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Sample records for repair modulates aging

  1. 'Relax and Repair' to restrain aging.

    PubMed

    Krishnan, Vaidehi; Liu, Baohua; Zhou, Zhongjun

    2011-10-01

    The maintenance of genomic integrity requires the precise identification and repair of DNA damage. Since DNA is packaged and condensed into higher order chromatin, the events associated with DNA damage recognition and repair are orchestrated within the layers of chromatin. Very similar to transcription, during DNA repair, chromatin remodelling events and histone modifications act in concert to 'open' and relax chromatin structure so that repair proteins can gain access to DNA damage sites. One such histone mark critical for maintaining chromatin structure is acetylated lysine 16 of histone H4 (AcH4K16), a modification that can disrupt higher order chromatin organization and convert it into a more 'relaxed' configuration. We have recently shown that impaired H4K16 acetylation delays the accumulation of repair proteins to double strand break (DSB) sites which results in defective genome maintenance and accelerated aging in a laminopathy-based premature aging mouse model. These results support the idea that epigenetic factors may directly contribute to genomic instability and aging by regulating the efficiency of DSB repair. In this article, the interplay between epigenetic misregulation, defective DNA repair and aging is discussed.

  2. DNA Damage, DNA Repair, Aging, and Neurodegeneration.

    PubMed

    Maynard, Scott; Fang, Evandro Fei; Scheibye-Knudsen, Morten; Croteau, Deborah L; Bohr, Vilhelm A

    2015-09-18

    Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.

  3. DNA Damage, DNA Repair, Aging, and Neurodegeneration

    PubMed Central

    Maynard, Scott; Fang, Evandro Fei; Scheibye-Knudsen, Morten; Croteau, Deborah L.; Bohr, Vilhelm A.

    2015-01-01

    Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span. PMID:26385091

  4. Chromatin Remodeling, DNA Damage Repair and Aging

    PubMed Central

    Liu, Baohua; Yip, Raymond KH; Zhou, Zhongjun

    2012-01-01

    Cells are constantly exposed to a variety of environmental and endogenous conditions causing DNA damage, which is detected and repaired by conserved DNA repair pathways to maintain genomic integrity. Chromatin remodeling is critical in this process, as the organization of eukaryotic DNA into compact chromatin presents a natural barrier to all DNA-related events. Studies on human premature aging syndromes together with normal aging have suggested that accumulated damages might lead to exhaustion of resources that are required for physiological functions and thus accelerate aging. In this manuscript, combining the present understandings and latest findings, we focus mainly on discussing the role of chromatin remodeling in the repair of DNA double-strand breaks (DSBs) and regulation of aging. PMID:23633913

  5. Aging processes, DNA damage, and repair.

    PubMed

    Gilchrest, B A; Bohr, V A

    1997-04-01

    The second triennial FASEB Summer Research Conference on "Clonal Senescence and Differentiation" (August 17-22, 1996) focused on the interrelationships between aging processes and DNA damage and repair. The attendees represented a cross section of senior and junior investigators working in fields ranging from classic cellular gerontology to yeast and nematode models of aging to basic mechanisms of DNA damage and repair. The meeting opened with a keynote address by Dr. Bruce Ames that emphasized the documented relationships between oxidative damage, cancer, and aging. This was followed by eight platform sessions, one poster discussion, one featured presentation, and an after-dinner address. The following sections highlight the key points discussed.

  6. Cartilage repair in the degenerative ageing knee

    PubMed Central

    Brittberg, Mats; Gomoll, Andreas H; Canseco, José A; Far, Jack; Lind, Martin; Hui, James

    2016-01-01

    Background and purpose Cartilage damage can develop due to trauma, resulting in focal chondral or osteochondral defects, or as more diffuse loss of cartilage in a generalized organ disease such as osteoarthritis. A loss of cartilage function and quality is also seen with increasing age. There is a spectrum of diseases ranging from focal cartilage defects with healthy surrounding cartilage to focal lesions in degenerative cartilage, to multiple and diffuse lesions in osteoarthritic cartilage. At the recent Aarhus Regenerative Orthopaedics Symposium (AROS) 2015, regenerative challenges in an ageing population were discussed by clinicians and basic scientists. A group of clinicians was given the task of discussing the role of tissue engineering in the treatment of degenerative cartilage lesions in ageing patients. We present the outcomes of our discussions on current treatment options for such lesions, with particular emphasis on different biological repair techniques and their supporting level of evidence. Results and interpretation Based on the studies on treatment of degenerative lesions and early OA, there is low-level evidence to suggest that cartilage repair is a possible treatment for such lesions, but there are conflicting results regarding the effect of advanced age on the outcome. We concluded that further improvements are needed for direct repair of focal, purely traumatic defects before we can routinely use such repair techniques for the more challenging degenerative lesions. Furthermore, we need to identify trigger mechanisms that start generalized loss of cartilage matrix, and induce subchondral bone changes and concomitant synovial pathology, to maximize our treatment methods for biological repair in degenerative ageing joints. PMID:27910738

  7. Bilingual Skills Training Program. Auto Body Repair. Module 3.0: Basic Metal Repair.

    ERIC Educational Resources Information Center

    Northern New Mexico Community Coll., El Rito.

    This module on basic metal repair is the third of four (CE 028 303-306) in the auto body repair course of a bilingual vocational training program. The course is designed to furnish theoretical and laboratory experience in welding, metal straightening, metal finishing, painting, and use of power and hand tools. Module objectives are for students to…

  8. Oxidative mutagenesis, mismatch repair, and aging.

    PubMed

    Skinner, Amy M; Turker, Mitchell S

    2005-03-02

    A PubMed search for the term "oxidative stress" yields over 29,000 articles published on the subject over the past 10 years; more than 2000 of these articles also include the term "aging" in their title or abstract. Many theories of aging predict causal roles for oxidative stress in the myriad of pathological changes that occur as a function of age, including an increasing propensity to develop cancer. A possible link between aging and cancer is the induction and accumulation of somatic mutations caused by oxidative stress. This Review focuses on small mutational events that are induced by oxidative stress and the role of mismatch repair (MMR) in preventing their formation. It also discusses a possible inhibitory effect of oxidative stress on MMR. We speculate that a synergistic interaction between oxidative damage to DNA and reduced MMR levels will, in part, account for an accumulation of small mutational events, and hence cancer, with aging.

  9. Anesthesia, Microcirculation and Wound Repair in Aging

    PubMed Central

    Bentov, Itay; Reed, May J.

    2014-01-01

    Age related changes in skin contribute to impaired wound healing after surgical procedures. Changes in skin with age include decline in thickness and composition, a decrease in the number of most cell types and diminished microcirculation. The microcirculation provides tissue perfusion, fluid homeostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause further disruption of the microvasculature of aged skin. Perioperative management can be modified to minimize insults to aged tissues. Judicious use of fluids, maintenance of normal body temperature, pain control and increased tissue oxygen tension are examples of adjustable variables that support the microcirculation. Anesthetic agents influence the microcirculation from a combination of effects on cardiac output, arterial pressure and local micro-vascular changes. We examine the role of anesthetic management in optimizing the microcirculation and potentially improving post-operative wound repair in older persons. PMID:24195972

  10. SOLERAS - Analysis of photovoltaic concentrator module failures and repair methods

    SciTech Connect

    Huraib, F.S.; Imamura, M.S.; Salim, A.A.; Rao, N.R.

    1987-06-01

    This report presents the results of the failure analysis, performed from early 1984 through September 1986 on the open-circuited modules, and the assessment of repairing these modules on site at the Solar Village. 16 refs., 26 figs., 19 tabs.

  11. SIRT6 IN DNA REPAIR, METABOLISM, AND AGEING

    PubMed Central

    Lombard, David B.; Schwer, Bjoern; Alt, Frederick W.; Mostoslavsky, Raul

    2008-01-01

    Ageing, or increased mortality with time, coupled with physiologic decline, is a nearly universal yet poorly understood biological phenomenon. Studies in model organisms suggest that two conserved pathways modulate longevity: DNA damage repair and insulin/Igf1-like signaling. In addition, homologs of yeast Sir2 – the sirtuins – regulate lifespan in diverse organisms. Here, we focus on one particular sirtuin, SIRT6. Mice lacking SIRT6 develop a degenerative disorder that in some respects mimics models of accelerated ageing [1]. We discuss how sirtuins in general and SIRT6 specifically relate to other evolutionarily conserved pathways affecting ageing, and how SIRT6 might function to ensure organismal homeostasis and normal lifespan. PMID:18226091

  12. Nanomedicine Approaches to Modulate Neural Stem Cells in Brain Repair.

    PubMed

    Santos, Tiago; Boto, Carlos; Saraiva, Cláudia M; Bernardino, Liliana; Ferreira, Lino

    2016-06-01

    We explore the concept of modulating neural stem cells and their niches for brain repair using nanotechnology-based approaches. These approaches include stimulating cell proliferation, recruitment, and differentiation to functionally recover damaged areas. Nanoscale-engineered materials potentially overcome limited crossing of the blood-brain barrier, deficient drug delivery, and cell targeting. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Immune modulation by MANF promotes tissue repair and regenerative success in the retina.

    PubMed

    Neves, Joana; Zhu, Jie; Sousa-Victor, Pedro; Konjikusic, Mia; Riley, Rebeccah; Chew, Shereen; Qi, Yanyan; Jasper, Heinrich; Lamba, Deepak A

    2016-07-01

    Regenerative therapies are limited by unfavorable environments in aging and diseased tissues. A promising strategy to improve success is to balance inflammatory and anti-inflammatory signals and enhance endogenous tissue repair mechanisms. Here, we identified a conserved immune modulatory mechanism that governs the interaction between damaged retinal cells and immune cells to promote tissue repair. In damaged retina of flies and mice, platelet-derived growth factor (PDGF)-like signaling induced mesencephalic astrocyte-derived neurotrophic factor (MANF) in innate immune cells. MANF promoted alternative activation of innate immune cells, enhanced neuroprotection and tissue repair, and improved the success of photoreceptor replacement therapies. Thus, immune modulation is required during tissue repair and regeneration. This approach may improve the efficacy of stem-cell-based regenerative therapies.

  14. Dietary and genetic modulation of DNA repair in healthy human adults.

    PubMed

    Tyson, J; Mathers, J C

    2007-02-01

    The DNA in all cells of the human body is subject to damage continuously from exogenous agents, internal cellular processes and spontaneous decomposition. Failure to repair such damage is fundamental to the development of many diseases and to ageing. Fortunately, the vast majority of DNA damage is detected and repaired by one of five complementary DNA repair systems. However, recent studies have shown that even in healthy individuals there is a wide inter-individual variation in DNA repair capacity. Part of this variation can be accounted for by polymorphisms in the genes encoding DNA repair proteins. However, it is probable that environmental factors, including dietary exposure as well as diet-gene interactions, are also responsible for much of the difference in repair capacity between individuals. Whilst there is some evidence from human studies that generalised malnutrition or low intakes of specific nutrients may affect DNA repair, as yet there is limited understanding of the molecular mechanisms through which nutrients can modulate this key cellular process.

