raiten, Daniel J; Hubbard, Van S; Starke-Reed, Pamela

    2015-05-01

    Homo sapiens harbor trillions of microbes, whose microbial metagenome (collective genome of a microbial community) using omic validation interrogation tools is estimated to be at least 100-fold that of human cells, which comprise 23,000 genes. This article highlights some of the current progress and open questions in nutrition-related areas of microbiome research. It also underscores the metabolic capabilities of microbial fermentation on nutritional substrates that require further mechanistic understanding and systems biology approaches of studying functional interactions between diet composition, gut microbiota, and host metabolism. Questions surrounding bacterial fermentation and degradation of dietary constituents (particularly by Firmicutes and Bacteroidetes) and deciphering how microbial encoding of enzymes and derived metabolites affect recovery of dietary energy by the host are more complex than previously thought. Moreover, it is essential to understand to what extent the intestinal microbiota is subject to dietary control and to integrate these data with functional metabolic signatures and biomarkers. Many lines of research have demonstrated the significant role of the gut microbiota in human physiology and disease. Probiotic and prebiotic products are proliferating in the market in response to consumer demand, and the science and technology around these products are progressing rapidly. With high-throughput molecular technologies driving the science, studying the bidirectional interactions of host-microbial cometabolism, epithelial cell maturation, shaping of innate immune development, normal vs. dysfunctional nutrient absorption and processing, and the complex signaling pathways involved is now possible. Substantiating the safety and mechanisms of action of probiotic/prebiotic formulations is critical. Beneficial modulation of the human microbiota by using these nutritional and biotherapeutic strategies holds considerable promise as next

  5. Canine Lymphoma as a Comparative Model for Human Non-Hodgkin Lymphoma: Recent Progress and Applications

    PubMed Central

    Ito, Daisuke; Frantz, Aric M.; Modiano, Jaime F.

    2016-01-01

    The term “lymphoma” describes a heterogeneous group of disorders involving monoclonal proliferation of malignant lymphocytes. As a group, lymphomas are among the most common tumors of dogs. Yet our enumeration and understanding of the many subtypes of lymphoma have been relatively slow, perhaps in part because for many years lymphoma was treated as a singular entity rather than a group of distinct diseases. The recognition that the full spectrum of lymphoid malignancies seen in humans also occurs in dogs, and that these tumors retain not only morphologic similarities and biological behavior but also synonymous driver molecular abnormalities, sets an ideal stage for dual-purpose research that can accelerate progress for these diseases in both species. Specifically, dogs represent exceptional models for defining causality, understanding progression, and developing new treatments for lymphoma in comparatively brief windows of time. Unique advantages of canine models include (1) spontaneous disease occurring without an isogenic background or genetic engineering; (2) chronology of disease adapted to lifespan, (3) shared environment and societal status that allows dogs to be treated as “patients,” while at the same time being able to ethically explore translational innovations that are not possible in human subjects; and (4) organization of dogs into breeds with relatively homogeneous genetic backgrounds and distinct predisposition for lymphomas. Here, we will review recent studies describing intrinsic and extrinsic factors that contribute to the pathogenesis of canine and human lymphomas, as well as newly developed tools that will enhance the fidelity of these models to improve diagnosis and develop new treatments. PMID:24642290

  6. Cellular morphometry of the bronchi of human and dog lungs. Progress report, April 1, 1991--October 1, 1991

    SciTech Connect

    Robbins, E.S.

    1991-09-01

    One hundred and forty-seven bronchial samples (generations 3--6) from 66 patients (62 usable; 36 female, 26 male; median age 61) have been dissected by generation from fixed surgical lung specimens obtained after the removal of pathological lesions. In addition, one hundred and fifty-six mongol dog bronchi (generations 2--6) dissected from different lobes of 26 dog lungs have also been similarly prepared. One hundred and twenty-seven human samples have been completely processed for electron microscopy and have yielded 994 electron micrographs of which 655 have been entered into the Computerized Stereological Analysis System (COSAS) and been used for the measurement of the distances of basal and mucous cell nuclei to the epithelial free surface. Similarly 328 micrographs of dog epithelium from 33 bronchial samples have been used to measure the distances of basal and mucous cell nuclei to the epithelial free surface and have been entered into COSAS. Using the COSAS planimetry program, we continue to expand our established data bases which describe the volume density and nuclear numbers per electron micrograph for 5 cell types of the human bronchial epithelial lining of men and women, as well as smokers, non-smokers and ex-smokers and similar parameters for the same 5 epithelial cell types of dog bronchi. Our micrographs of human bronchial epithelium have allowed us to analyze the recent suggestion that the DNA of lymphocytes may be subject to significant damage from Rn progeny while within the lung. Since the last progress report three papers have been submitted for publication. 17 refs., 4 tabs.

  7. Age Progression of Neuropathological Markers in the Brain of the Chilean Rodent Octodon degus, a Natural Model of Alzheimer's Disease.

    PubMed

    Inestrosa, Nibaldo C; Ríos, Juvenal A; Cisternas, Pedro; Tapia-Rojas, Cheril; Rivera, Daniela S; Braidy, Nady; Zolezzi, Juan M; Godoy, Juan A; Carvajal, Francisco J; Ardiles, Alvaro O; Bozinovic, Francisco; Palacios, Adrián G; Sachdev, Perminder S

    2015-11-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent Octodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α (PGC-1α). With these results, we suggest that the O. degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD. PMID:25351914

  8. Aging and the inhibition of competing hypotheses during visual word identification: evidence from the progressive demasking task.

    PubMed

    McArthur, Alisa D; Sears, Christopher R; Scialfa, Charles T; Sulsky, Lorne M

    2015-01-01

    Two experiments used the progressive demasking (PD) task to examine age differences in the ability to inhibit higher frequency competitors during the process of identifying a visually degraded word. In Experiment 1, older adults exhibited a larger inhibitory neighborhood frequency effect (i.e., slower identification of words with many higher frequency competitors) than younger adults, but additional analyses indicated that this difference could be explained by general slowing rather than a deficit in inhibitory abilities. In Experiment 2, a primed version of the PD task was used to promote hypothesis testing by semantically priming the target word (e.g., cry-weep) or a higher frequency competitor of the target (e.g, day-weep) prior to the onset of the demasking sequence. Although older adults were more likely to make identification errors consistent with an inhibitory deficit (e.g., identifying weep as week), these errors were infrequent overall and there was no corresponding evidence of a larger interference effect in the older adults' identification latencies. Taken together, performance in these two tasks provides little evidence of reduced inhibitory functioning in older adults. The implications for the inhibitory deficit hypothesis of cognitive aging and directions for future are discussed. PMID:24801737

  9. Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans?

    PubMed

    Wang, Haoran George; Jeffries, Joseph Joel; Wang, Tianren Frank

    2016-04-01

    Language and communication through it are two of the defining features of normally developed human beings. However, both these functions are often impaired in autism and schizophrenia. In the former disorder, the problem usually emerges in early childhood (~2 years old) and typically includes a lack of communication. In the latter condition, the language problems usually occur in adolescence and adulthood and presents as disorganized speech. What are the fundamental mechanisms underlying these two disorders? Is there a shared genetic basis? Are the traditional beliefs about them true? Are there any common strategies for their prevention and management? To answer these questions, we searched PubMed by using autism, schizophrenia, gene, and language abnormality as keywords, and we reconsidered the basic concepts about these two diseases or syndromes. We found many functional genes, for example, FOXP2, COMT, GABRB3, and DISC1, are actually implicated in both of them. After observing the symptoms, genetic correlates, and temporal progression of these two disorders as well as their relationships more carefully, we now infer that the occurrence of these two diseases is likely developmentally regulated via interaction between the genome and the environment. Furthermore, we propose a unified view of autism and schizophrenia: a single age-dependently occurred disease that is newly named as Systemic Integral Disorder: if occurring in children before age 2, it is called autism; if in adolescence or a later age, it is called schizophrenia. PMID:25686622

  10. Determination of Gender and Age Based on Pattern of Human Motion Using AdaBoost Algorithms

    NASA Astrophysics Data System (ADS)

    Handri, Santoso; Nomura, Shusaku; Nakamura, Kazuo

    Automated human identification by their walking behavior is a challenge attracting much interest among machine vision researchers. However, practical systems for such identification remain to be developed. In this study, a machine learning approach to understand human behavior based on motion imagery was proposed as the basis for developing pedestrian safety information systems. At the front end, image and video processing was performed to separate foreground from background images. Shape-width was then analyzed using 2D discrete wavelet transformation to extract human motion features. Finally, an adaptive boosting (AdaBoost) algorithm was performed to classify human gender and age into its class. The results demonstrated capability of the proposed systems to classify gender and age highly accurately.

  11. Developing Humanities Collections in the Digital Age: Exploring Humanities Faculty Engagement with Electronic and Print Resources

    ERIC Educational Resources Information Center

    Kachaluba, Sarah Buck; Brady, Jessica Evans; Critten, Jessica

    2014-01-01

    This article is based on quantitative and qualitative research examining humanities scholars' understandings of the advantages and disadvantages of print versus electronic information resources. It explores how humanities' faculty members at Florida State University (FSU) use print and electronic resources, as well as how they perceive these…

  12. Characterizing cognitive aging of recognition memory and related processes in animal models and in humans

    PubMed Central

    Burke, Sara N.; Ryan, Lee; Barnes, Carol A.

    2012-01-01

    Analyses of complex behaviors across the lifespan of animals can reveal the brain regions that are impacted by the normal aging process, thereby, elucidating potential therapeutic targets. Recent data from rats, monkeys, and humans converge, all indicating that recognition memory and complex visual perception are impaired in advanced age. These cognitive processes are also disrupted in animals with lesions of the perirhinal cortex, indicating that the the functional integrity of this structure is disrupted in old age. This current review summarizes these data, and highlights current methodologies for assessing perirhinal cortex-dependent behaviors across the lifespan. PMID:22988437

  13. Comparative effect of Piper betle, Chlorella vulgaris and tocotrienol-rich fraction on antioxidant enzymes activity in cellular ageing of human diploid fibroblasts

    PubMed Central

    2013-01-01

    Background Human diploid fibroblasts (HDFs) undergo a limited number of cellular divisions in culture and progressively reach a state of irreversible growth arrest, a process termed cellular ageing. Even though beneficial effects of Piper betle, Chlorella vulgaris and tocotrienol-rich fraction (TRF) have been reported, ongoing studies in relation to ageing is of interest to determine possible protective effects that may reverse the effect of ageing. The aim of this study was to evaluate the effect of P. betle, C. vulgaris and TRF in preventing cellular ageing of HDFs by determining the activity of antioxidant enzymes viz.; catalase, superoxide dismutase (SOD) and glutathione peroxidase. Methods Different passages of HDFs were treated with P. betle, C. vulgaris and TRF for 24 h prior to enzymes activity determination. Senescence-associated beta-galactosidase (SA β-gal) expression was assayed to validate cellular ageing. Results In cellular ageing of HDFs, catalase and glutathione peroxidase activities were reduced, but SOD activity was heightened during pre-senescence. P. betle exhibited the strongest antioxidant activity by reducing SA β-gal expression, catalase activities in all age groups, and SOD activity. TRF exhibited a strong antioxidant activity by reducing SA β-gal expression, and SOD activity in senescent HDFs. C. vulgaris extract managed to reduce SOD activity in senescent HDFs. Conclusion P. betle, C. vulgaris, and TRF have the potential as anti-ageing entities which compensated the role of antioxidant enzymes in cellular ageing of HDFs. PMID:23948056

  14. Age-related changes in human posture control: Motor coordination tests

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.

    1989-01-01

    Postural responses to support surface displacements were measured in 214 normal human subjects ranging in age from 7 to 81 years. Motor tests measured leg muscle Electromyography (EMG) latencies, body sway, and the amplitude and timing of changes in center of pressure displacements in response to sudden forward and backward horizontal translations of the support surface upon which the subjects stood. There were small increases in both EMG latencies and the time to reach the peak amplitude of center of pressure responses with increasing age. The amplitude of center of pressure responses showed little change with age if the amplitude measures were normalized by a factor related to subject height. In general, postural responses to sudden translations showed minimal changes with age, and all age related trends which were identified were small relative to the variability within the population.

  15. Collagen cross-linking effect on progressive keratoconus in patients younger than 18 years of age: A clinical trial

    PubMed Central

    Peyman, Alireza; Kamali, Ali; Khushabi, Maral; Nasrollahi, Kobra; Kargar, Neda; Taghaodi, Maryam; Razmjoo, Hasan; Fazel, Farhad; Salesi, Asiyeh

    2015-01-01

    Background: Keratoconus is a bilateral non-inflammatory corneal disease. Collagen cross-linking (CXL) is a new treatment option for the disease that uses ultraviolet A light irradiation and riboflavin administration. The aim of this study is to evaluate the effect of CXL on corneal topographic and refractive values in patients with keratoconus younger than 18 years of age. Materials and Methods: For the clinical trial study, 37 patients (64 eyes) younger than 18 years of age with progressive keratoconus were included. Age, sex, family history of keratoconus, and history of allergic disorders and eye rubbing were recorded. Refractive, topographic, and topometric indices were evaluated before and 12 months after the CXL with 3mW for 30 minutes. Results: Mean age (±SD) of the patients was 15.83 ± 1.53 years; 26 (70.3%) of the 37 patients were male. Fourteen (37.8%) had positive family history of keratoconus, 11 (29.7%) had history of allergic disorders, and 15 (40.5%) had positive history of eye rubbing. Of the refractive values, cylinder value decreased significantly from −4.50 ± 0.29 to −4.11 ± 0.28 (P = 0.001). Also, the logarithm of minimal angle of resolution (logMAR) uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) improved significantly 12 months after CXL (P = 0.012 and 0.001, respectively). Maximum keratometry before and after the operation was 53.82 ± 0.72 and 53.33 ± 0.72, respectively (P = 0.018). Differences for simulated K values, the thinnest cornea pachymetry, keratoconus index (KI), index of highest asymmetry (IHA), and index of highest decentration (IHD) before and 12 months after the CXL were statistically significant (P = 0.015, 0.034, <0.001, 0.017, 0.019, and 0.004, respectively). Conclusion: CXL improves the refractory, topographic, and topometric indices in patients with keratoconus younger than 18 years of age. PMID:26693470

  16. Regulation of skeletal muscle blood flow during exercise in ageing humans.

    PubMed

    Hearon, Christopher M; Dinenno, Frank A

    2016-04-15

    The regulation of skeletal muscle blood flow and oxygen delivery to contracting skeletal muscle is complex and involves the mechanical effects of muscle contraction; local metabolic, red blood cell and endothelium-derived substances; and the sympathetic nervous system (SNS). With advancing age in humans, skeletal muscle blood flow is typically reduced during dynamic exercise and this is due to a lower vascular conductance, which could ultimately contribute to age-associated reductions in aerobic exercise capacity, a primary predictor of mortality in both healthy and diseased ageing populations. Recent findings have highlighted the contribution of endothelium-derived substances to blood flow control in contracting muscle of older adults. With advancing age, impaired nitric oxide availability due to scavenging by reactive oxygen species, in conjunction with elevated vasoconstrictor signalling via endothelin-1, reduces the local vasodilatory response to muscle contraction. Additionally, ageing impairs the ability of contracting skeletal muscle to blunt sympathetic vasoconstriction (i.e. 'functional sympatholysis'), which is critical for the proper regulation of tissue blood flow distribution and oxygen delivery, and could further reduce skeletal muscle perfusion during high intensity and/or large muscle mass exercise in older adults. We propose that initiation of endothelium-dependent hyperpolarization is the underlying signalling event necessary to properly modulate sympathetic vasoconstriction in contracting muscle, and that age-associated impairments in red blood cell adenosine triphosphate release and stimulation of endothelium-dependent vasodilatation may explain impairments in both local vasodilatation and functional sympatholysis with advancing age in humans. PMID:26332887

  17. Alterations in Gene Array Patterns in Dendritic Cells from Aged Humans

    PubMed Central

    Cao, Jia-ning; Agrawal, Anshu; Sharman, Edward; Jia, Zhenyu; Gupta, Sudhir

    2014-01-01

    Dendritic cells (DCs) are major antigen-presenting cells that play a key role in initiating and regulating innate and adaptive immune responses. DCs are critical mediators of tolerance and immunity. The functional properties of DCs decline with age. The purpose of this study was to define the age-associated molecular changes in DCs by gene array analysis using Affymatrix GeneChips. The expression levels of a total of 260 genes (1.8%) were significantly different (144 down-regulated and 116 upregulated) in monocyte-derived DCs (MoDCs) from aged compared to young human donors. Of the 260 differentially expressed genes, 24% were down-regulated by more than 3-fold, suggesting that a large reduction in expression occurred for a notable number of genes in the aged. Our results suggest that the genes involved in immune response to pathogens, cell migration and T cell priming display significant age-related changes. Furthermore, downregulated genes involved in cell cycle arrest and DNA replication may play a critical role in aging-associated genetic instability. These changes in gene expression provide molecular based evidence for age-associated functional abnormalities in human DCs that may be responsible for the defects in adaptive immunity observed in the elderly. PMID:25191744

  18. Biomarkers of oxidative stress in erythrocytes as a function of human age.

    PubMed

    Maurya, Pawan Kumar; Kumar, Prabhanshu; Chandra, Pranjal

    2015-12-26

    Despite more than 300 theories to explain the aging process, oxidative stress theory offers the best mechanism to explain aging and age related disorders. Several studies has shown the importance of oxidative stress during aging. PubMed, Science Direct and Springer online data bases are taken into consideration to write this mini-review. Human erythrocytes are most abundant and specialized cells in the body. Erythrocytes were extensively studied due to their metabolism and gas transport functions. Recent studies on erythrocytes have provided us detailed information of cell membrane and its structural organization that may help in studying the aging and age associated changes. The susceptibility of an organism is associated with the antioxidant potential of the body. Erythrocytes have potent antioxidant protection consisting of enzymatic and non-enzymatic pathways that counteract with reactive oxygen species, thus maintaining the redox regulation in the body. The non-enzymatic and enzymatic antioxidants and other biomarkers associated with erythrocyte membrane transport functions are the main content of this review. Biomarkers of oxidative stress in erythrocytes and its membrane were taken into the consideration during human aging that will be the main subject of this mini- review. PMID:26713282

  19. Biomarkers of oxidative stress in erythrocytes as a function of human age

    PubMed Central

    Maurya, Pawan Kumar; Kumar, Prabhanshu; Chandra, Pranjal

    2015-01-01

    Despite more than 300 theories to explain the aging process, oxidative stress theory offers the best mechanism to explain aging and age related disorders. Several studies has shown the importance of oxidative stress during aging. PubMed, Science Direct and Springer online data bases are taken into consideration to write this mini-review. Human erythrocytes are most abundant and specialized cells in the body. Erythrocytes were extensively studied due to their metabolism and gas transport functions. Recent studies on erythrocytes have provided us detailed information of cell membrane and its structural organization that may help in studying the aging and age associated changes. The susceptibility of an organism is associated with the antioxidant potential of the body. Erythrocytes have potent antioxidant protection consisting of enzymatic and non-enzymatic pathways that counteract with reactive oxygen species, thus maintaining the redox regulation in the body. The non-enzymatic and enzymatic antioxidants and other biomarkers associated with erythrocyte membrane transport functions are the main content of this review. Biomarkers of oxidative stress in erythrocytes and its membrane were taken into the consideration during human aging that will be the main subject of this mini- review. PMID:26713282

  20. Human Age Estimation Method Robust to Camera Sensor and/or Face Movement.

    PubMed

    Nguyen, Dat Tien; Cho, So Ra; Pham, Tuyen Danh; Park, Kang Ryoung

    2015-01-01

    Human age can be employed in many useful real-life applications, such as customer service systems, automatic vending machines, entertainment, etc. In order to obtain age information, image-based age estimation systems have been developed using information from the human face. However, limitations exist for current age estimation systems because of the various factors of camera motion and optical blurring, facial expressions, gender, etc. Motion blurring can usually be presented on face images by the movement of the camera sensor and/or the movement of the face during image acquisition. Therefore, the facial feature in captured images can be transformed according to the amount of motion, which causes performance degradation of age estimation systems. In this paper, the problem caused by motion blurring is addressed and its solution is proposed in order to make age estimation systems robust to the effects of motion blurring. Experiment results show that our method is more efficient for enhancing age estimation performance compared with systems that do not employ our method. PMID:26334282

  1. Human Age Estimation Method Robust to Camera Sensor and/or Face Movement

    PubMed Central

    Nguyen, Dat Tien; Cho, So Ra; Pham, Tuyen Danh; Park, Kang Ryoung

    2015-01-01

    Human age can be employed in many useful real-life applications, such as customer service systems, automatic vending machines, entertainment, etc. In order to obtain age information, image-based age estimation systems have been developed using information from the human face. However, limitations exist for current age estimation systems because of the various factors of camera motion and optical blurring, facial expressions, gender, etc. Motion blurring can usually be presented on face images by the movement of the camera sensor and/or the movement of the face during image acquisition. Therefore, the facial feature in captured images can be transformed according to the amount of motion, which causes performance degradation of age estimation systems. In this paper, the problem caused by motion blurring is addressed and its solution is proposed in order to make age estimation systems robust to the effects of motion blurring. Experiment results show that our method is more efficient for enhancing age estimation performance compared with systems that do not employ our method. PMID:26334282

  2. Risk Factors for Four-Year Incidence and Progression of Age-Related Macular Degeneration: The Los Angeles Latino Eye Study

    PubMed Central

    CHOUDHURY, FARZANA; VARMA, ROHIT; MCKEAN-COWDIN, ROBERTA; KLEIN, RONALD; AZEN, STANLEY P.

    2011-01-01

    PURPOSE To identify risk factors for 4-year incidence and progression of age-related macular degeneration (AMD) in adult Latinos. DESIGN Population-based prospective cohort study. METHODS Participants, aged 40 or older, from The Los Angeles Latino Eye Study (LALES) underwent standardized comprehensive ophthalmologic examinations at baseline and at 4 years of follow-up. Age-related macular degeneration was detected by grading 30-degree stereoscopic fundus photographs using the modified Wisconsin Age-Related Maculopathy Grading System. Multivariate stepwise logistic regression was used to examine the independent association of incidence and progression of AMD and baseline sociodemographic, behavioral, clinical, and ocular characteristics. RESULTS Multivariate analyses revealed that older age (OR per decade of age: 1.52; 95% CI: 1.29, 1.85) and higher pulse pressure (OR per 10 mm Hg: 2.54; 95% CI: 1.36, 4.76) were independently associated with the incidence of any AMD. The same factors were associated with early AMD, soft indistinct drusen, and retinal pigmentary abnormalities. Additionally, presence of clinically diagnosed diabetes mellitus was independently associated with increased retinal pigment (OR: 1.66; 95% CI: 1.01, 2.85), and male gender was associated with retinal pigment epithelial depigmentation (OR 2.50; 95% CI: 1.48, 4.23). Older age (OR per decade of age: 2.20; 95% CI: 1.82, 2.67) and current smoking (OR: 2.85; 95% CI: 1.66, 4.90) were independently associated with progression of AMD. CONCLUSIONS Several modifiable risk factors were associated with 4-year incidence and progression of AMD in Latinos. The results suggest that interventions aimed at reducing pulse pressure and promoting smoking cessation may reduce incidence and progression of AMD, respectively. PMID:21679916

  3. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid

    PubMed Central

    Lee, Anita Y. H.; Song, Qinghua; Liaw, Andy; Wiener, Matt; Paweletz, Cloud P.; Seeburger, Jeffrey L.; Li, Jenny; Meng, Fanyu; Deyanova, Ekaterina G.; Mazur, Matthew T.; Settlage, Robert E.; Zhao, Xuemei; Southwick, Katie; Du, Yi; Holder, Dan; Sachs, Jeffrey R.; Laterza, Omar F.; Dallob, Aimee; Chappell, Derek L.; Snyder, Karen; Modur, Vijay; King, Elizabeth; Joachim, Catharine; Bondarenko, Andrey Y.; Shearman, Mark; Soper, Keith A.; Smith, A. David; Potter, William Z.; Koblan, Ken S.; Sachs, Alan B.