  15. Modulation of human nucleotide excision repair by 5-methylcytosines.

    PubMed

    Muheim, Regula; Buterin, Tonko; Colgate, Katharine C; Kolbanovsij, Alexander; Geacintov, Nicholas E; Naegeli, Hanspeter

    2003-03-25

    Previous reports showed that methylated CpG sites are primary targets of bulky lesions induced by UV radiation, benzo[a]pyrene (B[a]P), or other environmental genotoxic agents. This study was performed to determine whether the repair of DNA damage formed preferentially at CpG dinucleotides is sensitive to 5-methylcytosine substitutions. Reactivation assays using UV- or B[a]P diol epoxide-damaged shuttle vectors established that human nucleotide excision repair enzymes are able to process fully methylated target DNA molecules. Repair reactions in human cell extracts suggested that 5-methylcytosines modulate local repair efficiency in a seemingly unpredictable manner. In fact, excision of the predominant (+)-trans-anti-B[a]P-dG adduct situated in a mutational hot spot sequence (codon 273 of the p53 gene) was stimulated by CpG methylation. Interestingly, excision activity was increased by a single 5-methylcytosine residue flanking the adduct in the damaged strand, but the same stimulatory effect was also induced by a single 5-methylcytosine residue located opposite the adduct in the undamaged strand. No such stimulation was observed when the (+)-trans-anti-B[a]P-dG lesion was placed in a different site containing a sequence of contiguous guanines, and strong inhibition was detected when a representative of the rare (+)-cis-anti-B[a]P-dG isomer was tested in the same assay. These results raise the possibility that 5-methylcytosines in CpG dinucleotides modulate not only the distribution of bulky DNA lesions but, at least in some cases, also the kinetics of subsequent excision repair reactions. This study confirms that the efficiency of bulky lesion repair is determined by the configuration of base pairs at damaged sites.

  16. Identification of natural antimutagens with modulating effects on DNA repair.

    PubMed

    Vuković-Gacić, B; Simić, D

    1993-01-01

    The results of a study of bioantimutagenesis, with emphasis on natural antimutagens from plant extracts with modulating effects on DNA repair in Escherichia coli bacteria are presented in this chapter. Comparative screening for spontaneous or induced mutagenesis, as well as expression of the SOS gene, sfiA was accomplished. Antimutagenic capacity was obtained with nontoxic concentrations of the plant extracts; the same plant extract may decrease or increase the mutation rate, or even be ineffective, depending on the bacterial strain used and the concentration of the extract applied. Since antimutagenic effects may be the consequence of either stimulation of error-free repair, inhibition of error-prone repair, or involvement of multiple mechanisms, the effects of several plant extracts on the level of UV-induced beta-galactosidase were screened (to monitor SOS induction in cells). Reduction of the enzyme activity induced by UV was observed following addition of St. John's wort extract, while there was not reduction after thyme, aloe, camomile, or lime-tree and the level of UV-induced enzyme was even higher with sage extract. Our results indicate that the antimutagenic effect of St. John's wort is probably due to suppression of error-prone repair. Moreover, we assume that an antimutagenic effect obtained with thyme, mint, and sage under certain conditions may be due to enhanced error-free repair.

  17. Repairability of aged resin composites mediated by different restorative systems.

    PubMed

    Lemos, Cleidiel Aa; Mauro, Sílvio J; de Campos, Renata A; Dos Santos, Paulo H; Machado, Lucas S; Fagundes, Ticiane C

    2016-04-01

    The aim of this study was to evaluate the shear bond strength of resin composite repairs with and without aging of the surface to be repaired, using different adhesive systems and resin composites. Ninety specimens were prepared: 10 for the Control Group (GC - without repair); 40 for Group I (GI - repairs after 7 days) and 40 for Group II (GII - repairs after 180 days). Groups I and II were divided into 4 subgroups of 10 specimens each, according to the adhesive system and composite resin used: A) Adper Scotch Bond Multipurpose + Filtek Z350 XT; B) Adper Single Bond Plus + Filtek Z350 XT; C) Adper Scotch Bond Multipurpose + Esthet-X; D) Adper Single Bond Plus + Esthet-X. The specimens were tested for shear strength in a universal testing machine. The results were analyzed by two-factor one-way ANOVA and Fisher's post hoc tests (alpha=0.05). The control group had better performance than the other groups. There was no significant difference when comparing different adhesive systems and composite resins. Repairs performed at 7 days were better than those performed at 180 days. The composite repairs decreased the mechanical strength of the restoration. Aging of the resin substrate may decrease repair bond strength over time, regardless of the type of adhesive systems and resin composites used.

  18. Connecting the Dots: From DNA Damage and Repair to Aging

    PubMed Central

    Pan, Mei-Ren; Li, Kaiyi; Lin, Shiaw-Yih; Hung, Wen-Chun

    2016-01-01

    Mammalian cells evolve a delicate system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent the damage from both endogenous end exogenous insults. Emerging evidence suggests that aberrant DDR and deficient DNA repair are strongly associated with cancer and aging. Our understanding of the core program of DDR has made tremendous progress in the past two decades. However, the long list of the molecules involved in the DDR and DNA repair continues to grow and the roles of the new “dots” are under intensive investigation. Here, we review the connection between DDR and DNA repair and aging and discuss the potential mechanisms by which deficient DNA repair triggers systemic effects to promote physiological or pathological aging. PMID:27164092

  19. Effect of aging and dietary restriction on DNA repair

    SciTech Connect

    Weraarchakul, N.; Strong, R.; Wood, W.G.; Richardson, A.

    1989-03-01

    DNA repair was studied as a function of age in cells isolated from both the liver and the kidney of male Fischer F344 rats. DNA repair was measured by quantifying unscheduled DNA synthesis induced by UV irradiation. Unscheduled DNA synthesis decreased approximately 50% between the ages of 5 and 30 months in both hepatocytes and kidney cells. The age-related decline in unscheduled DNA synthesis in cells isolated from the liver and kidney was compared in rats fed ad libitum and rats fed a calorie-restricted diet; calorie restriction has been shown to increase the survival of rodents. The level of unscheduled DNA synthesis was significantly higher in hepatocytes and kidney cells isolated from the rats fed the restricted diet. Thus, calorie restriction appears to retard the age-related decline in DNA repair.

  20. Metabolism, Genomics, and DNA Repair in the Mouse Aging Liver

    PubMed Central

    Lebel, Michel; de Souza-Pinto, Nadja C.; Bohr, Vilhelm A.

    2011-01-01

    The liver plays a pivotal role in the metabolism of nutrients, drugs, hormones, and metabolic waste products, thereby maintaining body homeostasis. The liver undergoes substantial changes in structure and function within old age. Such changes are associated with significant impairment of many hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. It has become clear, using rodent models as biological tools, that genetic instability in the form of gross DNA rearrangements or point mutations accumulate in the liver with age. DNA lesions, such as oxidized bases or persistent breaks, increase with age and correlate well with the presence of senescent hepatocytes. The level of DNA damage and/or mutation can be affected by changes in carcinogen activation, decreased ability to repair DNA, or a combination of these factors. This paper covers some of the DNA repair pathways affecting liver homeostasis with age using rodents as model systems. PMID:21559242

  1. Metabolism, genomics, and DNA repair in the mouse aging liver.

    PubMed

    Lebel, Michel; de Souza-Pinto, Nadja C; Bohr, Vilhelm A

    2011-01-01

    The liver plays a pivotal role in the metabolism of nutrients, drugs, hormones, and metabolic waste products, thereby maintaining body homeostasis. The liver undergoes substantial changes in structure and function within old age. Such changes are associated with significant impairment of many hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. It has become clear, using rodent models as biological tools, that genetic instability in the form of gross DNA rearrangements or point mutations accumulate in the liver with age. DNA lesions, such as oxidized bases or persistent breaks, increase with age and correlate well with the presence of senescent hepatocytes. The level of DNA damage and/or mutation can be affected by changes in carcinogen activation, decreased ability to repair DNA, or a combination of these factors. This paper covers some of the DNA repair pathways affecting liver homeostasis with age using rodents as model systems.

  2. Tissue-specific accelerated aging in nucleotide excision repair deficiency

    PubMed Central

    Niedernhofer, Laura J.

    2008-01-01

    Nucleotide excision repair (NER) is a multi-step DNA repair mechanism that removes helix-distorting modified nucleotides from the genome. NER is divided into two subpathways depending on the location of DNA damage in the genome and how it is first detected. Global genome NER identifies and repairs DNA lesions throughout the genome. This subpathway of NER primarily protects against the accumulation of mutations in the genome. Transcription-coupled (TC) NER rapidly repairs lesions in the transcribed strand of DNA that block transcription by RNA polymerase II. TC-NER prevents cell death in response to stalled transcription. Defects in NER cause three distinct human diseases: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Each of these syndromes is characterized by premature onset of pathologies that overlap with those associated with old age in humans. This reveals the contribution of DNA damage to multiple age-related diseases. Tissues affected include the skin, eye, bone marrow, nervous system and endocrine axis. This review emphasizes accelerated aging associated with xeroderma pigmentosum and discusses the cause of these pathologies, either mutation accumulation or cell death as a consequence of failure to repair DNA damage. PMID:18538374

  3. DNA damage and repair in telomeres: relation to aging.

    PubMed Central

    Kruk, P A; Rampino, N J; Bohr, V A

    1995-01-01

    We have established a method for the detection of DNA damage and its repair in human telomeres, the natural ends of chromosomes which are necessary for replication and critical for chromosomal stability. We find that ultraviolet light-induced pyrimidine dimers in telomeric DNA are repaired less efficiently than endogenous genes but more efficiently than inactive, noncoding regions. We have also measured telomeric length, telomeric DNA damage, and its repair in relation to the progression of aging. Telomeres are shorter in fibroblasts from an old donor compared to fibroblasts from a young donor, shortest in cells from a patient with the progeroid disorder Werner syndrome, and relatively long in fibroblasts from a patient with Alzheimer disease. Telomeric DNA repair efficiency is lower in cells from an old donor than in cells from a young donor, normal in Alzheimer cells, and slightly lower in Werner cells. It is possible that this decline in telomeric repair with aging is of functional significance to an age-related decline in genomic stability. Images Fig. 1 Fig. 2 PMID:7816828

  4. DNA double strand break repair, aging and the chromatin connection.

    PubMed

    Gorbunova, Vera; Seluanov, Andrei

    2016-06-01

    Are DNA damage and mutations possible causes or consequences of aging? This question has been hotly debated by biogerontologists for decades. The importance of DNA damage as a possible driver of the aging process went from being widely recognized to then forgotten, and is now slowly making a comeback. DNA double strand breaks (DSBs) are particularly relevant to aging because of their toxicity, increased frequency with age and the association of defects in their repair with premature aging. Recent studies expand the potential impact of DNA damage and mutations on aging by linking DNA DSB repair and age-related chromatin changes. There is overwhelming evidence that increased DNA damage and mutations accelerate aging. However, an ultimate proof of causality would be to show that enhanced genome and epigenome stability delays aging. This is not an easy task, as improving such complex biological processes is infinitely more difficult than disabling it. We will discuss the possibility that animal models with enhanced DNA repair and epigenome maintenance will be generated in the near future.