    2015-01-01

    Disease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic. PMID:26270474

  4. In vivo quantification of human dermal skin aging using SHG and autofluorescence

    NASA Astrophysics Data System (ADS)

    Puschmann, Stefan; Rahn, Christian-Dennis; Wenck, Horst; Gallinat, Stefan; Fischer, Frank

    2012-03-01

    There are visible changes during skin aging. In the extracellular matrix these changes referred to as intrinsic aging (skin areas not exposed to sunlight) and extrinsic aging can be measured using various methods, such as subjective clinical evaluation, histology and molecular analysis. In this study we developed a new parameter for the non-invasive quantitative determination of dermal skin aging utilizing a five-dimensional intravital tomography (5D-IVT). This device, also known as 5D - multi-photon laser scanning microscopy, is a powerful tool to investigate (photo)aging-associated alterations in vivo. Structural alterations in the dermis of extrinsically aged (chronically sun-exposed) and intrinsically aged (sun-protected) human skin were recorded utilizing the collagen-specific second harmonic generation (SHG) signal and the elastin-specific autofluorescence (AF) signal. Recording took place in young and elderly volunteers. The resulting images were processed in order to gain the elastin percentage and the collagen percentage per image. Then, the elastin - to - collagen ratio (ELCOR) was calculated. With respect to volar forearm skin, the ELCOR significantly increased with age. In elderly volunteers, the ELCOR value calculated for the chronically sun-exposed temple area was significantly augmented compared with the sun-protected upper arm area. Based on 5D-IVT we introduce the ELCOR as a new means to quantify age-associated alterations in the extracellular matrix of in vivo human skin. This novel parameter is compared to the currently used "SHG to AF aging index" of the dermis (SAAID).

  5. [Dietary habits and the state of the human oral cavity in the prehistoric age].

    PubMed

    Kee, C D

    1990-06-01

    This is an age-by-age summation of literature on over 100 sites (of more than 250 excavated prehistoric ruins on the Korean Peninsula: about 160 places in South Korea--Paleolithic Age 15, Neolithic Age 21, Bronze Age 90 and Iron Age 35--and about 90 places in North Korea) which produced dietary-habit-related devices such as hunting tools, fishing instruments, farming equipments, tools of daily life, and human bones and teeth. 1) Various dietary-habit-related Old Stone-Age tools, instruments and other items were found. Among them were stone axes, stone hand axes, fish spears and hooks made of bone or horn, stone blades, stone scrapers and stone drills believed to have been used in daily life, and charcoal and sites of furnaces used for cooking. Furthermore, it was found that there were severe dental abrasions and dental caries among the inhabitants of the Korean Peninsula in the Old Stone Age. 2) Some evidences were found which lead us to believe that hunting was practiced with stone arrowheads in the New Stone Age. Stone net sinkers, which is the evidence of the use of fish nets, were also found. In addition, farming stone tools and charred cereals, both of which date back to the latter part of this period, were unearthed. Millstones, which began to be used in this age, and livestock bones were found. Where these items were discovered, 23 maxillae and mandibles with teeth and a total of 231 separate teeth of Neolithic period human beings were reported. However, there are no records indicating dental caries, but some records describe severe abrasion. PMID:2130134

  6. Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

    PubMed Central

    Stranger, Barbara E.; Stahl, Eli A.; Raj, Towfique

    2011-01-01

    Enormous progress in mapping complex traits in humans has been made in the last 5 yr. There has been early success for prevalent diseases with complex phenotypes. These studies have demonstrated clearly that, while complex traits differ in their underlying genetic architectures, for many common disorders the predominant pattern is that of many loci, individually with small effects on phenotype. For some traits, loci of large effect have been identified. For almost all complex traits studied in humans, the sum of the identified genetic effects comprises only a portion, generally less than half, of the estimated trait heritability. A variety of hypotheses have been proposed to explain why this might be the case, including untested rare variants, and gene–gene and gene–environment interaction. Effort is currently being directed toward implementation of novel analytic approaches and testing rare variants for association with complex traits using imputed variants from the publicly available 1000 Genomes Project resequencing data and from direct resequencing of clinical samples. Through integration with annotations and functional genomic data as well as by in vitro and in vivo experimentation, mapping studies continue to characterize functional variants associated with complex traits and address fundamental issues such as epistasis and pleiotropy. This review focuses primarily on the ways in which genome-wide association studies (GWASs) have revolutionized the field of human quantitative genetics. PMID:21115973

  7. Recent progress in the development and testing of vaccines against human tuberculosis.

    PubMed

    McMurray, David N

    2003-05-01

    The growing pandemic of human tuberculosis has not been affected significantly by the widespread use of the only currently available vaccine, bacille Calmette Guerin. Bacille Calmette Guerin protects uniformly against serious paediatric forms of tuberculosis and against adult pulmonary tuberculosis in some parts of the world, but there are clearly populations in high-burden countries which do not benefit from the current vaccination regimen. New tuberculosis vaccines will be essential for the ultimate control of this ancient disease. Research over the past 10 years has produced literally hundreds of new tuberculosis vaccine candidates representing all of the major vaccine design strategies; protein/peptide vaccines in adjuvants, DNA vaccines, naturally and rationally attenuated strains of mycobacteria, recombinant mycobacteria and other living vaccine vectors expressing genes coding for immunodominant mycobacterial antigens, and non-peptide vaccines. Many of these vaccines have been tested for immunogenicity and protective efficacy in mouse and guinea pig models of low-dose pulmonary tuberculosis. In addition, alternative routes of tuberculosis vaccine delivery (e.g. oral, respiratory, gene gun) and various combinations of priming or boosting an experimental vaccine with bacille Calmette Guerin have been examined in relevant animal models. One of the most promising of these vaccines is currently in Phase I trials in human subjects, and others are expected to follow in the near future. This review will summarise the most recent progress made toward the development and preclinical evaluation of novel vaccines for human tuberculosis. PMID:12782054

  8. Human genetic marker for resistance to radiations and chemicals. 1998 annual progress report

    SciTech Connect

    Lieberman, H.B.

    1998-06-01

    'The broad objective of the project is to understand the molecular basis for the response of cells to radiations and chemicals, with the pragmatic goal of being able to identify human subpopulations that are exceptionally sensitive to DNA damaging agents. The project focuses on HRAD9, a human orthologue of the fission yeast Schizosaccharomyces pombe gene rad9. S. pombe rad9::ura4+ mutant cells are highly sensitive to ionizing radiation, UV and many chemicals, such as the DNA synthesis inhibitor hydroxyurea. They also lack the ability to delay cycling transiently in S phase or in G2 following a block in DNA replication or after incurring DNA damage, respectively -i.e., they lack checkpoint controls. The attempt by mutant cells to progress through mitosis in the absence of fully intact DNA accounts at least in part for their sensitivity to DNA damaging agents. Cells bearing rad9::ura4+ also aberrantly regulate UVDE, an enzyme that participates in a secondary DNA excision repair pathway. The key role played by S. pombe rad9 in promoting resistance to chemicals and radiations suggests that the evolutionarily conserved human cognate also has important functions in mammals. The first set of aims in this proposal centers on characterizing the structure and expression of HRAD9, to assess structure/function relationships and potentially link protein activity to a specific tissue. The next set of aims focuses on determining the role of HRAD9 in radio/chemoresponsiveness and cancer.'

  9. Architectural Transcription Factor HMGI(Y) Promotes Tumor Progression and Mesenchymal Transition of Human Epithelial Cells

    PubMed Central

    Reeves, Raymond; Edberg, Dale D.; Li, Ying

    2001-01-01

    Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events. PMID:11134344

  10. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells.

    PubMed

    Reeves, R; Edberg, D D; Li, Y

    2001-01-01

    Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events. PMID:11134344

  11. Allicin inhibits human renal clear cell carcinoma progression via suppressing HIF pathway

    PubMed Central

    Song, Bin; Shu, Ying; Cui, Tianlei; Fu, Ping

    2015-01-01

    Hypoxia-inducible factor 1-alpha (HIF-1α) protects hypoxic cells from apoptosis or necrosis under ischemic and anoxic conditions. Allicin is characterized by the anti-cancer characteristics. This study aims to explore whether allicin is involved in renal clear cell carcinoma progression through HIF-1α. A total of 40 RCC tissues and 39 normal renal tissues were collected H&E and immunohistochemistry were applied to study morphology changes. MTT assay and flow cytometry (FCM) were used to analyze cell viability and apoptosis. In vitro colony formation assay and wound healing assay were conducted to explore cell migration. The protein levels of Bcl-2, VEGF and HIF-1α were increased in RCC tissues. More importantly, treatment with allicin significantly decreased HIF-1α protein level, thereby reducing Bcl-2 and VEGF expression. In addition, allicin also obviously enhanced apoptotic cells. And colony formation capacity and cell migration rate were reduced in RCC-9863 cells treated with allicin. Further study revealed that overexpression of HIF-1α could partially repress allicin-induced downstream effects. To conclude, allicin inhibits human renal clear cell carcinoma progression partially by suppressing HIF pathway. PMID:26884975

  12. Allicin inhibits human renal clear cell carcinoma progression via suppressing HIF pathway.

    PubMed

    Song, Bin; Shu, Ying; Cui, Tianlei; Fu, Ping

    2015-01-01

    Hypoxia-inducible factor 1-alpha (HIF-1α) protects hypoxic cells from apoptosis or necrosis under ischemic and anoxic conditions. Allicin is characterized by the anti-cancer characteristics. This study aims to explore whether allicin is involved in renal clear cell carcinoma progression through HIF-1α. A total of 40 RCC tissues and 39 normal renal tissues were collected H&E and immunohistochemistry were applied to study morphology changes. MTT assay and flow cytometry (FCM) were used to analyze cell viability and apoptosis. In vitro colony formation assay and wound healing assay were conducted to explore cell migration. The protein levels of Bcl-2, VEGF and HIF-1α were increased in RCC tissues. More importantly, treatment with allicin significantly decreased HIF-1α protein level, thereby reducing Bcl-2 and VEGF expression. In addition, allicin also obviously enhanced apoptotic cells. And colony formation capacity and cell migration rate were reduced in RCC-9863 cells treated with allicin. Further study revealed that overexpression of HIF-1α could partially repress allicin-induced downstream effects. To conclude, allicin inhibits human renal clear cell carcinoma progression partially by suppressing HIF pathway. PMID:26884975

  13. Human Immunodeficiency Virus-related Microbial Translocation and Progression of Hepatitis C

    PubMed Central

    Balagopal, Ashwin; Philp, Frances H.; Astemborski, Jacquie; Block, Timothy M.; Mehta, Anand; Long, Ronald; Kirk, Gregory D.; Mehta, Shruti H.; Cox, Andrea L.; Thomas, David L.; Ray, Stuart C.

    2009-01-01

    Background & Aims HIV-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation. Methods We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized. Results HIV-related CD4+ lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS binding protein, soluble CD14, fucose-binding lectin (AAL) reactive to IgG specific for the alpha galactose epitope, and suppressed levels of endotoxin-core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), e.g. LPS, odds ratio 19.0 (p = 0.002), AAL, odds ratio 27.8 (p<0.0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis. Conclusions Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease. PMID:18457674

  14. Dysregulation of JAM-A plays an important role in human tumor progression

    PubMed Central

    Zhao, Chen; Lu, Funian; Chen, Hongxia; Zhao, Xianda; Sun, Jun; Chen, Honglei

    2014-01-01

    Junctional adhesion molecule A (JAM-A) is a transmembrane protein that belongs to the immunoglobulin (Ig) superfamily. Evidence determines that JAM-A plays a role in numerous cellular processes, including tight junction assembly, leukocyte migration, platelet activation, angiogenesis and virus binding. Recent research suggests that JAM-A is dysregulated in various cancers and is vital for tumor progression. JAM-A is implicated in carcinogenesis via different signal pathways such as TGF-β1 signaling. Furthermore, JAM-A expression in cancers is usually associated with certain outcome of patients and might be a prognostic indicator. In this review, the correlation between JAM-A expression and human cancers will be described. PMID:25400822

  15. A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression.

    PubMed

    Marmorstein, L Y; Kinev, A V; Chan, G K; Bochar, D A; Beniya, H; Epstein, J A; Yen, T J; Shiekhattar, R

    2001-01-26

    Germline mutations of the human BRCA2 gene confer susceptibility to breast cancer. Although the function of the BRCA2 protein remains to be determined, murine cells homozygous for BRCA2 inactivation display chromosomal aberrations. We have isolated a 2 MDa BRCA2-containing complex and identified a structural DNA binding component, designated as BRCA2-Associated Factor 35 (BRAF35). BRAF35 contains a nonspecific DNA binding HMG domain and a kinesin-like coiled coil domain. Similar to BRCA2, BRAF35 mRNA expression levels in mouse embryos are highest in proliferating tissues with high mitotic index. Strikingly, nuclear staining revealed a close association of BRAF35/BRCA2 complex with condensed chromatin coincident with histone H3 phosphorylation. Importantly, antibody microinjection experiments suggest a role for BRCA2/BRAF35 complex in modulation of cell cycle progression. PMID:11207365

  16. Multi-system progressive angiomatosis in a dog resembling blue rubber bleb nevus syndrome in humans.

    PubMed

    Ide, K; Uchida, N; Iyori, K; Mochizuki, T; Fukushima, R; Iwasaki, T; Nishifuji, K

    2013-04-01

    A six-year-old, neutered, female golden retriever was presented with generalised, dark purple to black cutaneous nodules and gastrointestinal haemorrhage. Histopathologically, all cutaneous nodules were diagnosed as benign cavernous haemangiomas. Endoscopic analysis revealed similar nodules in the oesophagus, stomach and duodenum. At laparotomy, similar nodules were seen on the visceral peritoneal lining of abdominal organs. Metastatic haemangiosarcoma was ruled out based on histological features and lack of primary tumour in spleen, liver or heart ultrasonographically. Blood loss associated with gastrointestinal haemorrhage was managed with blood transfusion. To the authors' knowledge, this is the first canine case of multi-system progressive angiomatosis resembling blue rubber bleb nevus syndrome in humans. PMID:23496103

  17. [Research progress in roles of high-risk human papillomavirus E2 protein].

    PubMed

    Wu, En-Qi; Tang, Yuan-Yu

    2014-03-01

    High-risk human papillomavirus (HPV) is the principal cause of various cancers including cervical cancer, anal cancer, vulvar cancer, and some head and neck cancers. In the viral life cycle, by interacting with both viral and host DNA and proteins, the HPV E2 protein plays a pivotal role in viral transcriptional regulation and DNA replication, and it is also associated with modification of various cellular processes, including host gene transcription, RNA processing, apoptosis, ubiquitination, and intracellular trafficking, to create a convenient environment for a replicative cycle of the virus and contribute to the HPV pathogenesis. Elucidating the roles of E2 protein throughout the viral life cycle will improve our understanding of the viral life cycle and pathogenesis and help us identify novel antiviral agents with therapeutic potential. This article reviews the research progress in the structure, roles, and activity of high-risk HPV E2 protein, particularly that of HPV-16. PMID:24923176

  18. A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans

    PubMed Central

    Whitehead, Jocelyne C.; Hildebrand, Barbara A.; Sun, Michael; Rockwood, Michael R.; Rose, Robert A.; Rockwood, Kenneth

    2014-01-01

    We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5–28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight-item FI increased from 0.06±0.01 at 5 months to 0.36±0.06 at 19 months and 0.38±0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02±0.005 at 5 months; 0.12±0.008 at 19 months; 0.33±0.02 at 28 months; n = 14). FI scores calculated from 70 self-report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans. PMID:24051346

  19. Individual Differences in Spatial Pattern Separation Performance Associated with Healthy Aging in Humans

    ERIC Educational Resources Information Center

    Stark, Shauna M.; Yassa, Michael A.; Stark, Craig E. L.

    2010-01-01

    Rodent studies have suggested that "pattern separation," the ability to distinguish among similar experiences, is diminished in a subset of aged rats. We extended these findings to the human using a task designed to assess spatial pattern separation behavior (determining at time of test whether pairs of pictures shown during the study were in the…

  20. Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function.

    PubMed

    Arda, H Efsun; Li, Lingyu; Tsai, Jennifer; Torre, Eduardo A; Rosli, Yenny; Peiris, Heshan; Spitale, Robert C; Dai, Chunhua; Gu, Xueying; Qu, Kun; Wang, Pei; Wang, Jing; Grompe, Markus; Scharfmann, Raphael; Snyder, Michael S; Bottino, Rita; Powers, Alvin C; Chang, Howard Y; Kim, Seung K

    2016-05-10

    Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α cells or β cells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature β cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function. PMID:27133132

  1. Not so Big Communities: A Promising Future for Human Beings of All Ages

    ERIC Educational Resources Information Center

    Susanka, Sarah

    2011-01-01

    In many American communities today, the methods of construction, as well as the almost exclusive orientation to the convenience of the automobile, limit the functioning and independence of the aging population, and offer little opportunity for human interaction. Sarah Susanka's "Not So Big" series of books points toward a new way of building…

  2. Nutrition and the biology of human ageing: Proceedings of the ninth nestle international nutrition symposium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This 9th Nestle Nutrition Symposium on “Nutrition and the Biology of Human Ageing” is presented at a time of unprecedented demographic change worldwide. The UN population division forecasts that the number of people living over age 65 will rise to almost 1 billion (12% percent of the world’s populat...

  3. HUMAN SUBJECT AGE AND ACTIVITY LEVEL: FACTORS ADDRESSED IN A BIOMATHEMATICAL DEPOSITION PROGRAM FOR EXTRAPOLATION MODELING

    EPA Science Inventory

    A deterministic aerosol deposition model, previously validated by data from adult inhalation exposure experiments, is used to study factors affecting particle behavior within the developing human lung. ere, an age dependent lung morphology is presented in which the number of trac...

  4. The aging baboon: comparative demography in a non-human primate.

    PubMed

    Bronikowski, Anne M; Alberts, Susan C; Altmann, Jeanne; Packer, Craig; Carey, K Dee; Tatar, Marc

    2002-07-01

    Why do closely related primate genera vary in longevity, and what does this teach us about human aging? Life tables of female baboons (Papio hamadryas) in two wild populations of East Africa and in a large captive population in San Antonio, Texas, provide striking similarities and contrasts to human mortality patterns. For captive baboons at the Southwest Foundation for Biomedical Research, we estimate the doubling time of adult mortality rate as 4.8 years. Wild females in free-living populations in Tanzania and in Kenya showed doubling times of 3.5 and 3.8 years, respectively. Although these values are considerably faster than the estimates of 7-8 years for humans, these primates share a demographic feature of human aging: within each taxon populations primarily vary in the level of Gompertz mortality intercept (frailty) and vary little in the demographic rate of aging. Environmental and genetic factors within taxa appear to affect the level of frailty underlying senescence. In contrast, primate taxa are differentiated by rates of demographic aging, even if they cannot be characterized by species-specific lifespan. PMID:12082185

  5. COMPARISON OF BIAXIAL MECHANICAL PROPERTIES OF CORONARY SINUS TISSUES FROM PORCINE, OVINE AND AGED HUMAN SPECIES

    PubMed Central

    Pham, Thuy; Sun, Wei

    2011-01-01

    Due to its proximity to the mitral valve, the coronary sinus (CS) vessel serves as a conduit for the deployment and implantation of the percutaneous transvenous mitral annuloplasty (PTMA) devices that can potentially reduce the mitral regurgitation. Because CS vessel is a venous tissue and seldom diseased, its mechanical properties have not been well studied. In this study, we performed the multi-axial mechanical test and histological analysis to characterize the mechanical and structural properties of the aged human, porcine and ovine CS tissues. The results showed that the aged human CS tissues exhibited much stiffer and highly anisotropic behaviors compared to the porcine and ovine. Both of the porcine and ovine CS vessel walls were thicker and mainly composed of striated muscle fibers (SMF), whereas the thinner aged human CS had higher collagen, lesser SMF, and more fragmented elastin fibers, which are possibly due to the aging effects. We also observed that the anatomical features of porcine CS vessel might be not suitable for the PTMA deployment. These differences between animal and human models raise questions for the validity of using animal models to investigate the biomechanics involved in the PTMA intervention. Therefore, caution must be taken in future studies of PTMA stents using animal models. PMID:22301170

  6. History of the USDA Human Nutrition Research Center on Aging at Tufts University

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, while quite a mouthful, is aptly named, since it has contributed substantially to the legacy of Jean Mayer, to the scientific stature of the USDA and, in Atwater’s tradition, to the d...

  7. Rural origin, age, and endoparasite fecal prevalence in dogs surrendered to the Regina Humane Society, 2013

    PubMed Central

    Schurer, Janna M.; Hamblin, Brie; Davenport, Laura; Wagner, Brent; Jenkins, Emily J.

    2014-01-01

    We report the results of fecal parasite surveillance in dogs surrendered to the Regina Humane Society, Saskatchewan, Canada, between May and November 2013. Overall, 23% of 231 dogs were infected with at least 1 intestinal parasite. Endoparasite infection was positively associated with rural origin (P = 0.002) and age (< 12 months; P < 0.001). PMID:25477549

  8. Human age estimation from blood using mRNA, DNA methylation, DNA rearrangement, and telomere length.

    PubMed

    Zubakov, Dmitry; Liu, Fan; Kokmeijer, Iris; Choi, Ying; van Meurs, Joyce B J; van IJcken, Wilfred F J; Uitterlinden, André G; Hofman, Albert; Broer, Linda; van Duijn, Cornelia M; Lewin, Jörn; Kayser, Manfred

    2016-09-01

    Establishing the age of unknown persons, or persons with unknown age, can provide important leads in police investigations, disaster victim identification, fraud cases, and in other legal affairs. Previous methods mostly relied on morphological features available from teeth or skeletal parts. The development of molecular methods for age estimation allowing to use human specimens that possess no morphological age information, such as bloodstains, is extremely valuable as this type of samples is commonly found at crime scenes. Recently, we introduced a DNA-based approach for human age estimation from blood based on the quantification of T-cell specific DNA rearrangements (sjTRECs), which achieves accurate assignment of blood DNA samples to one of four 20-year-interval age categories. Aiming at improving the accuracy of molecular age estimation from blood, we investigated different types of biomarkers. We started out by systematic genome-wide surveys for new age-informative mRNA and DNA methylation markers in blood from the same young and old individuals using microarray technologies. The obtained candidate markers were validated in independent samples covering a wide age range using alternative technologies together with previously proposed DNA methylation, sjTREC, and telomere length markers. Cross-validated multiple regression analysis was applied for estimating and validating the age predictive power of various sets of biomarkers within and across different marker types. We found that DNA methylation markers outperformed mRNA, sjTREC, and telomere length in age predictive power. The best performing model included 8 DNA methylation markers derived from 3 CpG islands reaching a high level of accuracy (cross-validated R(2)=0.88, SE±6.97 years, mean absolute deviation 5.07 years). However, our data also suggest that mRNA markers can provide independent age information: a model using a combined set of 5 DNA methylation markers and one mRNA marker could provide

  9. Basement membrane proteins promote progression of intraepithelial neoplasia in 3-dimensional models of human stratified epithelium.