  5. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

    PubMed Central

    Bettencourt, Conceição; Hensman‐Moss, Davina; Flower, Michael; Wiethoff, Sarah; Brice, Alexis; Goizet, Cyril; Stevanin, Giovanni; Koutsis, Georgios; Karadima, Georgia; Panas, Marios; Yescas‐Gómez, Petra; García‐Velázquez, Lizbeth Esmeralda; Alonso‐Vilatela, María Elisa; Lima, Manuela; Raposo, Mafalda; Traynor, Bryan; Sweeney, Mary; Wood, Nicholas; Giunti, Paola; Durr, Alexandra; Holmans, Peter; Houlden, Henry; Tabrizi, Sarah J.

    2016-01-01

    Objective The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS. Interpretation We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990 PMID:27044000

  6. Beyond Repair: Literacy, Technology, and a Curriculum of Aging

    ERIC Educational Resources Information Center

    Bowen, Lauren Marshall

    2012-01-01

    The magazine of the American Association of Retired Persons (AARP) often relies on problematic rhetorics that privilege youth-centered ideals and create limited representations of older adults' literacy in digital times. These rhetorics rest on a metaphor of repair, which labels aging adults as primarily bodies in need of fixing or protection. In…

  7. Beyond Repair: Literacy, Technology, and a Curriculum of Aging

    ERIC Educational Resources Information Center

    Bowen, Lauren Marshall

    2012-01-01

    The magazine of the American Association of Retired Persons (AARP) often relies on problematic rhetorics that privilege youth-centered ideals and create limited representations of older adults' literacy in digital times. These rhetorics rest on a metaphor of repair, which labels aging adults as primarily bodies in need of fixing or protection. In…

  8. Premature aging in mice deficient in DNA repair and transcription.

    PubMed

    de Boer, Jan; Andressoo, Jaan Olle; de Wit, Jan; Huijmans, Jan; Beems, Rudolph B; van Steeg, Harry; Weeda, Geert; van der Horst, Gijsbertus T J; van Leeuwen, Wibeke; Themmen, Axel P N; Meradji, Morteza; Hoeijmakers, Jan H J

    2002-05-17

    One of the factors postulated to drive the aging process is the accumulation of DNA damage. Here, we provide strong support for this hypothesis by describing studies of mice with a mutation in XPD, a gene encoding a DNA helicase that functions in both repair and transcription and that is mutated in the human disorder trichothiodystrophy (TTD). TTD mice were found to exhibit many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early greying, cachexia, infertility, and reduced life-span. TTD mice carrying an additional mutation in XPA, which enhances the DNA repair defect, showed a greatly accelerated aging phenotype, which correlated with an increased cellular sensitivity to oxidative DNA damage. We hypothesize that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.

  9. Electrochemical aging effects in photovoltaic modules

    NASA Technical Reports Server (NTRS)

    Mon, G. R.

    1986-01-01

    Leakage currents were experimentally measured in PV modules undergoing natural aging outdoors, and in PV modules undergoing accelerated aging in laboratory environmental chambers. The significant contributors to module leakage current were identified with a long range goal to develop techniques to reduce or stop module leakage currents. For outdoor aging in general, module leakage current is relatively insensitive to temperature fluctuations, but is very sensitive to moisture effects such as dew, precipitation, and fluctuations in relative humidity. Comparing ethylene vinyl acetate (EVA) and polyvinyl butyral (PVB), module leakage currents are much higher in PVB as compared to EVA for all environmental conditions investigated. Leakage currents proceed in series along two paths, bulk conduction followed by interfacial (surfaces) conduction.

  10. BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging1

    PubMed Central

    Oktay, Kutluk; Turan, Volkan; Titus, Shiny; Stobezki, Robert; Liu, Lin

    2015-01-01

    Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging. PMID:26224004

  11. BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging.

    PubMed

    Oktay, Kutluk; Turan, Volkan; Titus, Shiny; Stobezki, Robert; Liu, Lin

    2015-09-01

    Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.

  12. Effect of modulating macrophage phenotype on peripheral nerve repair.

    PubMed

    Mokarram, Nassir; Merchant, Alishah; Mukhatyar, Vivek; Patel, Gaurangkumar; Bellamkonda, Ravi V

    2012-12-01

    Peripheral nerve repair across long gaps remains clinically challenging despite progress made with autograft transplantation. While scaffolds that present trophic factors and extracellular matrix molecules have been designed, matching the performance of autograft-induced repair has been challenging. In this study, we explored the effect of cytokine mediated 'biasing' of macrophage phenotypes on Schwann cell (SC) migration and axonal regeneration in vitro and in vivo. Macrophage phenotype was successfully modulated by local delivery of either Interferon-gamma (IFN-γ) or Interleukin-4 (IL-4) within polymeric nerve guidance channels, polarizing them toward pro-inflammatory (M1) or pro-healing (M2a and M2c) phenotypes, respectively. The initial polarization of macrophages to M2a and M2c phenotype results in enhanced SC infiltration and substantially faster axonal growth in a critically-sized rat sciatic nerve gap model (15 mm). The ratio of pro-healing to pro-inflammatory population of macrophages (CD206+/CCR7+), defined as regenerative bias, demonstrates a linear relationship with the number of axons at the distal end of the nerve scaffolds. The present results clearly suggest that rather than the extent of macrophage presence, their specific phenotype at the site of injury regulates the regenerative outcomes.

  13. Getting Down to Business: Auto Repair Shop, Module 31. Teacher Guide. Entrepreneurship Training Components.

    ERIC Educational Resources Information Center

    McFarlane, Carolyn

    This is the thirty-first in a set of 36 teacher guides to the Entrepreneurial Training modules and accompanies CE 031 090. The purpose of the module is to give students some idea of what it is like to own and operate an auto repair shop. Following an overview are general notes on use of the module. Suggested steps for module use contain…

  14. Rotator Cuff Repair in Patients over 75 Years of Age: Clinical Outcome and Repair Integrity

    PubMed Central

    Park, Jung Gwan; Cho, Nam Su; Song, Jong Hoon; Baek, Jong Hun; Jeong, Ho Yeon

    2016-01-01

    Background Some studies have shown significant functional improvement after rotator cuff (RC) repair in elderly patients. However, few studies have reported the healing potential of RC tears in elderly patients. Methods Twenty-five patients aged ≥ 75 years who underwent RC repair were enrolled. The mean age at the time of surgery was 78.3 years (range, 75 to 88 years) while the mean follow-up was 36.3 months (range, 18 to 114 months). We evaluated clinical and structural outcomes after RC repair in the retear and healed groups. Results Of 25 patients, 16 (64%) had healed RC lesions and 9 (36%) had retorn cuff lesions. The retear rate increased significantly with increasing initial tear size (small to medium, 13%; large, 60%; massive, 80%; p = 0.024) but not with increasing age (p = 0.072). The mean visual analog scale (VAS), University of California Los Angeles (UCLA), and Constant scores significantly improved from 5.2, 15.8, and 49.3 preoperatively to 1.4, 31.1, and 71.9 in the healed group and from 6.0, 14.4, and 39.5 preoperatively to 2.4, 28.3, and 63.6 in the retear group at the final follow-up (p < 0.05, respectively). There were no significant differences in clinical outcomes between the 2 groups at the final follow-up. Retear was significantly correlated with initial tear size (p = 0.001; odds ratio [OR], 2.771; 95% confidence interval [CI], 1.394 to 5.509 for large to massive tears) (p = 0.001; OR, 0.183; 95% CI, 0.048 to 0.692 for small to medium tears). Conclusions There were significant improvements in clinical outcomes after RC repair in patients ≥ 75 years. Structural integrity after cuff repair did not affect the final clinical outcome. Even in elderly patients aged ≥ 75 years, healing of repaired RC can be expected in cases of small to medium tears. Although the retear rate was relatively high for large to massive tears, clinical outcomes still showed significant improvement. PMID:27904725

  15. TRIM72 modulates caveolar endocytosis in repair of lung cells.

    PubMed

    Nagre, Nagaraja; Wang, Shaohua; Kellett, Thomas; Kanagasabai, Ragu; Deng, Jing; Nishi, Miyuki; Shilo, Konstantin; Oeckler, Richard A; Yalowich, Jack C; Takeshima, Hiroshi; Christman, John; Hubmayr, Rolf D; Zhao, Xiaoli

    2016-03-01

    Alveolar epithelial and endothelial cell injury is a major feature of the acute respiratory distress syndrome, in particular when in conjunction with ventilation therapies. Previously we showed [Kim SC, Kellett T, Wang S, Nishi M, Nagre N, Zhou B, Flodby P, Shilo K, Ghadiali SN, Takeshima H, Hubmayr RD, Zhao X. Am J Physiol Lung Cell Mol Physiol 307: L449-L459, 2014.] that tripartite motif protein 72 (TRIM72) is essential for amending alveolar epithelial cell injury. Here, we posit that TRIM72 improves cellular integrity through its interaction with caveolin 1 (Cav1). Our data show that, in primary type I alveolar epithelial cells, lack of TRIM72 led to significant reduction of Cav1 at the plasma membrane, accompanied by marked attenuation of caveolar endocytosis. Meanwhile, lentivirus-mediated overexpression of TRIM72 selectively increases caveolar endocytosis in rat lung epithelial cells, suggesting a functional association between these two. Further coimmunoprecipitation assays show that deletion of either functional domain of TRIM72, i.e., RING, B-box, coiled-coil, or PRY-SPRY, abolishes the physical interaction between TRIM72 and Cav1, suggesting that all theoretical domains of TRIM72 are required to forge a strong interaction between these two molecules. Moreover, in vivo studies showed that injurious ventilation-induced lung cell death was significantly increased in knockout (KO) TRIM72(KO) and Cav1(KO) lungs compared with wild-type controls and was particularly pronounced in double KO mutants. Apoptosis was accompanied by accentuation of gross lung injury manifestations in the TRIM72(KO) and Cav1(KO) mice. Our data show that TRIM72 directly and indirectly modulates caveolar endocytosis, an essential process involved in repair of lung epithelial cells through removal of plasma membrane wounds. Given TRIM72's role in endomembrane trafficking and cell repair, we consider this molecule an attractive therapeutic target for patients with injured lungs.