    PubMed

    Andriani, Frank; Garfield, Jackie; Fusenig, Norbert E; Garlick, Jonathan A

    2004-01-20

    We have developed novel 3-dimensional in vitro and in vivo tissue models that mimic premalignant disease of human stratified epithelium in order to analyze the stromal contribution of extracellular matrix and basement membrane proteins to the progression of intraepithelial neoplasia. Three-dimensional, organotypic cultures were grown either on a de-epidermalized human dermis with pre-existing basement membrane components on its surface (AlloDerm), on a Type I collagen gel that lacked basement membrane proteins or on polycarbonate membranes coated with purified extracellular matrix proteins. When tumor cells (HaCaT-II4) were mixed with normal keratinocytes (4:1/normals:HaCaT-II4), tumor cells selectively attached, persisted and proliferated at the dermal-epidermal interface in vitro and generated dysplastic tissues when transplanted to nude mice only when grown in the presence of the AlloDerm substrate. This stromal interface was permissive for tumor cell attachment due to the rapid assembly of structured basement membrane. When tumor cells were mixed with normal keratinocytes and grown on polycarbonate membranes coated with individual extracellular matrix or basement membrane components, selective attachment and significant intraepithelial expansion occurred only on laminin 1 and Type IV collagen-coated membranes. This preferential adhesion of tumor cells restricted the synthesis of laminin 5 to basal cells where it was deposited in a polarized distribution. Western blot analysis revealed that tumor cell attachment was not due to differences in the synthesis or processing of laminin 5. Thus, intraepithelial progression towards premalignant disease is dependent on the selective adhesion of cells with malignant potential to basement membrane proteins that provide a permissive template for their persistence and expansion. PMID:14648700

  10. Characterization of biomechanical properties of aged human and ovine mitral valve chordae tendineae.

    PubMed

    Zuo, Keping; Pham, Thuy; Li, Kewei; Martin, Caitlin; He, Zhaoming; Sun, Wei

    2016-09-01

    The mitral valve (MV) is a highly complex cardiac valve consisting of an annulus, anterior and posterior leaflets, chordae tendineae (chords) and two papillary muscles. The chordae tendineae mechanics play a pivotal role in proper MV function: the chords help maintain proper leaflet coaptation and rupture of the chordae tendineae due to disease or aging can lead to mitral valve insufficiency. Therefore, the aim of this study was to characterize the mechanical properties of aged human and ovine mitral chordae tendineae. The human and ovine chordal specimens were categorized by insertion location (i.e., marginal, basal and strut) and leaflet type (i.e., anterior and posterior). The results show that human and ovine chords of differing types vary largely in size but do not have significantly different elastic and failure properties. The excess fibrous tissue layers surrounding the central core of human chords added thickness to the chords but did not contribute to the overall strength of the chords. In general, the thinner marginal chords were stiffer than the thicker basal and strut chords, and the anterior chords were stiffer and weaker than the posterior chords. The human chords of all types were significantly stiffer than the corresponding ovine chords and exhibited much lower failure strains. These findings can be explained by the diminished crimp pattern of collagen fibers of the human mitral chords observed histologically. Moreover, the mechanical testing data was modeled with the nonlinear hyperelastic Ogden strain energy function to facilitate accurate computational modeling of the human MV. PMID:27315372

  11. Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia

    PubMed Central

    Garbe, James C; Pepin, Francois; Pelissier, Fanny; Sputova, Klara; Fridriksdottir, Agla J; Guo, Diana E; Villadsen, Rene; Park, Morag; Petersen, Ole W; Borowsky, Alexander D.; Stampfer, Martha R; LaBarge, Mark A

    2012-01-01

    Women over 50 years of age account for 75% of new breast cancer diagnoses, and the majority of these tumors are of a luminal subtype. Although age-associated changes, including endocrine profiles and alterations within the breast microenvironment, increase cancer risk, an understanding of the molecular mechanisms that underlie these observations is lacking. In this study, we generated a large collection of normal human mammary epithelial cell strains from women aged 16 to 91 years, derived from primary tissues, to investigate the molecular changes that occur in aging breast cells. We found that in finite-lifespan cultured and uncultured epithelial cells, aging is associated with a reduction of myoepithelial cells and an increase in luminal cells that express keratin 14 and integrin α6, a phenotype that is usually expressed exclusively in myoepithelial cells in women under 30. Changes to the luminal lineage resulted from age-dependent expansion of defective multipotent progenitors that gave rise to incompletely differentiated luminal or myoepithelial cells. The aging process therefore results in both a shift in the balance of luminal/myoepithelial lineages and to changes in the functional spectrum of multipotent progenitors, which together increase the potential for malignant transformation. Together, our findings provide a cellular basis to explain the observed vulnerability to breast cancer that increases with age. PMID:22552289

  12. Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition

    PubMed Central

    Finch, Caleb E.

    2009-01-01

    Humans have evolved much longer lifespans than the great apes, which rarely exceed 50 years. Since 1800, lifespans have doubled again, largely due to improvements in environment, food, and medicine that minimized mortality at earlier ages. Infections cause most mortality in wild chimpanzees and in traditional forager-farmers with limited access to modern medicine. Although we know little of the diseases of aging under premodern conditions, in captivity, chimpanzees present a lower incidence of cancer, ischemic heart disease, and neurodegeneration than current human populations. These major differences in pathology of aging are discussed in terms of genes that mediate infection, inflammation, and nutrition. Apolipoprotein E alleles are proposed as a prototype of pleiotropic genes, which influence immune responses, arterial and Alzheimer’s disease, and brain development. PMID:19966301

  13. The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches.

    PubMed

    Cotman, Carl W; Head, Elizabeth

    2008-12-01

    Aged dogs (beagles) develop losses in executive function, learning and memory. The severity of decline in these cognitive domains represents a spectrum that captures normal aging, mild cognitive impairment and early/mild Alzheimer's disease (AD) in humans. In parallel, dogs naturally accumulate several types of neuropathology (although not all) consistent with human brain aging and AD including cortical atrophy, neuron loss, loss of neurogenesis, amyloid-beta (Abeta) plaques, cerebral amyloid angiopathy and oxidative damage. Many of these neuropathological features correlate with the extent of cognitive decline in a brain region-dependent manner. Dogs are ideally suited for longitudinal studies, and we provide a summary of the beneficial effects of an antioxidant diet, behavioral enrichment, and Abeta immunotherapy. In addition, combinatorial treatment approaches can be a powerful strategy for improving brain function through enhancement of multiple molecular pathways. PMID:19096165

  14. Human bladder carcinoma cell lines as indicators of oncogenic change relevant to urothelial neoplastic progression.

    PubMed Central

    Rieger, K. M.; Little, A. F.; Swart, J. M.; Kastrinakis, W. V.; Fitzgerald, J. M.; Hess, D. T.; Libertino, J. A.; Summerhayes, I. C.

    1995-01-01

    Analysis of human tumour-derived cell lines has previously resulted in the identification of novel transformation-related elements and provided a useful tool for functional studies of different genes. To establish the utility of such cell lines as indicators of change relevant to urothelial cancer, we have characterised the expression of five genes (p53, MDM2, Rb, E-cadherin, APC) within a panel of human bladder carcinoma cell lines. Using single-strand conformation polymorphism (SSCP) and direct sequencing, p53 mutations were identified in 7/15 (47%) cell lines reflecting events reported in bladder tumours. Immunohistochemical analysis of p53 in cultured cells and in paraffin-embedded sections of xenografts from the cell line panel revealed discordant results. An absence of p53 nuclear staining was associated with an exon 5 mutation in EJ and with multiple p53 mutations found in J82. Two cell lines positive for p53 staining in the absence of detectable mutation displayed overexpression of MDM2 (PSI, HT1197) in Western blot analysis. Loss or aberrant Rb expression was recorded in 5/15 (TCCSUP, SCaBER, 5637, HT1376, J82) cell lines. Absence of E-cadherin was recorded in 5/15 cell lines (TCCSUP, EJ, KK47, UM-UC-3, J82) with loss of alpha-catenin in immunoprecipitated E-cadherin complexes of CUBIII. Western blot analysis of APC revealed a truncated protein in 1/15 (CUBIII) cell lines. The characterisation of oncogenic events within this panel of human bladder carcinoma cell lines establishes a representation of change observed in bladder tumours and better defines the genotypic background in these experimental human cell models of neoplastic progression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7669581

  15. Influence of sex, smoking and age on human hprt mutation frequencies and spectra.

    PubMed Central

    Curry, J; Karnaoukhova, L; Guenette, G C; Glickman, B W

    1999-01-01

    Examination of the literature for hprt mutant frequencies from peripheral T cells yielded data from 1194 human subjects. Relationships between mutant frequency, age, sex, and smoking were examined, and the kinetics were described. Mutant frequency increases rapidly with age until about age 15. Afterward, the rate of increase falls such that after age 53, the hprt mutant frequency is largely stabilized. Sex had no effect on mutant frequency. Cigarette smoking increased mean mutant frequency compared to nonsmokers, but did not alter age vs. mutant frequency relationships. An hprt in vivo mutant database containing 795 human hprt mutants from 342 individuals was prepared. No difference in mutational spectra was observed comparing smokers to nonsmokers, confirming previous reports. Sex affected the frequency of deletions (>1 bp) that are recovered more than twice as frequently in females (P = 0. 008) compared to males. There is no indication of a significant shift in mutational spectra with age for individuals older than 19 yr, with the exception of A:T --> C:G transversions. These events are recovered more frequently in older individuals. PMID:10388825

  16. Confocal Raman study of aging process in diabetes mellitus human voluntaries

    NASA Astrophysics Data System (ADS)

    Pereira, Liliane; Téllez Soto, Claudio Alberto; dos Santos, Laurita; Ali, Syed Mohammed; Fávero, Priscila Pereira; Martin, Airton A.

    2015-06-01

    Accumulation of AGEs [Advanced Glycation End - products] occurs slowly during the human aging process. However, its formation is accelerated in the presence of diabetes mellitus. In this paper, we perform a noninvasive analysis of glycation effect on human skin by in vivo confocal Raman spectroscopy. This technique uses a laser of 785 nm as excitation source and, by the inelastic scattering of light, it is possible to obtain information about the biochemical composition of the skin. Our aim in this work was to characterize the aging process resulting from the glycation process in a group of 10 Health Elderly Women (HEW) and 10 Diabetic Elderly Women (DEW). The Raman data were collected from the dermis at a depth of 70-130 microns. Through the theory of functional density (DFT) the bands positions of hydroxyproline, proline and AGEs (pentosidine and glucosepane) were calculated by using Gaussian 0.9 software. A molecular interpretation of changes in type I collagen was performed by the changes in the vibrational modes of the proline (P) and hydroxyproline (HP). The data analysis shows that the aging effects caused by glycation of proteins degrades type I collagen differently and leads to accelerated aging process.