  16. Getting Down to Business: Farm Equipment Repair, Module 2. Teacher Guide. Entrepreneurship Training Components.

    ERIC Educational Resources Information Center

    McBain, Susan

    This is the second in a set of 36 teacher guides to the Entrepreneurship Training modules and accompanies CE 031 032. Its purpose is to give students some idea of what it is like to own and operate a farm equipment repair business. Following an overview are general notes on use of the module. Suggested steps for module use contain suggestions on…

  17. A long lifetime, low error rate RRAM design with self-repair module

    NASA Astrophysics Data System (ADS)

    Zhiqiang, You; Fei, Hu; Liming, Huang; Peng, Liu; Jishun, Kuang; Shiying, Li

    2016-11-01

    Resistive random access memory (RRAM) is one of the promising candidates for future universal memory. However, it suffers from serious error rate and endurance problems. Therefore, exploring a technical solution is greatly demanded to enhance endurance and reduce error rate. In this paper, we propose a reliable RRAM architecture that includes two reliability modules: error correction code (ECC) and self-repair modules. The ECC module is used to detect errors and decrease error rate. The self-repair module, which is proposed for the first time for RRAM, can get the information of error bits and repair wear-out cells by a repair voltage. Simulation results show that the proposed architecture can achieve lowest error rate and longest lifetime compared to previous reliable designs. Project supported by the New Century Excellent Talents in University (No. NCET-12-0165) and the National Natural Science Foundation of China (Nos. 61472123, 61272396).

  18. Neutrophil depletion delays wound repair in aged mice

    PubMed Central

    Nishio, Naomi; Okawa, Yayoi; Sakurai, Hidetoshi

    2008-01-01

    One of the most important clinical problems in caring for elderly patients is treatment of pressure ulcers. One component of normal wound healing is the generation of an inflammatory reaction, which is characterized by the sequential infiltration of neutrophils, macrophages and lymphocytes. Neutrophils migrate early in the wound healing process. In aged C57BL/6 mice, wound healing is relatively inefficient. We examined the effects of neutrophil numbers on wound healing in both young and aged mice. We found that the depletion of neutrophils by anti-Gr-1 antibody dramatically delayed wound healing in aged mice. The depletion of neutrophils in young mice had less effect on the kinetics of wound healing. Intravenous G-CSF injection increased the migration of neutrophils to the wound site. While the rate of wound repair did not change significantly in young mice following G-CSF injection, it increased significantly in old mice. PMID:19424869

  19. Reversible protein phosphorylation modulates nucleotide excision repair of damaged DNA by human cell extracts.

    PubMed

    Ariza, R R; Keyse, S M; Moggs, J G; Wood, R D

    1996-02-01

    Nucleotide excision repair of DNA in mammalian cells uses more than 20 polypeptides to remove DNA lesions caused by UV light and other mutagens. To investigate whether reversible protein phosphorylation can significantly modulate this repair mechanism we studied the effect of specific inhibitors of Ser/Thr protein phosphatases. The ability of HeLa cell extracts to carry out nucleotide excision repair in vitro was highly sensitive to three toxins (okadaic acid, microcystin-LR and tautomycin), which block PP1- and PP2A-type phosphatases. Repair was more sensitive to okadaic acid than to tautomycin, suggesting the involvement of a PP2A-type enzyme, and was insensitive to inhibitor-2, which exclusively inhibits PP1-type enzymes. In a repair synthesis assay the toxins gave 70% inhibition of activity. Full activity could be restored to toxin-inhibited extracts by addition of purified PP2A, but not PP1. The p34 subunit of replication protein A was hyperphosphorylated in cell extracts in the presence of phosphatase inhibitors, but we found no evidence that this affected repair. In a coupled incision/synthesis repair assay okadaic acid decreased the production of incision intermediates in the repair reaction. The formation of 25-30mer oligonucleotides by dual incision during repair was also inhibited by okadaic acid and inhibition could be reversed with PP2A. Thus Ser/Thr- specific protein phosphorylation plays an important role in the modulation of nucleotide excision repair in vitro.

  20. Optical modulation study of repaired damage morphologies of fused silica by scalar diffraction theory

    NASA Astrophysics Data System (ADS)

    Li, Bo; Zhou, Qingyan; Jiang, Yong; Xiang, Xia; Liao, Wei; Jiang, Xiaolong; Wang, Haijun; Luan, Xiaoyu; Zheng, Wanguo; Yuan, Xiaodong

    2017-01-01

    The cone and Gaussian repaired damage craters are two typical morphologies induced by CO2 laser evaporation and nonevaporation technologies. The mathematical models are built for these two types of repaired craters, and the light modulation at 355 nm induced by the millimeter-scale repaired damage morphology is studied by scalar diffraction theory. The results show that the modulation of the Gaussian repaired morphology has one peak and then decreases with the increasing distance from 0 to 30 cm. While the modulation for cone repaired morphology remains stable after decreasing quickly with the increasing distance. When the horizontal radius increases, the modulation looks like a saw-tooth. However, the modulation has irregular variations for two kinds of morphologies with the increasing vertical depth. The simulated results agree well with experimental results. The horizontal and vertical dimensions, and downstream distance have different influences on the modulation. The risk of damage to downstream optical components can be suppressed to improve the stability of the optical system if the shape and size of repaired craters are well controlled and the positions of downstream optical components are selected appropriately.

  1. A potential impact of DNA repair on ageing and lifespan in the ageing model organism Podospora anserina: decrease in mitochondrial DNA repair activity during ageing.

    PubMed

    Soerensen, Mette; Gredilla, Ricardo; Müller-Ohldach, Mathis; Werner, Alexandra; Bohr, Vilhelm A; Osiewacz, Heinz D; Stevnsner, Tinna

    2009-08-01

    The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the sexually reproducing ascomycete Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA instability and mitochondrial dysfunction. Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER). Alignments of known BER protein sequences with the P. anserina genome revealed high homology. We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. DNA glycosylase activities decrease with age, suggesting that the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage and hence contribute to ageing and lifespan control in this ageing model. Additionally, we find low DNA glycosylase activities in the long-lived mutants grisea and DeltaPaCox17::ble, which are characterized by low mitochondrial ROS generation. Overall, our data identify a potential role of mtDNA repair in controlling ageing and life span in P. anserina, a mechanism possibly regulated in response to ROS levels.

  2. A potential impact of DNA repair on ageing and lifespan in the ageing model organism Podospora anserina: Decrease in mitochondrial DNA repair activity during ageing

    PubMed Central

    Soerensen, Mette; Gredilla, Ricardo; Müller-Ohldach, Mathis; Werner, Alexandra; Bohr, Vilhelm A.; Osiewacz, Heinz D.; Stevnsner, Tinna

    2009-01-01

    Summary The free radical theory of ageing states that ROS play a key role in age-related decrease in mitochondrial function via the damage of mitochondrial DNA (mtDNA), proteins and lipids. In the sexually reproducing ascomycete Podospora anserina ageing is, as in other eukaryotes, associated with mtDNA instability and mitochondrial dysfunction. Part of the mtDNA instabilities may arise due to accumulation of ROS induced mtDNA lesions, which, as previously suggested for mammals, may be caused by an age-related decrease in base excision repair (BER). Alignments of known BER protein sequences with the P. anserina genome revealed high homology. We report for the first time the presence of BER activities in P. anserina mitochondrial extracts. DNA glycosylase activities decrease with age, suggesting that the increased mtDNA instability with age may be caused by decreased ability to repair mtDNA damage and hence contribute to ageing and lifespan control in this ageing model. Additionally, we find low DNA glycosylase activities in the long-lived mutants grisea and ΔPaCox17∷ble, which are characterized by among others low mitochondrial ROS generation. Overall, our data identify a potential role of mtDNA repair in controlling ageing and life span in P. anserina, a mechanism possibly regulated in response to ROS levels. PMID:19486911

  3. New Technologies for Repairing Aging Cables in Nuclear Power Plants

    SciTech Connect

    Simmons, Kevin L.; Fifield, Leonard S.; Westman, Matthew P.

    2013-09-11

    The goal of this project is to demonstrate a proof-of-concept for a technique to repair aging cables that have been subjected to degradation associated with long-term thermal and radiation exposure in nuclear power plants. The physical degradation of the aging cables manifests itself primarily as cracking and increased brittleness of the polymeric electrical insulation. Therefore, the proposed cable-repair concept comprises development of techniques to impart a softening agent within the deteriorated polymer insulation jacket so as to regain the ability of the insulation to stretch without failing and possibly to heal existing cracks in the insulation. Our approach is to use commercially available ethylene-propylene rubber (EPR) as the relevant test material, demonstrate the adsorption of chemical treatments in the EPR and quantify changes in resulting physical and mechanical properties. EPR cable samples have been thermally treated in air to produce specimens corresponding to the full range of cable age-performance points from new (>350% elongation at break) to end-of-life (<50% elongation at break). The current focus is on two chemical treatments selected as candidates for restoring age-related cable elasticity loss: a rubber plasticizer and a reactive silane molecule. EPR specimens of 200, 150, 100, and 50% elongation at break have been soaked in the candidate chemical treatments and the kinetics of chemical uptake, measured by change in mass of the samples, has been determined. Mechanical properties as a function of aging and chemical treatment have been measured including ultimate tensile strength, tensile modulus at 50% strain, elongation at break, and storage modulus. Dimensional changes with treatment and changes in glass transition temperature were also investigated. These ongoing experiments are expected to provide insight into the physical-chemical nature of the effect of thermal degradation on EPR rejuvenation limits and to advance novel methods for

  4. Human premature aging, DNA repair and RecQ helicases.

    PubMed

    Brosh, Robert M; Bohr, Vilhelm A

    2007-01-01

    Genomic instability leads to mutations, cellular dysfunction and aberrant phenotypes at the tissue and organism levels. A number of mechanisms have evolved to cope with endogenous or exogenous stress to prevent chromosomal instability and maintain cellular homeostasis. DNA helicases play important roles in the DNA damage response. The RecQ family of DNA helicases is of particular interest since several human RecQ helicases are defective in diseases associated with premature aging and cancer. In this review, we will provide an update on our understanding of the specific roles of human RecQ helicases in the maintenance of genomic stability through their catalytic activities and protein interactions in various pathways of cellular nucleic acid metabolism with an emphasis on DNA replication and repair. We will also discuss the clinical features of the premature aging disorders associated with RecQ helicase deficiencies and how they relate to the molecular defects.

  5. DNA repair and aging: the impact of the p53 family

    PubMed Central

    Nicolai, Sara; Rossi, Antonello; Di Daniele, Nicola; Melino, Gerry; Annicchiarico-Petruzzelli, Margherita; Raschellà, Giuseppe

    2015-01-01

    Cells are constantly exposed to endogenous and exogenous factors that threaten the integrity of their DNA. The maintenance of genome stability is of paramount importance in the prevention of both cancer and aging processes. To deal with DNA damage, cells put into operation a sophisticated and coordinated mechanism, collectively known as DNA damage response (DDR). The DDR orchestrates different cellular processes, such as DNA repair, senescence and apoptosis. Among the key factors of the DDR, the related proteins p53, p63 and p73, all belonging to the same family of transcription factors, play multiple relevant roles. Indeed, the members of this family are directly involved in the induction of cell cycle arrest that is necessary to allow the cells to repair. Alternatively, they can promote cell death in case of prolonged or irreparable DNA damage. They also take part in a more direct task by modulating the expression of core factors involved in the process of DNA repair or by directly interacting with them. In this review we will analyze the fundamental roles of the p53 family in the aging process through their multifaceted function in DDR. PMID:26668111

  6. DNA repair and aging: the impact of the p53 family.

    PubMed

    Nicolai, Sara; Rossi, Antonello; Di Daniele, Nicola; Melino, Gerry; Annicchiarico-Petruzzelli, Margherita; Raschellà, Giuseppe

    2015-12-01

    Cells are constantly exposed to endogenous and exogenous factors that threaten the integrity of their DNA. The maintenance of genome stability is of paramount importance in the prevention of both cancer and aging processes. To deal with DNA damage, cells put into operation a sophisticated and coordinated mechanism, collectively known as DNA damage response (DDR). The DDR orchestrates different cellular processes, such as DNA repair, senescence and apoptosis. Among the key factors of the DDR, the related proteins p53, p63 and p73, all belonging to the same family of transcription factors, play multiple relevant roles. Indeed, the members of this family are directly involved in the induction of cell cycle arrest that is necessary to allow the cells to repair. Alternatively, they can promote cell death in case of prolonged or irreparable DNA damage. They also take part in a more direct task by modulating the expression of core factors involved in the process of DNA repair or by directly interacting with them. In this review we will analyze the fundamental roles of the p53 family in the aging process through their multifaceted function in DDR.

  7. Use of tear ring permits repair of sealed module circuitry

    NASA Technical Reports Server (NTRS)

    1965-01-01

    Improved packaging technique for modular electronic circuitry utilizes a tear ring which may be removed for repair and resealed. The tear ring is put over the container and header to which the electronic circuit assembly has been attached.

  8. Bilingual Vocational Training Program. Auto Body Repair. Module 2.0: Tools and Equipment.

    ERIC Educational Resources Information Center

    Northern New Mexico Community Coll., El Rito.

    This module on tools and equipment is the second of four (CE 028 303-306) in the auto body repair course of a bilingual vocational training program. The course is designed to furnish theoretical and laboratory experience in welding, metal straightening, metal finishing, painting, and use of power and hand tools. Module objectives are for students…

  9. Bilingual Vocational Training Program. Auto Body Repair. Module 4.0: Auto Body Welding.

    ERIC Educational Resources Information Center

    Northern New Mexico Community Coll., El Rito.

    This module on auto body welding is the fourth of four (CE 028 303-306) in the auto body repair course of a bilingual vocational training program. The course is designed to furnish theoretical and laboratory experience in welding, metal straightening, metal finishing, painting, and use of power and hand tools. Module objectives are for students to…

  10. Getting Down to Business: Farm Equipment Repair, Module 2. [Student Guide]. Entrepreneurship Training Components.

    ERIC Educational Resources Information Center

    McBain, Susan

    This module on owning and operating a farm equipment repair business is one of 36 in a series on entrepreneurship. The introduction tells the student what topics will be covered and suggests other modules to read in related occupations. Each unit includes student goals, a case study, and a discussion of the unit subject matter. Learning…

  11. Bilingual Vocational Training Program. Auto Body Repair. Module 1.0: Beginning Auto Body.

    ERIC Educational Resources Information Center

    Northern New Mexico Community Coll., El Rito.

    This module on beginning auto body is the first of four (CE 028 303-306) in the auto body repair course of a bilingual vocational training program. The course is designed to furnish theoretical and laboratory experience in welding, metal straightening, metal finishing, painting, and use of power and hand tools. Module objectives are for students…

  12. Bilingual Vocational Training Program. Auto Body Repair. Module 4.0: Auto Body Welding.

    ERIC Educational Resources Information Center

    Northern New Mexico Community Coll., El Rito.

    This module on auto body welding is the fourth of four (CE 028 303-306) in the auto body repair course of a bilingual vocational training program. The course is designed to furnish theoretical and laboratory experience in welding, metal straightening, metal finishing, painting, and use of power and hand tools. Module objectives are for students to…

  13. Bilingual Vocational Training Program. Auto Body Repair. Module 2.0: Tools and Equipment.

    ERIC Educational Resources Information Center

    Northern New Mexico Community Coll., El Rito.

    This module on tools and equipment is the second of four (CE 028 303-306) in the auto body repair course of a bilingual vocational training program. The course is designed to furnish theoretical and laboratory experience in welding, metal straightening, metal finishing, painting, and use of power and hand tools. Module objectives are for students…

  14. Analysis of gene expression dynamics revealed delayed and abnormal epidermal repair process in aged compared to young skin.

    PubMed

    Sextius, Peggy; Marionnet, Claire; Tacheau, Charlotte; Bon, François-Xavier; Bastien, Philippe; Mauviel, Alain; Bernard, Bruno A; Bernerd, Françoise; Dubertret, Louis

    2015-05-01

    With aging, epidermal homeostasis and barrier function are disrupted. In a previous study, we analyzed the transcriptomic response of young skin epidermis after stratum corneum removal, and obtained a global kinetic view of the molecular processes involved in barrier function recovery. In the present study, the same analysis was performed in aged skin in order to better understand the defects which occur with aging. Thirty healthy male volunteers (67 ± 4 years old) were involved. Tape-strippings were carried out on the inner face of one forearm, the other unstripped forearm serving as control. At 2, 6, 18, 30 and 72 h after stripping, TEWL measurements were taken, and epidermis samples were collected. Total RNA was extracted and analyzed using DermArray(®) cDNA microarrays. The results highlighted that barrier function recovery and overall kinetics of gene expression were delayed following stripping in aged skin. Indeed, the TEWL measurements showed that barrier recovery in the young group appeared to be dramatically significant during the overall kinetics, while there were no significant evolution in the aged group until 30 h. Moreover, gene expression analysis revealed that the number of modulated genes following tape stripping increased as a function of time and reached a peak at 6 h after tape stripping in young skin, while it was at 30 h in aged skin, showing that cellular activity linked to the repair process may be engaged earlier in young epidermis than in aged epidermis. A total of 370 genes were modulated in the young group. In the aged group, 382 genes were modulated, whose 184 were also modulated in the young group. Only eight genes that were modulated in both groups were significantly differently modulated. The characterization of these genes into 15 functional families helped to draw a scenario for the aging process affecting epidermal repair capacity.

  15. beta-Adrenergic receptor modulation of wound repair.

    PubMed

    Pullar, Christine E; Manabat-Hidalgo, Catherine G; Bolaji, Ranti S; Isseroff, R Rivkah

    2008-08-01

    Adrenergic receptors and their downstream effector molecules are expressed in all cell types in the skin, and it is only recently that functionality of the catecholamine agonist activated signaling in the cutaneous repair process has been revealed. In addition to responding to systemic elevations in catecholamines (as in stress situations) or to pharmacologically administered adrenergic agonists, epidermal keratinocytes themselves can synthesize catecholamine ligands. They also respond to these systemic or self-generated agonists via receptor mediated signaling, resulting in altered migration, and changes in wound re-epithelialization. Endothelial cells, inflammatory cells, dermal fibroblasts, and mesenchymal stem cells, all cells that contribute to the wound repair process, express multiple subtypes of adrenergic receptors and exhibit responses that can be either contribute or impair healing-and occasionally, depending on the species and assay conditions, results can be conflicting. There is still much to be uncovered regarding how this self-contained autocrine and paracrine signaling system contributes to cutaneous wound repair.

  16. Weld repair of aged Cr-Mo steel piping -- A review of literature

    SciTech Connect

    Viswanathan, R.; Gandy, D.

    2000-02-01

    Power plant piping operating at elevated temperatures is subject to several types of service aging-related degradation, such as softening, spheroidization, embrittlement, and creep. When cracks are found in these components, weld repair is often employed to ensure continued operation. The efficacy of the weld repairs in terms of extending the life of the aged components has, however, not been documented quantitatively. The Electric Power Research institute (EPRI) has recently undertaken a comprehensive study to evaluate weld repairs performed to aged piping. In connection with this study, results from other worldwide activities have been reviewed, leading to significant conclusions regarding weld repair. this review of results from several worldwide studies has confirmed that aged high-temperature piping can be successfully weld repaired to gain additional lives in excess of several decades. The key aspects of successful weld repair include excavation and removal of all prior creep cavitation damage, elimination of external bending stresses, and implementation of good welding practice. From merely a creep rupture point of view, postweld heat treatment (PWHT) has been concluded to be superfluous by several authors. Temperbead repairs appear to offer a promising alternative to PWHT repairs from a creep, tensile, and toughness standpoint. Choice of the repair process ultimately is dictated by many considerations such as toughness, notch sensitivity, residual stresses and hydrogen embrittlement susceptibility. Several reports suggest that gas tungsten arc welding (GTAW) repairs may outperform shielded metal arc welding (SMAW) repairs with or without PWHT.

  17. Matrix metalloproteinase 9 modulates collagen matrices and wound repair

    PubMed Central

    LeBert, Danny C.; Squirrell, Jayne M.; Rindy, Julie; Broadbridge, Elizabeth; Lui, Yuming; Zakrzewska, Anna; Eliceiri, Kevin W.; Meijer, Annemarie H.; Huttenlocher, Anna

    2015-01-01

    Acute and chronic injuries are characterized by leukocyte infiltration into tissues. Although matrix metalloproteinase 9 (Mmp9) has been implicated in both conditions, its role in wound repair remains unclear. We previously reported a zebrafish chronic inflammation mutant caused by an insertion in the hepatocyte growth factor activator inhibitor gene 1 (hai1; also known as spint1) that is characterized by epithelial extrusions and neutrophil infiltration into the fin. Here, we performed a microarray analysis and found increased inflammatory gene expression in the mutant larvae, including a marked increase in mmp9 expression. Depletion of mmp9 partially rescued the chronic inflammation and epithelial phenotypes, in addition to restoring collagen fiber organization, as detected by second-harmonic generation imaging. Additionally, we found that acute wounding induces epithelial cell mmp9 expression and is associated with a thickening of collagen fibers. Interestingly, depletion of mmp9 impaired this collagen fiber reorganization. Moreover, mmp9 depletion impaired tissue regeneration after tail transection, implicating Mmp9 in acute wound repair. Thus, Mmp9 regulates both acute and chronic tissue damage and plays an essential role in collagen reorganization during wound repair. PMID:26015541

  18. [DNA repair--a fundamental factor in ageing and development of cancer].

    PubMed

    Rasmussen, Lene Juel; Stevnsner, Tinna; Bohr, Vilhelm A

    2006-06-12

    Advanced age and increased incidence of many illnesses such as cancer are closely linked. The reasons for such a link are numerous but one important factor is DNA repair. DNA repair pathways in both nuclei and mitochondria ensure that genomic instability is minimised, thus preventing transformation and premature cellular decay. However, overall cellular DNA repair capacity decreases with age; moreover, some individuals are born with defects in repair systems. The resulting lower capacity for repair of DNA damage increases mutation load and changes normal cellular functions such as transcription, thereby contributing to the ageing process as well to the onset of various cancers. DNA repair capacity is an important cellular marker that should be considered as a standard clinical test.