  17. Kate's Journey: Introducing Students to the Human Side of Aging Services and Supports.

    PubMed

    Brown, Pamela Pitman; Niles-Yokum, Kelly

    2016-01-01

    Although using novels to teach aging is not a new concept, teaching the human side of long-term services and supports from the perspective of the care recipient via novels has not been thoroughly explored. Literature often reflects societal norms and issues; thus, the use of a novel in the classroom allows for critical reflection and analysis of self and other, particularly when engaging students in aging concepts and experiences of growing old. This article describes the employment of Kate Quinton's Days (1984), a novel that brings into focus the important, and often forgotten, human side of aging services and supports. Additionally, the novel focuses on administrative and medical bureaucracy within the context of home health, and family dynamics that come into play with issues of aging and long-term care. Students may have had limited exposure to various aspects of aging and care that play out in the novel, and bringing the character Kate and her life story into the classroom allows for discussions that would not otherwise be as meaningful or instructive. The authors found that students related in important ways to Kate and went beyond the "system" to consider the lived experience of care and support as we age. PMID:27267464

  18. Molecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human disease.

    PubMed

    Frieman, Matthew; Yount, Boyd; Agnihothram, Sudhakar; Page, Carly; Donaldson, Eric; Roberts, Anjeanette; Vogel, Leatrice; Woodruff, Becky; Scorpio, Diana; Subbarao, Kanta; Baric, Ralph S

    2012-01-01

    SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease. PMID:22072787

  19. Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease

    PubMed Central

    Yount, Boyd; Agnihothram, Sudhakar; Page, Carly; Donaldson, Eric; Roberts, Anjeanette; Vogel, Leatrice; Woodruff, Becky; Scorpio, Diana; Subbarao, Kanta; Baric, Ralph S.

    2012-01-01

    SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease. PMID:22072787

  20. Age and the means of bypassing stasis influence the intrinsic subtype of immortalized human mammary epithelial cells.

    PubMed

    Lee, Jonathan K; Garbe, James C; Vrba, Lukas; Miyano, Masaru; Futscher, Bernard W; Stampfer, Martha R; LaBarge, Mark A

    2015-01-01

    Based on molecular features, breast cancers are grouped into intrinsic subtypes that have different prognoses and therapeutic response profiles. With increasing age, breast cancer incidence increases, with hormone receptor-positive and other luminal-like subtype tumors comprising a majority of cases. It is not known at what stage of tumor progression subtype specification occurs, nor how the process of aging affects the intrinsic subtype. We examined subtype markers in immortalized human mammary epithelial cell lines established following exposure of primary cultured cell strains to a two-step immortalization protocol that targets the two main barriers to immortality: stasis (stress-associated senescence) and replicative senescence. Cell lines derived from epithelial cells obtained from non-tumorous pre- and post-menopausal breast surgery tissues were compared. Additionally, comparisons were made between lines generated using two different genetic interventions to bypass stasis: transduction of either an shRNA that down-regulated p16(INK4A), or overexpressed constitutive active cyclin D1/CDK2. In all cases, the replicative senescence barrier was bypassed by transduction of c-Myc. Cells from all resulting immortal lines exhibited normal karyotypes. Immunofluorescence, flow cytometry, and gene expression analyses of lineage-specific markers were used to categorize the intrinsic subtypes of the immortalized lines. Bypassing stasis with p16 shRNA in young strains generated cell lines that were invariably basal-like, but the lines examined from older strains exhibited some luminal features such as keratin 19 and estrogen receptor expression. Overexpression of cyclin D1/CDK2 resulted in keratin 19 positive, luminal-like cell lines from both young and old strains, and the lines examined from older strains exhibited estrogen receptor expression. Thus age and the method of bypassing stasis independently influence the subtype of immortalized human mammary epithelial cells

  1. Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.

    PubMed

    Das, Melanie M; Avalos, Pablo; Suezaki, Patrick; Godoy, Marlesa; Garcia, Leslie; Chang, Christine D; Vit, Jean-Philippe; Shelley, Brandon; Gowing, Genevieve; Svendsen, Clive N

    2016-06-01

    Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population. PMID:27032721

  2. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes

    SciTech Connect

    Vaziri, H.; Uchida, I.; Lan Wei; Harley, C.B. ); Schaechter, F.; Cohen, D. ); Xiaoming Zhu; Effros, R. )

    1993-04-01

    The telomere hypothesis of cellular aging proposes that loss of telomeric DNA (TTAGGG) from human chromosomes may ultimately cause cell-cycle exit during replicative senescence. Since lymphocytes have a limited replicative capacity and since blood cells were previously shown to lose telomeric DNA during aging in vivo, the authors wished to determine (a) whether accelerated telomere loss is associated with the premature immunosenescence of lymphocytes in individuals with Down syndrome (DS) and (b) whether telomeric DNA is also lost during aging of lymphocytes in vitro. To investigate the effects of aging and trisomy 21 on telomere loss in vivo, genomic DNA was isolated from peripheral blood lymphocytes of 140 individuals (age 0--107 years), including 21 DS patients (age 0--45 years). Digestion with restriction enzymes HinfI and RsaI generated terminal restriction fragments (TRFs), which were detected by Southern analysis using a telomere-specific probe ([sup 32]P-(C[sub 3]TA[sub 2])[sub 3]). The rate of telomere loss was calculated from the decrease in mean TRF length, as a function of donor age. DS patients showed a significantly higher rate of telomere loss with donor age (133 [+-] 15 bp/year) compared with age-matched controls (41 [+-] 7.7 bp/year) (P < .0005), suggesting that accelerated telomere loss is a biomarker of premature immunosenescence of DS patients and that it may play a role in this process. Telomere loss during aging in vitro was calculated for lymphocytes from four normal individuals, grown in culture for 10--30 population doublings. The rate of telomere loss was [approximately]120 bp/cell doubling, comparable to that seen in other somatic cells. Moreover, telomere lengths of lymphocytes from centenarians and from older DS patients were similar to those of senescent lymphocytes in culture, which suggests that replicative senescence could partially account for aging of the immune system in DS patients and in elderly individuals. 31 refs., 3 figs.

  3. Bisected, complex N-glycans and galectins in mouse mammary tumor progression and human breast cancer

    PubMed Central

    Miwa, Hazuki E; Koba, Wade R; Fine, Eugene J; Giricz, Orsi; Kenny, Paraic A; Stanley, Pamela

    2013-01-01

    Bisected, complex N-glycans on glycoproteins are generated by the glycosyltransferase MGAT3 and cause reduced cell surface binding of galectins. Previously, we showed that MGAT3 reduces growth factor signaling and retards mammary tumor progression driven by the Polyoma middle T antigen (PyMT) expressed in mammary epithelium under the mouse mammary tumor virus (MMTV) promoter. However, the penetrance of the tumor phenotype became variable in mixed FVB/N and C57BL/6 female mice and we therefore investigated a congenic C57BL/6 Mgat3−/−/MMTV-PyMT model. In the absence of MGAT3, C57BL/6 Mgat3−/−/MMTV-PyMT females exhibited accelerated tumor appearance and increased tumor burden, glucose uptake in tumors and lung metastasis. Nevertheless, activation of extracellular signal-regulated kinase (ERK)1/2 or protein kinase B (AKT) was reduced in ∼20-week C57BL/6 MMTV-PyMT tumors lacking MGAT3. Activation of focal adhesion kinase (FAK), protein tyrosine kinase Src, and p38 mitogen-activated protein kinase were similar to that of controls. All the eight mouse galectin genes were expressed in mammary tumors and tumor epithelial cells (TECs), but galectin-2 and -12 were not detected by western analysis in tumors, and galectin-7 was not detected in 60% of the TEC lines. From microarray data reported for human breast cancers, at least 10 galectin and 7 N-glycan N-acetylglucosaminyl (GlcNAc)-transferase (MGAT) genes are expressed in tumor tissue, and expression often varies significantly between different breast cancer subtypes. Thus, in summary, while MGAT3 and bisected complex N-glycans retard mouse mammary tumor progression, genetic background may modify this effect; identification of key galectins that promote mammary tumor progression in mice is not straightforward because all the eight galectin genes are expressed; and high levels of MGAT3, galectin-4, -8, -10, -13 and -14 transcripts correlate with better relapse-free survival in human breast cancer. PMID:24037315

  4. Individual variability in human blood metabolites identifies age-related differences

    PubMed Central

    Murakami, Itsuo; Takada, Junko; Kondoh, Hiroshi; Yanagida, Mitsuhiro

    2016-01-01

    Metabolites present in human blood document individual physiological states influenced by genetic, epigenetic, and lifestyle factors. Using high-resolution liquid chromatography-mass spectrometry (LC-MS), we performed nontargeted, quantitative metabolomics analysis in blood of 15 young (29 ± 4 y of age) and 15 elderly (81 ± 7 y of age) individuals. Coefficients of variation (CV = SD/mean) were obtained for 126 blood metabolites of all 30 donors. Fifty-five RBC-enriched metabolites, for which metabolomics studies have been scarce, are highlighted here. We found 14 blood compounds that show remarkable age-related increases or decreases; they include 1,5-anhydroglucitol, dimethyl-guanosine, acetyl-carnosine, carnosine, ophthalmic acid, UDP-acetyl-glucosamine, N-acetyl-arginine, N6-acetyl-lysine, pantothenate, citrulline, leucine, isoleucine, NAD+, and NADP+. Six of them are RBC-enriched, suggesting that RBC metabolomics is highly valuable for human aging research. Age differences are partly explained by a decrease in antioxidant production or increasing inefficiency of urea metabolism among the elderly. Pearson’s coefficients demonstrated that some age-related compounds are correlated, suggesting that aging affects them concomitantly. Although our CV values are mostly consistent with those CVs previously published, we here report previously unidentified CVs of 51 blood compounds. Compounds having moderate to high CV values (0.4–2.5) are often modified. Compounds having low CV values, such as ATP and glutathione, may be related to various diseases because their concentrations are strictly controlled, and changes in them would compromise health. Thus, human blood is a rich source of information about individual metabolic differences. PMID:27036001

  5. Individual variability in human blood metabolites identifies age-related differences.

    PubMed

    Chaleckis, Romanas; Murakami, Itsuo; Takada, Junko; Kondoh, Hiroshi; Yanagida, Mitsuhiro

    2016-04-19

    Metabolites present in human blood document individual physiological states influenced by genetic, epigenetic, and lifestyle factors. Using high-resolution liquid chromatography-mass spectrometry (LC-MS), we performed nontargeted, quantitative metabolomics analysis in blood of 15 young (29 ± 4 y of age) and 15 elderly (81 ± 7 y of age) individuals. Coefficients of variation (CV = SD/mean) were obtained for 126 blood metabolites of all 30 donors. Fifty-five RBC-enriched metabolites, for which metabolomics studies have been scarce, are highlighted here. We found 14 blood compounds that show remarkable age-related increases or decreases; they include 1,5-anhydroglucitol, dimethyl-guanosine, acetyl-carnosine, carnosine, ophthalmic acid, UDP-acetyl-glucosamine,N-acetyl-arginine,N6-acetyl-lysine, pantothenate, citrulline, leucine, isoleucine, NAD(+), and NADP(+) Six of them are RBC-enriched, suggesting that RBC metabolomics is highly valuable for human aging research. Age differences are partly explained by a decrease in antioxidant production or increasing inefficiency of urea metabolism among the elderly. Pearson's coefficients demonstrated that some age-related compounds are correlated, suggesting that aging affects them concomitantly. Although our CV values are mostly consistent with those CVs previously published, we here report previously unidentified CVs of 51 blood compounds. Compounds having moderate to high CV values (0.4-2.5) are often modified. Compounds having low CV values, such as ATP and glutathione, may be related to various diseases because their concentrations are strictly controlled, and changes in them would compromise health. Thus, human blood is a rich source of information about individual metabolic differences. PMID:27036001