  19. DNA repair: Dynamic defenders against cancer and aging

    SciTech Connect

    Fuss, Jill O.; Cooper, Priscilla K.

    2006-04-01

    You probably weren't thinking about your body's cellular DNA repair systems the last time you sat on the beach in the bright sunshine. Fortunately, however, while you were subjecting your DNA to the harmful effects of ultraviolet light, your cells were busy repairing the damage. The idea that our genetic material could be damaged by the sun was not appreciated in the early days of molecular biology. When Watson and Crick discovered the structure of DNA in 1953 [1], it was assumed that DNA is fundamentally stable since it carries the blueprint of life. However, over 50 years of research have revealed that our DNA is under constant assault by sunlight, oxygen, radiation, various chemicals, and even our own cellular processes. Cleverly, evolution has provided our cells with a diverse set of tools to repair the damage that Mother Nature causes. DNA repair processes restore the normal nucleotide sequence and DNA structure of the genome after damage [2]. These responses are highly varied and exquisitely regulated. DNA repair mechanisms are traditionally characterized by the type of damage repaired. A large variety of chemical modifications can alter normal DNA bases and either lead to mutations or block transcription if not repaired, and three distinct pathways exist to remove base damage. Base excision repair (BER) corrects DNA base alterations that do not distort the overall structure of the DNA helix such as bases damaged by oxidation resulting from normal cellular metabolism. While BER removes single damaged bases, nucleotide excision repair (NER) removes short segments of nucleotides (called oligonucleotides) containing damaged bases. NER responds to any alteration that distorts the DNA helix and is the mechanism responsible for repairing bulky base damage caused by carcinogenic chemicals such as benzo [a]pyrene (found in cigarette smoke and automobile exhaust) as well as covalent linkages between adjacent pyrimidine bases resulting from the ultraviolet (UV

  20. Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells.

    PubMed

    Delabaere, Laetitia; Ertl, Henry A; Massey, Dashiell J; Hofley, Carolyn M; Sohail, Faraz; Bienenstock, Elisa J; Sebastian, Hans; Chiolo, Irene; LaRocque, Jeannine R

    2017-04-01

    Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double-strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood. Here, we show that premeiotic germline cells of young and old flies have distinct differences in their ability to repair DSBs by the error-free pathway homologous recombination (HR). Repair of DSBs induced by either ionizing radiation (IR) or the endonuclease I-SceI is markedly defective in older flies. This correlates with a remarkable reduction in HR repair measured with the DR-white DSB repair reporter assay. Strikingly, most of this repair defect is already present at 8 days of age. Finally, HR defects correlate with increased expression of early HR components and increased recruitment of Rad51 to damage in older organisms. Thus, we propose that the defect in the HR pathway for germ cells in older flies occurs following Rad51 recruitment. These data reveal that DSB repair defects arise early in the aging process and suggest that HR deficiencies are a leading cause of genome instability in germ cells of older animals. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  1. p53 modulation of TFIIH-associated nucleotide excision repair activity.

    PubMed

    Wang, X W; Yeh, H; Schaeffer, L; Roy, R; Moncollin, V; Egly, J M; Wang, Z; Freidberg, E C; Evans, M K; Taffe, B G

    1995-06-01

    p53 has pleiotropic functions including control of genomic plasticity and integrity. Here we report that p53 can bind to several transcription factor IIH-associated factors, including transcription-repair factors, XPD (Rad3) and XPB, as well as CSB involved in strand-specific DNA repair, via its C-terminal domain. We also found that wild-type, but not Arg273His mutant p53 inhibits XPD (Rad3) and XPB DNA helicase activities. Moreover, repair of UV-induced dimers is slower in Li-Fraumeni syndrome cells (heterozygote p53 mutant) than in normal human cells. Our findings indicate that p53 may play a direct role in modulating nucleotide excision repair pathways.

  2. The Impact of Base Excision DNA Repair in Age-Related Neurodegenerative Diseases

    PubMed Central

    Leandro, Giovana S.; Sykora, Peter; Bohr, Vilhelm A.

    2017-01-01

    The aging process and several age-related neurodegenerative disorders have been linked to elevated levels of DNA damage induced by ROS and deficiency in DNA repair mechanisms. DNA damage induced by ROS is a byproduct of cellular respiration and accumulation of damage over time, is a fundamental aspect of a main theory of aging. Mitochondria have a pivotal role in generating cellular oxidative stress, and mitochondrial dysfunction has been associated with several diseases. DNA base excision repair is considered the major pathway for repair of oxidized bases in DNA both in the nuclei and in mitochondria, and in neurons this mechanism is particularly important because non-diving cells have limited back-up DNA repair mechanisms. An association between elevated oxidative stress and a decrease in BER is strongly related to the aging process and has special relevance in age-related neurodegenerative diseases. Here, we review the role of DNA repair in aging, focusing on the implications of the DNA base excision repair pathways and how alterations in expression of these DNA repair proteins are related to the aging process and to age-related neurodegenerative diseases. PMID:26255938

  3. OPERATING, REPAIRING, AND MAINTAINING SMALL POWER EQUIPMENT. HORTICULTURE-SERVICE OCCUPATIONS, MODULE NO. 10.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Center for Vocational and Technical Education.

    ONE OF A SERIES DESIGNED TO PREPARE HIGH SCHOOL STUDENTS FOR HORTICULTURE SERVICE OCCUPATIONS, THIS MODULE HAS AS ITS MAJOR OBJECTIVE TO DEVELOP A PROFICIENCY IN THE OPERATION, MAINTENANCE, AND REPAIR OF SMALL POWER EQUIPMENT USED IN HORTICULTURAL ENTERPRISES. IT WAS DEVELOPED BY A NATIONAL TASK FORCE ON THE BASIS OF DATA FROM STATE STUDIES.…

  4. Ageing airplane repair assessment program for Airbus A300

    NASA Technical Reports Server (NTRS)

    Gaillardon, J. M.; Schmidt, HANS-J.; Brandecker, B.

    1992-01-01

    This paper describes the current status of the repair categorization activities and includes all details about the methodologies developed for determination of the inspection program for the skin on pressurized fuselages. For inspection threshold determination two methods are defined based on fatigue life approach, a simplified and detailed method. The detailed method considers 15 different parameters to assess the influences of material, geometry, size location, aircraft usage, and workmanship on the fatigue life of the repair and the original structure. For definition of the inspection intervals a general method is developed which applies to all concerned repairs. For this the initial flaw concept is used by considering 6 parameters and the detectable flaw sizes depending on proposed nondestructive inspection methods. An alternative method is provided for small repairs allowing visual inspection with shorter intervals.

  5. Ageing airplane repair assessment program for Airbus A300

    NASA Technical Reports Server (NTRS)

    Gaillardon, J. M.; Schmidt, HANS-J.; Brandecker, B.

    1992-01-01

    This paper describes the current status of the repair categorization activities and includes all details about the methodologies developed for determination of the inspection program for the skin on pressurized fuselages. For inspection threshold determination two methods are defined based on fatigue life approach, a simplified and detailed method. The detailed method considers 15 different parameters to assess the influences of material, geometry, size location, aircraft usage, and workmanship on the fatigue life of the repair and the original structure. For definition of the inspection intervals a general method is developed which applies to all concerned repairs. For this the initial flaw concept is used by considering 6 parameters and the detectable flaw sizes depending on proposed nondestructive inspection methods. An alternative method is provided for small repairs allowing visual inspection with shorter intervals.

  6. The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness

    PubMed Central

    Thangavel, Chellappagounder; Liu, Yi; O’Neill, Raymond; Sharma, Ankur; McMahon, Steve B.; Mellert, Hestia; Addya, Sankar; Ertel, Adam; Birbe, Ruth; Fortina, Paolo; Dicker, Adam P; Knudsen, Karen E; Den, Robert B

    2014-01-01

    Purpose Perturbations in the RB pathway are overrepresented in advanced prostate cancer; RB loss promotes bypass of first line hormone therapy. Conversely, preliminary studies suggested that RB-deficient tumors may become sensitized to a subset of DNA damaging agents. Here, the molecular and in vivo consequence of RB status was analyzed in models of clinical relevance. Experimental Design Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts. Results Loss of RB enhanced the radioresponsiveness of both hormone sensitive and castrate resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. RB loss led to alteration in DNA damage repair and activation of the NFκB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with ionizing radiation (p<0.05). Conclusions Loss of RB confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of RB loss, but also credential RB status as a putative biomarker for predicting response to radiation therapy. PMID:25165096

  7. Opioid receptor delta as a global modulator of skin differentiation and barrier function repair.

    PubMed

    Chajra, H; Amstutz, B; Schweikert, K; Auriol, D; Redziniak, G; Lefèvre, F

    2015-08-01

    The aims of this study were to confirm the properties of selective agonist peptide (Rubixyl) contained in the spinach towards opioid receptor delta. In fact, agonist properties of both spinach peptides (Rubiscolin-5 and Rubixyl) towards opioid receptor delta were demonstrated by Zang et al., but their effects on the other opioid receptors were not studied [1]. We also studied the expression of opioid receptor delta in epidermis under normal and stress condition (inflammatory) and its role in epidermis homeostasis under stress condition in vitro and in vivo. Agonist properties studies were performed using functional agonist cellular model containing human opioid receptors. Opioid receptor delta expression and epidermis homeostasis were studied on human reconstructed epidermis under normal and stress conditions (inflammatory stress) using gene expression (RT-qPCR) and protein expression analysis (immunohistological analysis). Skin repair properties of opioid receptor delta agonist were based on the following parameters TEWL (trans epidermal water loss, hydration and wrinkle depth at periocular and perilabial area) on human volunteers having either intrinsic ageing (more than 40 years old and non-smoker group) and both intrinsic ageing and extrinsic ageing (more than 40 years old and smoker group). We have demonstrated that the Rubixyl peptide is a specific agonist of opioid receptor delta. We have demonstrated that opioid receptor delta expression is modulated under inflammatory condition. The agonist Rubixyl was able to block the depletion of opioid receptor delta seen under inflammatory condition in reconstructed human epidermis. Inflammatory conditions lead to the unbalanced gene and protein expressions of markers involved in epidermis integrity and barrier function properties. The treatment of human reconstructed epidermis with the agonist Rubixyl leads to the normalization of unbalanced gene and protein expressions. In vivo study has confirmed the

  8. Modulation of tissue repair by regeneration enhancer elements.

    PubMed

    Kang, Junsu; Hu, Jianxin; Karra, Ravi; Dickson, Amy L; Tornini, Valerie A; Nachtrab, Gregory; Gemberling, Matthew; Goldman, Joseph A; Black, Brian L; Poss, Kenneth D

    2016-04-14

    How tissue regeneration programs are triggered by injury has received limited research attention. Here we investigate the existence of enhancer regulatory elements that are activated in regenerating tissue. Transcriptomic analyses reveal that leptin b (lepb) is highly induced in regenerating hearts and fins of zebrafish. Epigenetic profiling identified a short DNA sequence element upstream and distal to lepb that acquires open chromatin marks during regeneration and enables injury-dependent expression from minimal promoters. This element could activate expression in injured neonatal mouse tissues and was divisible into tissue-specific modules sufficient for expression in regenerating zebrafish fins or hearts. Simple enhancer-effector transgenes employing lepb-linked sequences upstream of pro- or anti-regenerative factors controlled the efficacy of regeneration in zebrafish. Our findings provide evidence for 'tissue regeneration enhancer elements' (TREEs) that trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs.

  9. Performance of repair welds on aged Cr-Mo piping girth welds

    SciTech Connect

    Viswanathan, R.; Gandy, D.W.

    1999-10-01

    This article documents the results of an industry survey of weld repair practices and describes the results of experimental evaluations performed on service-aged 2{1/4}Cr-1 Mo steel piping using SMAW with both conventional postweld heat treatments and temper bead repair techniques. The overall results of this program provide substantial evidence that service-aged piping systems can be successfully weld repaired with and without postweld heat treatments and that life extension by several decades is achievable under the right design and repair conditions. Weld repairs performed on degraded exservice welds resulted in restoration or improvement of tensile and creep properties. Microhardness test results within the heat-affected zone of each weldment indicated that the temper bead weld repairs produced only slightly higher peak hardness values than those measured for the fully postweld heat treated repairs. Finally, in terms of toughness, temper bead weld repairs consistently produced higher impact properties than those measured for the postweld heat treated weldments. Gas tungsten arc weld repairs with postweld heat treatment resulted in the best combination of tensile strength, uniform microhardness distribution across the weld, Charpy toughness, and creep rupture life.

  10. Performance of repair welds on aged Cr-Mo piping girth welds

    NASA Astrophysics Data System (ADS)

    Viswanathan, R.; Gandy, D. W.

    1999-10-01

    This article documents the results of an industry survey of weld repair practices and describes the results of experimental evaluations performed on service-aged 21/4 Cr-1Mo steel piping using SMAW with both conventional postweld heat treatments and temper bead repair techniques. The overall results of this program provide substantial evidence that service-aged piping systems can be successfully weld repaired with and without postweld heat treatments and that life extension by several decades is achievable under the right design and repair conditions. Weld repairs performed on degraded exservice welds resulted in restoration or improvement of tensile and creep properties. Microhardness test results within the heat-affected zone of each weldment indicated that the temper bead weld repairs produced only slightly higher peak hardness values than those measured for the fully postweld heat treated repairs. Finally, in terms of toughness, temper bead weld repairs consistently produced higher impact properties than those measured for the postweld heat treated weldments. Gas tungsten arc weld repairs with postweld heat treatment resulted in the best combination of tensile strength, uniform microhardness distribution across the weld, Charpy toughness, and creep rupture life.

  11. Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology.

    PubMed

    Jaarsma, Dick; van der Pluijm, Ingrid; de Waard, Monique C; Haasdijk, Elize D; Brandt, Renata; Vermeij, Marcel; Rijksen, Yvonne; Maas, Alex; van Steeg, Harry; Hoeijmakers, Jan H J; van der Horst, Gijsbertus T J

    2011-12-01

    Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR-deficient Csa(-/-) and Csb(-/-) CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER-deficient Xpa(-/-) and Xpc(-/-) XP mice, but also occurred in Xpd(XPCS) mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR-deficient mice are compatible with focal dysmyelination in CS patients. Both TCR-deficient and NER-deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa(-/-), Csb(-/-)) or highly sporadic (Xpa(-/-), Xpc(-/-)) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR-deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa(-/-) and Csb(-/-) TCR-deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron

  12. Alleviation of Aflatoxin B1-Induced Genomic Damage by Proanthocyanidins via Modulation of DNA Repair.

    PubMed

    Bakheet, Saleh A; Alhuraishi, Ahmed M; Al-Harbi, Naif O; Al-Hosaini, Khaled A; Al-Sharary, Shakir D; Attia, Mohammed M; Alhoshani, Ali R; Al-Shabanah, Othman A; Al-Harbi, Mohammed M; Imam, Faisal; Ahmad, Sheikh F; Attia, Sabry M

    2016-11-01

    In order to study the mechanisms underlying the alleviation of aflatoxin B1-induced genomic damage by proanthocyanidins (PAs), we examined the modulation of oxidative DNA damage induced by aflatoxin B1 in PAs-pretreated animals. The effects of PAs on changes in the expression of DNA damage and repair genes induced by aflatoxin B1 were also evaluated in rat marrow cells. Administration of PAs before aflatoxin B1 significantly mitigated aflatoxin B1-induced oxidative DNA damage in a dose-dependent manner. Aflatoxin B1 treatment induced significant alterations in the expression of specific DNA repair genes, and the pre-treatment of rats with PAs ameliorated the altered expression of these genes. Conclusively, PAs protect against aflatoxin B1-induced oxidative DNA damage in rats. These protective effects are attributed to the antioxidant effects of PA and enhanced DNA repair through modulation of DNA repair gene expression. Therefore, PAs are a promising chemoprotective agent for averting genotoxic risks associated with aflatoxin B1 exposure.

  13. The Ageing Brain: Effects on DNA Repair and DNA Methylation in Mice

    PubMed Central

    Langie, Sabine A. S.; Cameron, Kerry M.; Ficz, Gabriella; Oxley, David; Tomaszewski, Bartłomiej; Gorniak, Joanna P.; Maas, Lou M.; Godschalk, Roger W. L.; van Schooten, Frederik J.; Reik, Wolf; von Zglinicki, Thomas; Mathers, John C.

    2017-01-01

    Base excision repair (BER) may become less effective with ageing resulting in accumulation of DNA lesions, genome instability and altered gene expression that contribute to age-related degenerative diseases. The brain is particularly vulnerable to the accumulation of DNA lesions; hence, proper functioning of DNA repair mechanisms is important for neuronal survival. Although the mechanism of age-related decline in DNA repair capacity is unknown, growing evidence suggests that epigenetic events (e.g., DNA methylation) contribute to the ageing process and may be functionally important through the regulation of the expression of DNA repair genes. We hypothesize that epigenetic mechanisms are involved in mediating the age-related decline in BER in the brain. Brains from male mice were isolated at 3–32 months of age. Pyrosequencing analyses revealed significantly increased Ogg1 methylation with ageing, which correlated inversely with Ogg1 expression. The reduced Ogg1 expression correlated with enhanced expression of methyl-CpG binding protein 2 and ten-eleven translocation enzyme 2. A significant inverse correlation between Neil1 methylation at CpG-site2 and expression was also observed. BER activity was significantly reduced and associated with increased 8-oxo-7,8-dihydro-2′-deoxyguanosine levels. These data indicate that Ogg1 and Neil1 expression can be epigenetically regulated, which may mediate the effects of ageing on DNA repair in the brain. PMID:28218666

  14. Suffering and Generativity: Repairing Threats to Self in Old Age

    PubMed Central

    de Medeiros, Kate

    2009-01-01

    Suffering is a powerful experience that can be difficult to articulate. Suffering differs from pain alone and includes an individual’s awareness of a threat to self through death, loss of identity, or uncertaintly of the meaningfulness of one’s life. In response to this threat, generative acts, especially creative expressions imbued with the self, may act as a means to repair the self in crisis. The case of Mr. A., an 85-year old man in good health, illustrates how various artistic pieces he created – a wooden dog and several poems -- helps him to restore a “fading” self. For Mr. A, the idea of “fading away” or becoming weaker and less useful until eventually disappearing is a major source of personal suffering. Through his art, he creates unique, interactive and tangible entities that can outlive his physical body and help him reclaim or repair threats to selfhood. PMID:20161268

  15. Suffering and Generativity: Repairing Threats to Self in Old Age.

    PubMed

    de Medeiros, Kate

    2009-04-01

    Suffering is a powerful experience that can be difficult to articulate. Suffering differs from pain alone and includes an individual's awareness of a threat to self through death, loss of identity, or uncertaintly of the meaningfulness of one's life. In response to this threat, generative acts, especially creative expressions imbued with the self, may act as a means to repair the self in crisis. The case of Mr. A., an 85-year old man in good health, illustrates how various artistic pieces he created - a wooden dog and several poems -- helps him to restore a "fading" self. For Mr. A, the idea of "fading away" or becoming weaker and less useful until eventually disappearing is a major source of personal suffering. Through his art, he creates unique, interactive and tangible entities that can outlive his physical body and help him reclaim or repair threats to selfhood.

  16. Trypanosoma cruzi modulates gene expression of plasma membrane repair-related proteins.

    PubMed

    Brígido, Rebecca Tavares E Silva; Tavares, Paula Cristina Brígido; Santos, Marlus Alves Dos; Santos, Júlia de Gouveia; Souza, Maria Aparecida de; Goulart, Isabela Maria Bernardes; Silva, Claudio Vieira da

    2017-10-01

    Plasma membrane injury and repair is particularly prevalent in muscle cells. Here, we aimed to verify dysferlin, acid sphingomyelinase and transcriptional factor EB gene expression during Trypanosoma cruzi infection in vitro and in vivo. Our results showed that the parasite modulates gene expression of these proteins in a way dependent on the number of plasma membrane interacting parasites and in a rapamycin-sensitive manner. Copyright © 2016 Elsevier B.V. All rights reserved.

  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.

  18. Weld repair of 2-1/4Cr-1Mo service-aged header welds

    SciTech Connect

    Viswanathan, R.; Gandy, D.; Findlan, S.

    1999-11-01

    The objective of this investigation was to evaluate the efficacy of different weld repair techniques as applied to service-aged 2-1/4Cr-1Mo steel weldments. A header which had been in service for 244,000 h at 1,050 F (565 C) was utilized for the study. Three girth welds were partially excavated and subjected to repairs using gas tungsten arc welding (GTAW), shielded metal arc welding (SMAW) with postweld heat treatment (PWHT), and without postweld heat treatment using a temperbead technique. Results show that all the weld repairs improved the creep rupture lives of the ex-service weldments and that remaining lives of several decades could be achieved in the repaired condition. The SMAW-temperbead repairs resulted in increase of future life, tensile strength, and impact toughness compared to the SMAW-PWHT repairs. The GTAW-PWHT repairs also produced a superior combination of mechanical properties. Remaining creep rupture lives were a function of the extrapolation procedure and specimen size. These results are described here and discussed in comparison with results previously reported for a less severely degraded condition of the steel in order to delineate the effect of prior degradation on weld repair performance.

  19. Elevated level of acetylation of APE1 in tumor cells modulates DNA damage repair

    PubMed Central

    Sengupta, Shiladitya; Mantha, Anil K.; Song, Heyu; Roychoudhury, Shrabasti; Nath, Somsubhra; Ray, Sutapa; Bhakat, Kishor K.