  6. Femoral neck-shaft angle in humans: variation relating to climate, clothing, lifestyle, sex, age and side.

    PubMed

    Gilligan, Ian; Chandraphak, Supichya; Mahakkanukrauh, Pasuk

    2013-08-01

    The femoral neck-shaft angle (NSA) varies among modern humans but measurement problems and sampling limitations have precluded the identification of factors contributing to its variation at the population level. Potential sources of variation include sex, age, side (left or right), regional differences in body shape due to climatic adaptation, and the effects of habitual activity patterns (e.g. mobile and sedentary lifestyles and foraging, agricultural, and urban economies). In this study we addressed these issues, using consistent methods to assemble a global NSA database comprising over 8000 femora representing 100 human groups. Results from the analyses show an average NSA for modern humans of 127° (markedly lower than the accepted value of 135°); there is no sex difference, no age-related change in adults, but possibly a small lateral difference which could be due to right leg dominance. Climatic trends consistent with principles based on Bergmann's rule are evident at the global and continental levels, with the NSA varying in relation to other body shape indices: median NSA, for instance, is higher in warmer regions, notably in the Pacific (130°), whereas lower values (associated with a more stocky body build) are found in regions where ancestral populations were exposed to colder conditions, in Europe (126°) and the Americas (125°). There is a modest trend towards increasing NSA with the economic transitions from forager to agricultural and urban lifestyles and, to a lesser extent, from a mobile to a sedentary existence. However, the main trend associated with these transitions is a progressive narrowing in the range of variation in the NSA, which may be attributable to thermal insulation provided by improved cultural buffering from climate, particularly clothing. PMID:23781912

  7. Femoral neck-shaft angle in humans: variation relating to climate, clothing, lifestyle, sex, age and side

    PubMed Central

    Gilligan, Ian; Chandraphak, Supichya; Mahakkanukrauh, Pasuk

    2013-01-01

    The femoral neck-shaft angle (NSA) varies among modern humans but measurement problems and sampling limitations have precluded the identification of factors contributing to its variation at the population level. Potential sources of variation include sex, age, side (left or right), regional differences in body shape due to climatic adaptation, and the effects of habitual activity patterns (e.g. mobile and sedentary lifestyles and foraging, agricultural, and urban economies). In this study we addressed these issues, using consistent methods to assemble a global NSA database comprising over 8000 femora representing 100 human groups. Results from the analyses show an average NSA for modern humans of 127° (markedly lower than the accepted value of 135°); there is no sex difference, no age-related change in adults, but possibly a small lateral difference which could be due to right leg dominance. Climatic trends consistent with principles based on Bergmann's rule are evident at the global and continental levels, with the NSA varying in relation to other body shape indices: median NSA, for instance, is higher in warmer regions, notably in the Pacific (130°), whereas lower values (associated with a more stocky body build) are found in regions where ancestral populations were exposed to colder conditions, in Europe (126°) and the Americas (125°). There is a modest trend towards increasing NSA with the economic transitions from forager to agricultural and urban lifestyles and, to a lesser extent, from a mobile to a sedentary existence. However, the main trend associated with these transitions is a progressive narrowing in the range of variation in the NSA, which may be attributable to thermal insulation provided by improved cultural buffering from climate, particularly clothing. PMID:23781912

  8. Aging of the cingulum in the human brain: Preliminary study of a diffusion tensor imaging study.

    PubMed

    Jang, Sung Ho; Kwon, Yong Hyun; Lee, Mi Young; Kim, Jae-Ryong; Seo, Jeong Pyo

    2016-01-01

    The cingulum, a major structure of the limbic system, is closely associated with memory function. In the current study, we investigated aging of the cingulum according to the location of the cingulum in each part of the cingulum after dividing the cingulum into five parts in normal subjects, using DTT parameters (fractional anisotropy (FA) and fiber number (FN)). Ninety healthy subjects (males: 44, females: 46, mean age: 49.0 years; range: 20-78 years) were enrolled in this study. Subjects were categorized according to six groups by age intervals of 10 years; each age group consisted of 15 subjects. The cingulum was divided into five parts (anterior, anterior superior, posterior superior cingulum, posterior, and inferior cingulum). The FA and FN of each part were measured. The FA value indicates the degree of directionality and integrity of white matter microstructures such as axons, myelin, and microtubules, and the FN reflects the total number of fibers in a neural tract. Age-related decline in the FA value may indicate demyelination, and a decline in the number of myelinated fibers of a neural tract can also lead to a decline of the FN. Significant differences in the FA value of the anterior cingulum and anterior superior cingulum, and the FN of the inferior cingulum were observed between age groups (AVOVA, p<0.05). A significant decrease was observed in the FA values of the anterior and anterior superior cingulum of the 60s and 70s age groups compared with those of the 20s and 30s age groups, and in the FN of the inferior cingulum of the 60s and 70s age groups compared with that of the 20s age group (LSD post hoc test, p<0.05). Aging of the cingulum began at both ends of the cingulum in the 20s or 30s, and progressed steadily at a near continuous rate over the lifespan and a significant degenerative aging effect at both ends of the cingulum occurred into the 60s, compared with the 20s or 30s. PMID:26598020

  9. Function of RasGRP3 in the formation and progression of human breast cancer

    PubMed Central

    2014-01-01

    Introduction Ras guanine nucleotide exchange factors (RasGEFs) mediate the activation of the Ras signaling pathway that is over activated in many human cancers. The RasGRP3, an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types. Here, we investigated the putative alteration of expression and potential function of RasGRP3 in the formation and progression of human breast cancer. Methods The RasGRP3 and phosphoRasGRP3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT-474, JIMT-1, MCF7, SK-BR-3, MDA-MB-453, T-47D) both in mRNA (Q-PCR) and protein (Western blot; immunohistochemistry) levels. To explore the biological function of the protein, RasGRP3 knockdown cultures were established. To assess the role of RasGRP3 in the viability of cells, annexin-V/PI staining and MitoProbe™ DilC1 (5) assay were performed. To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance, CyQuant assay was performed. To observe the RasGRP3 function in tumor formation, the Severe combined immunodeficiency (SCID) mouse model was used. To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed. Results RasGRP3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines. Down-regulation of RasGRP3 expression in breast cancer cells decreased cell proliferation, induced apoptosis in MCF7 cells, and sensitized T-47D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin). Gene silencing of RasGRP3 reduced tumor formation in mouse xenografts as well. Inhibition of RasGRP3 expression also reduced Akt, ERK1/2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor-I (IGF-I) or epidermal growth factor (EGF) stimulation confirming the functional

  10. Age-related changes in human vestibulo-ocular and optokinetic reflexes: Pseudorandom rotation tests

    NASA Technical Reports Server (NTRS)

    Peterka, R. J.; Black, F. O.; Schoenhoff, M. B.

    1989-01-01

    The dynamic response properties of horizontal vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) were characterized in 216 human subjects ranging in age from 7 to 81 years. The object of this cross-sectional study was to determine the effects of aging on VOR and OKR reflex dynamics, and to identify the distributions of parameters which describe VOR and OKR responses to pseudorandom stimuli in a putatively normal population. In general, VOR and OKR response parameters changed in a manner consistent with declining function with increasing age. For the VOR this was reflected in declining response amplitudes, although the magnitude of the decline was small relative to the variability of the data. For the OKR the lag time of the response, probably associated with the time required for visual information processing, increased linearly with age at a rate of about 1 ms per year.

  11. Peripheral mechanisms of thermoregulatory control of skin blood flow in aged humans

    PubMed Central

    Kenney, W. Larry

    2010-01-01

    Human skin blood flow is controlled via dual innervation from the sympathetic nervous system. Reflex cutaneous vasoconstriction and vasodilation are both impaired with primary aging, rendering the aged more vulnerable to hypothermia and cardiovascular complications from heat-related illness. Age-related alterations in the thermoregulatory control of skin blood flow occur at multiple points along the efferent arm of the reflex, including 1) diminished sympathetic outflow, 2) altered presynaptic neurotransmitter synthesis, 3) reduced vascular responsiveness, and 4) impairments in downstream (endothelial and vascular smooth muscle) second-messenger signaling. This mechanistic review highlights some of the recent findings in the area of aging and the thermoregulatory control of skin blood flow. PMID:20413421

  12. A Validated Normative Model for Human Uterine Volume from Birth to Age 40 Years

    PubMed Central

    Ginbey, Eleanor; Chowdhury, Moti M.; Bath, Louise E.; Anderson, Richard A.; Wallace, W. Hamish B.

    2016-01-01

    Transabdominal pelvic ultrasound and/or pelvic Magnetic Resonance Imaging are safe, accurate and non-invasive means of determining the size and configuration of the internal female genitalia. The assessment of uterine size and volume is helpful in the assessment of many conditions including disorders of sex development, precocious or delayed puberty, infertility and menstrual disorders. Using our own data from the assessment of MRI scans in healthy young females and data extracted from four studies that assessed uterine volume using transabdominal ultrasound in healthy females we have derived and validated a normative model of uterine volume from birth to age 40 years. This shows that uterine volume increases across childhood, with a faster increase in adolescence reflecting the influence of puberty, followed by a slow but progressive rise during adult life. The model suggests that around 84% of the variation in uterine volumes in the healthy population up to age 40 is due to age alone. The derivation of a validated normative model for uterine volume from birth to age 40 years has important clinical applications by providing age-related reference values for uterine volume. PMID:27295032

  13. Plasma Protein Oxidation and Its Correlation with Antioxidant Potential During Human Aging

    PubMed Central

    Pandey, Kanti Bhooshan; Mehdi, Mohd Murtaza; Maurya, Pawan Kumar; Rizvi, Syed Ibrahim

    2010-01-01

    Previous studies have indicated that the main molecular characteristic of aging is the progressive accumulation of oxidative damages in cellular macromolecules. Proteins are one of the main molecular targets of age-related oxidative stress, which have been observed during aging process in cellular systems. Reactive oxygen species (ROS) can lead to oxidation of amino acid side chains, formation of protein-protein cross-linkages, and oxidation of the peptide backbones. In the present study, we report the age-dependent oxidative alterations in biomarkers of plasma protein oxidation: protein carbonyls (PCO), advanced oxidation protein products (AOPPs) and plasma total thiol groups (T-SH) in the Indian population and also correlate these parameters with total plasma antioxidant potential. We show an age dependent decrease in T-SH levels and increase in PCO and AOPPs level. The alterations in the levels of these parameters correlated significantly with the total antioxidant capacity of the plasma. The levels of oxidized proteins in plasma provide an excellent biomarker of oxidative stress due to the relative long half-life of such oxidized proteins. PMID:20826915

  14. Human Rights for Children: A Curriculum for Teaching Human Rights to Children Ages 3-12.

    ERIC Educational Resources Information Center

    Hatch, Virginia; And Others

    Created to heighten teachers' awareness of human rights issues, particularly those related to children's rights, this guide offers children knowledge and skills in developing both self-worth and empathy for others. These feelings, the curriculum argues, are the foundation children need if they are to understand their rights as children and the…

  15. The development of a functionally relevant cell culture model of progressive human breast cancer.

    PubMed

    Weaver, V M; Howlett, A R; Langton-Webster, B; Petersen, O W; Bissell, M J

    1995-06-01

    Normal mammary homeostasis, and by implication tumorigenesis, are dependent upon the dynamic interplay between epithelial cells, stromal components and the extracellular matrix. To study the evolution of human breast cancer, a functionally relevant cell culture model is required which recognizes the complexity of the mammary gland's microenvironment. The development of an appropriate breast epithelial cancer cell model will be dependent on the ability to recreate the 'normal' and 'neoplastic' tissue microenvironment in culture. Towards this goal, a 3-dimensional extracellular matrix (ECM) assay, employing a reconstituted basement membrane, has been developed which allows for the rapid and accurate discrimination of normal and neoplastic cells when cultured. To investigate stromal/epithelial cell interactions, we have developed a tumor environment assay which essentially mirrors the tumor microenvironment histologically. The use of a novel, near diploid, human breast epithelial cell line, HMT-3522, which has transformed spontaneously with passage in culture, together with these 3-dimensional culture assays is expected to provide meaningful markers of initiation and progression. PMID:7495986

  16. Orphan nuclear receptor nurr1 as a potential novel marker for progression in human prostate cancer.

    PubMed

    Wang, Jian; Yang, Jing; Zou, Ying; Huang, Guo-Liang; He, Zhi-Wei

    2013-01-01

    A number of studies have indicated that Nurr1, which belongs to a novel class of orphan nuclear receptors (the NR4A family), is important for carcinogenesis. Here we investigated expression of Nurr1 protein in benign and malignant human prostate tissues and association with clinicopathologic features using immunohistochemical techniques. Moreover, we also investigated the ability of Nurr1 to influence proliferation, migration, invasion and apoptosis of human prostate cancer cells using small interfering RNA silencing. Immunohistochemical analysis revealed that the expression of Nurr1 protein was higher in prostate cancer tissues than in benign prostate tissue (P < 0.001), levels being positively correlated with tumor T classification (P = 0.003), N classification (P = 0.017), M classification (P = 0.011) and the Gleason score (P = 0.020) of prostate cancer patients. In vitro, silencing of endogenous Nurr1 attenuated cell proliferation, migration and invasion, and induced apoptosis of prostate cancer cells. These results suggest that Nurr1 may be used as an indicator for prostate cancer progression and be useful for novel potential therapeutic strategies. PMID:23679312

  17. Production of Human Pluripotent Stem Cell Therapeutics Under Defined Xeno-free Conditions: Progress and Challenges

    PubMed Central

    Fan, Yongjia; Wu, Jincheng; Ashok, Preeti; Hsiung, Michael; Tzanakakis, Emmanuel S.

    2014-01-01

    Recent advances on human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have brought us closer to the realization of their clinical potential. Nonetheless, tissue engineering and regenerative medicine applications will require the generation of hPSC products well beyond the laboratory scale. This also mandates the production of hPSC therapeutics in fully-defined, xeno-free systems and in a reproducible manner. Toward this goal, we summarize current developments in defined media free of animal-derived components for hPSC culture. Bioinspired and synthetic extracellular matrices for the attachment growth and differentiation of hPSCs are also reviewed. Given that most progress in xeno-free medium and substrate development has been demonstrated in two-dimensional rather than three dimensional culture systems, translation from the former to the latter poses unique difficulties. These challenges are discussed in the context of cultivation platforms of hPSCs as aggregates, on microcarriers or after encapsulation in biocompatible scaffolds. PMID:25077810

  18. Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: Prospective analysis of 435 liver biopsy pairs

    PubMed Central

    Konerman, Monica A.; Mehta, Shruti H.; Sutcliffe, Catherine G.; Vu, Trang; Higgins, Yvonne; Torbenson, Michael S.; Moore, Richard D.; Thomas, David L.; Sulkowski, Mark S.

    2013-01-01

    Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection is associated with progressive liver disease. However, the rate of progression is variable and the ability to differentiate patients with stable versus progressive HCV disease is limited. The objective of this study was to assess the incidence of and risk factors for fibrosis progression in a prospective cohort of coinfected patients. Overall, 435 liver biopsy pairs from 282 non-cirrhotic patients were analyzed. Biopsies were scored according to the METAVIR system by a single pathologist blind to biopsy sequence. Fibrosis progression was defined as an increase of at least one METAVIR fibrosis stage between paired biopsies. The majority of patients were African American (84.8%), male (67.7%) and infected with HCV genotype 1 (93.4%). On initial biopsy, no or minimal fibrosis was identified in 243 patients (86%). The median interval between biopsies was 2.5 years. Fibrosis progression was observed in 97 of 282 (34%) patients and 149 of 435 (34%) biopsy pairs. After adjustment, greater body mass index (adjusted odds ratio [aOR]: 1.04 per 1 unit increase), diabetes (aOR: 1.56) and hepatic steatosis (aOR: 1.78) at time of initial biopsy were associated with subsequent fibrosis progression. Between biopsies, elevated serum aspartate and alanine aminotransferase (AST, ALT) (aOR AST: 3.34, ALT: 2.18 for >25% values >100 U/l vs. < 25% values >100 U/l) were strongly associated with fibrosis progression. Conclusion Fibrosis progression is common among HIV/HCV coinfected patients; these data suggest that progression can be rapid. Persistent elevations in serum transaminase levels may serve as important non-invasive markers to identify subsets of patients who are more likely to progress and thus warrant closer monitoring and consideration of HCV treatment. PMID:24436062

  19. A prospective study to compare serum human placental lactogen and menstrual dates for determining gestational age.

    PubMed

    Whittaker, P G; Lind, T; Lawson, J Y

    1987-01-01

    In a group of 575 healthy pregnant women with certain menstrual dates the estimation of the length of gestation from maternal serum human placental lactogen concentrations has been compared with gestational age calculated from the last menstrual period and ultrasonic measurements of the fetal biparietal diameter. In 412 of these patients labor started spontaneously, and the estimated dates of delivery determined by these three methods were also compared. In the range of 9 to 17 weeks of pregnancy, gestational age can be determined by human placental lactogen measurement to within 7 days (+/- 1 SD) which compares favorably with other methods. Regarding the prediction of the expected date of delivery, 88% were delivered within 2 weeks of the date predicted by last menstrual period, 82% within 2 weeks of the sonar date, and 80% by the date determined by human placental lactogen assessment. Prediction of delivery in a further group of 139 women with uncertain dates gave 73% within 2 weeks by sonar date and 69% within 2 weeks by human placental lactogen determination. We suggest human placental lactogen measurements should become part of routine antenatal care complementing rather than replacing the role of ultrasonic scanning. For those doctors and patients who wish to avoid more exposure to ultrasonic scanning than absolutely necessary, human placental lactogen estimates offer an alternative method for assessing the length of gestation. PMID:3541617

  20. Elephants can determine ethnicity, gender, and age from acoustic cues in human voices

    PubMed Central

    McComb, Karen; Shannon, Graeme; Sayialel, Katito N.; Moss, Cynthia

    2014-01-01

    Animals can accrue direct fitness benefits by accurately classifying predatory threat according to the species of predator and the magnitude of risk associated with an encounter. Human predators present a particularly interesting cognitive challenge, as it is typically the case that different human subgroups pose radically different levels of danger to animals living around them. Although a number of prey species have proved able to discriminate between certain human categories on the basis of visual and olfactory cues, vocalizations potentially provide a much richer source of information. We now use controlled playback experiments to investigate whether family groups of free-ranging African elephants (Loxodonta africana) in Amboseli National Park, Kenya can use acoustic characteristics of speech to make functionally relevant distinctions between human subcategories differing not only in ethnicity but also in sex and age. Our results demonstrate that elephants can reliably discriminate between two different ethnic groups that differ in the level of threat they represent, significantly increasing their probability of defensive bunching and investigative smelling following playbacks of Maasai voices. Moreover, these responses were specific to the sex and age of Maasai presented, with the voices of Maasai women and boys, subcategories that would generally pose little threat, significantly less likely to produce these behavioral responses. Considering the long history and often pervasive predatory threat associated with humans across the globe, it is likely that abilities to precisely identify dangerous subcategories of humans on the basis of subtle voice characteristics could have been selected for in other cognitively advanced animal species. PMID:24616492

  1. Elephants can determine ethnicity, gender, and age from acoustic cues in human voices.

    PubMed

    McComb, Karen; Shannon, Graeme; Sayialel, Katito N; Moss, Cynthia

    2014-04-01

    Animals can accrue direct fitness benefits by accurately classifying predatory threat according to the species of predator and the magnitude of risk associated with an encounter. Human predators present a particularly interesting cognitive challenge, as it is typically the case that different human subgroups pose radically different levels of danger to animals living around them. Although a number of prey species have proved able to discriminate between certain human categories on the basis of visual and olfactory cues, vocalizations potentially provide a much richer source of information. We now use controlled playback experiments to investigate whether family groups of free-ranging African elephants (Loxodonta africana) in Amboseli National Park, Kenya can use acoustic characteristics of speech to make functionally relevant distinctions between human subcategories differing not only in ethnicity but also in sex and age. Our results demonstrate that elephants can reliably discriminate between two different ethnic groups that differ in the level of threat they represent, significantly increasing their probability of defensive bunching and investigative smelling following playbacks of Maasai voices. Moreover, these responses were specific to the sex and age of Maasai presented, with the voices of Maasai women and boys, subcategories that would generally pose little threat, significantly less likely to produce these behavioral responses. Considering the long history and often pervasive predatory threat associated with humans across the globe, it is likely that abilities to precisely identify dangerous subcategories of humans on the basis of subtle voice characteristics could have been selected for in other cognitively advanced animal species. PMID:24616492

  2. Exercise intervention increases spontaneous locomotion but fails to attenuate dopaminergic system loss in a progressive MPTP model in aged mice.

    PubMed

    Hood, Rebecca L; Liguore, William A; Moore, Cynthia; Pflibsen, Lacey; Meshul, Charles K

    2016-09-01

    While exercise is commonly recommended for PD patients to improve motor function, little is known about the disease-altering potential of exercise. Although others have demonstrated neuroprotective or neurorestorative effects of exercise in animal models of PD, the majority of these studies utilize young animals. In order to assess the effects of exercise intervention in a more clinically relevant model, we have subjected aged mice to progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning and daily treadmill exercise, initiated early in the course of the disease. The MPTP model elicited a 55% reduction in striatal TH as measured by immunohistochemistry compared to sedentary controls, and exercise did not attenuate this loss in exercised MPTP animals. Furthermore, striatal TH and DAT loss, as assessed by western blotting, were not significantly impacted by treadmill exercise in MPTP-lesioned mice. We did find an increase in spontaneous locomotion in exercised mice that was not decreased by MPTP lesioning. This finding may be due, in part, to an increase in TH expression in the motor cortex in exercised MPTP mice. PMID:27350080

  3. Progressive alopecia reveals decreasing stem cell activation probability during aging of mice with epidermal deletion of DNA methyltransferase 1.

    PubMed

    Li, Ji; Jiang, Ting-Xin; Hughes, Michael W; Wu, Ping; Yu, Juehua; Widelitz, Randall B; Fan, Guoping; Chuong, Cheng-Ming

    2012-12-01

    To examine the roles of epigenetic modulation on hair follicle regeneration, we generated mice with a K14-Cre-mediated loss of DNA methyltransferase 1 (DNMT1). The mutant shows an uneven epidermal thickness and alterations in hair follicle size. When formed, hair follicle architecture and differentiation appear normal. Hair subtypes exist but hair fibers are shorter and thinner. Hair numbers appear normal at birth but gradually decrease to <50% of control in 1-year-old mice. Sections of old mutant skin show follicles in prolonged telogen with hyperplastic sebaceous glands. Anagen follicles in mutants exhibit decreased proliferation and increased apoptosis in matrix transient-amplifying cells. Although K15-positive stem cells in the mutant bulge are comparable in number to the control, their ability to proliferate and become activated to form a hair germ is reduced. As mice age, residual DNMT activity declines further, and the probability of successful anagen reentry decreases, leading to progressive alopecia. Paradoxically, there is increased proliferation in the epidermis, which also shows aberrant differentiation. These results highlight the importance of DNA methylation in maintaining stem cell homeostasis during the development and regeneration of ectodermal organs. PMID:22763785

  4. An iPS Cell Line From Human Pancreatic Ductal Adenocarcinoma Undergoes Early to Invasive Stages of Pancreatic Cancer Progression

    PubMed Central

    Kim, Jungsun; Hoffman, John P.; Alpaugh, R. Katherine; Rhim, Andrew D.; Reichert, Maximilian; Stanger, Ben Z.; Furth, Emma E.; Sepulveda, Antonia R.; Yuan, Chao-Xing; Won, Kyoung-Jae; Donahue, Greg; Sands, Jessica; Gumbs, Andrew A.; Zaret, Kenneth S.

    2013-01-01

    Pancreatic ductal ade