    2016-01-01

    Apurinic/apyrimidinic (AP) sites are frequently generated in the genome by spontaneous depurination/depyrimidination or after removal of oxidized/modified bases by DNA glycosylases during the base excision repair (BER) pathway. Unrepaired AP sites are mutagenic and block DNA replication and transcription. The primary enzyme to repair AP sites in mammalian cells is AP endonuclease (APE1), which plays a key role in this repair pathway. Although overexpression of APE1 in diverse cancer types and its association with chemotherapeutic resistance are well documented, alteration of posttranslational modification of APE1 and modulation of its functions during tumorigenesis are largely unknown. Here, we show that both classical histone deacetylase HDAC1 and NAD+-dependent deacetylase SIRT1 regulate acetylation level of APE1 and acetylation of APE1 enhances its AP-endonuclease activity both in vitro and in cells. Modulation of APE1 acetylation level in cells alters AP site repair capacity of the cell extracts in vitro. Primary tumor tissues of diverse cancer types have higher level of acetylated APE1 (AcAPE1) compared to adjacent non-tumor tissue and exhibit enhanced AP site repair capacity. Importantly, in the absence of APE1 acetylation, cells accumulate AP sites in the genome and show increased sensitivity to DNA damaging agents. Together, our study demonstrates that elevation of acetylation level of APE1 in tumor could be a novel mechanism by which cells handle the elevated levels of DNA damages in response to genotoxic stress and maintain sustained proliferation. PMID:27655688

  20. The role of DNA damage repair in aging of adult stem cells.

    PubMed

    Kenyon, Jonathan; Gerson, Stanton L

    2007-01-01

    DNA repair maintains genomic stability and the loss of DNA repair capacity results in genetic instability that may lead to a decline of cellular function. Adult stem cells are extremely important in the long-term maintenance of tissues throughout life. They regenerate and renew tissues in response to damage and replace senescent terminally differentiated cells that no longer function. Oxidative stress, toxic byproducts, reduced mitochondrial function and external exposures all damage DNA through base modification or mis-incorporation and result in DNA damage. As in most cells, this damage may limit the survival of the stem cell population affecting tissue regeneration and even longevity. This review examines the hypothesis that an age-related loss of DNA damage repair pathways poses a significant threat to stem cell survival and longevity. Normal stem cells appear to have strict control of gene expression and DNA replication whereas stem cells with loss of DNA repair may have altered patterns of proliferation, quiescence and differentiation. Furthermore, stem cells with loss of DNA repair may be susceptible to malignant transformation either directly or through the emergence of cancer-prone stem cells. Human diseases and animal models of loss of DNA repair provide longitudinal analysis of DNA repair processes in stem cell populations and may provide links to the physiology of aging.

  1. Repair of DNA double-strand breaks is not modulated by low-dose gamma radiation in C57BL/6J mice.

    PubMed

    Blimkie, Melinda S J; Fung, Luke C W; Petoukhov, Eugenia S; Girard, Cyrielle; Klokov, Dmitry

    2014-05-01

    In this study, we sought to determine whether low-dose ionizing radiation, previously shown to induce a systemic adaptive response in C57BL/6J mice, is capable of enhancing the rate of DNA double-strand break repair. Repair capacity was determined by measuring γ-H2AX levels in splenic and thymic lymphocytes, using flow cytometry, at different times after a challenge irradiation (2 Gy, (60)Co). Irradiation with low doses (20 and 100 mGy) was conducted in vivo, whereas the challenge dose was applied to primary cultures of splenocytes and thymocytes in vitro 24 h later. Obtained kinetics curves of formation and loss of γ-H2AX indicated that cells from low-dose irradiated mice did not express more efficient DNA double-strand break repair compared to controls. Immunoblot analysis of γ-H2AX and Phospho-Ser-1981 ATM confirmed that DNA damage signaling was not modulated by preliminary low-dose radiation. Mouse embryonic fibroblasts of C57BL genetic background failed to show clonogenic survival radioadaptive response or enhanced repair of DNA double-strand breaks as evaluated by immunofluorescence microscopy of γ-H2AX foci. Our results indicate that radiation adaptive responses at systemic levels, such as increases in the tumor latency times in aging mice, may not be mediated by modulated DNA repair, and that the genetic background may affect expression of a radioadaptive response.

  2. Psychological Aspects of Aging. Module A-7. Block A. Basic Knowledge of the Aging Process.

    ERIC Educational Resources Information Center

    Harvey, Dexter; Cap, Orest

    This instructional module on psychological aspects of aging is one in a block of 10 modules designed to provide the human services worker who works with older adults with basic information regarding the aging process. An introduction provides an overview of the module content. A listing of general objectives follows. Six sections present…

  3. Social Aspects of Aging. Module A-4. Block A. Basic Knowledge of the Aging Process.

    ERIC Educational Resources Information Center

    Harvey, Dexter; Cap, Orest

    This instructional module on social aspects of aging is one in a block of 10 modules designed to provide the human services worker who works with older adults with basic information regarding the aging process. An introduction provides an overview of the module content. A listing of general objectives follows. Four sections present informative…

  4. Physiological Aspects of Aging. Module A-5. Block A. Basic Knowledge of the Aging Process.

    ERIC Educational Resources Information Center

    Harvey, Dexter; Cap, Orest

    This instructional module on physiological aspects of aging is one in a block of 10 modules designed to provide the human services worker who works with older adults with basic information regarding the aging process. An introduction provides an overview of the module content. A listing of general objectives follows. Nine sections present…

  5. Effect of the repaired damage morphology of fused silica on the modulation of incident laser

    NASA Astrophysics Data System (ADS)

    Gao, X.; Jiang, Y.; Qiu, R.; Zhou, Q.; Zuo, R.; Zhou, G. R.; Yao, K.

    2017-02-01

    Local CO2 laser treatment has proved to be the most promising method to extend the life-time of fused silica. However, previous experimental data show that some raised rims are observed around the mitigated sites left from the mitigation process, which will result in hazardous light modulation to the downstream optics. In this work, the morphology features of mitigated sites on the surface of fused silica optics were analyzed in detail. According to measured morphology features, a 3D analytical model for simulating the modulation value induced by mitigated site has been developed based on the scalar diffraction theory. The diffraction patterns at a discrete distance downstream from each mitigated site are measured. The influences of geometry, laser wavelength and refractive index of substrates on the modulation by repaired damage morphology at different distances are discussed, respectively. The analytical model is usable and representative to evaluate the hazardous modulation induced by repaired damage morphology to downstream optics. Results on this research suggest that the downstream intensification can be suppressed by controlling the morphology features of mitigated sites, which provides a direction for the development and improvement of the mitigated techniques of damage optics.

  6. Advanced age diminishes tendon-to-bone healing in a rat model of rotator cuff repair.

    PubMed

    Plate, Johannes F; Brown, Philip J; Walters, Jordan; Clark, John A; Smith, Thomas L; Freehill, Michael T; Tuohy, Christopher J; Stitzel, Joel D; Mannava, Sandeep

    2014-04-01

    Advanced patient age is associated with recurrent tearing and failure of rotator cuff repairs clinically; however, basic science studies have not evaluated the influence of aging on tendon-to-bone healing after rotator cuff repair in an animal model. Hypothesis/ This study examined the effect of aging on tendon-to-bone healing in an established rat model of rotator cuff repair using the aged animal colony from the National Institute on Aging of the National Institutes of Health. The authors hypothesized that normal aging decreases biomechanical strength and histologic organization at the tendon-to-bone junction after acute repair. Controlled laboratory study. In 56 F344xBN rats, 28 old and 28 young (24 and 8 months of age, respectively), the supraspinatus tendon was transected and repaired. At 2 or 8 weeks after surgery, shoulder specimens underwent biomechanical testing to compare load-to-failure and load-relaxation response between age groups. Histologic sections of the tendon-to-bone interface were assessed with hematoxylin and eosin staining, and collagen fiber organization was assessed by semiquantitative analysis of picrosirius red birefringence under polarized light. Peak failure load was similar between young and old animals at 2 weeks after repair (31% vs 26% of age-matched uninjured controls, respectively; P > .05) but significantly higher in young animals compared with old animals 8 weeks after repair (86% vs 65% of age-matched uninjured controls, respectively; P < .01). Eight weeks after repair, fibroblasts appeared more organized and uniformly aligned in young animals on hematoxylin and eosin slides compared with old animals. Collagen birefringence analysis of the tendon-to-bone junction demonstrated that young animals had increased collagen fiber organization and similar histologic structure compared with age-matched controls (53.7 ± 2.4 gray scales; P > .05). In contrast, old animals had decreased collagen fiber organization and altered structure

  7. Age of the mother as a risk factor and timing of hypospadias repair according to severity

    PubMed Central

    Jorge, Juan Carlos; Pérez-Brayfield, Marcos Raymond; Torres, Camille M.; Piñeyro-Ruiz, Coriness; Torres, Naillil

    2016-01-01

    Background & Objectives Hypospadias is characterized by a displacement of the urethral opening in males that can change from the typical position within the glans penis to a subcoronal position (Type I), to anywhere along the ventral shaft (Type II), to penoscrotal, scrotal, or perineal positions (Type III). We and others have previously reported that age of the mother (≥ 40 years old) is a risk factor for having a child with hypospadias, but there is a scarcity of reports on whether such risk is higher for having a child with the mild (Type I) or the more severe forms (Types II and III). In addition, we aimed to assess the timing of hypospadias repair according to severity. Methods Parents of children with hypospadias were interviewed by using a series of questionnaires (n = 128 cases). Severity was confirmed in the clinic and age of the mother was self-reported. Number of surgeries, age of child by the first and the last intervention was also assessed. Ordered logistic regression and the Brant test were employed to calculate risk between mild (Type I) and severe cases (Types II and III), and the assumption of proportional odds, respectively. The Mann-Whitney U Test was used to compare number of surgeries and age by the last repair between mild and severe cases. One-way ANOVA was employed to compare age of the child at the time of first surgery across severities (Types I - III). Results Women ≥ 40 years of age are 3.89 times [95% CI: 1.20-12.64] at a higher risk for having a child with the more severe forms of the condition than younger women. Repair of Type I was accomplished with 1 intervention whereas more severe cases required 1 – 4 (2 ± 0.5) surgical interventions. The timing for hypospadias repair of Type I cases occurred at an average age of 16.2 ± 4.88 months, of Type II cases occurred at an average age of 20.3 ± 8.15 months whereas the average age of the first hypospadias repair among Type III cases was 12.68 ± 2.52 months. Number of surgeries

  8. Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing.

    PubMed

    Watanabe, Reiko; Kanno, Shin-Ichiro; Mohammadi Roushandeh, Amaneh; Ui, Ayako; Yasui, Akira

    2017-10-05

    Nucleosome remodelling (NR) regulates transcription in an ATP-dependent manner, and influences gene expression required for development and cellular functions, including those involved in anti-cancer and anti-ageing processes. ATP-utilizing chromatin assembly and remodelling factor (ACF) and Brahma-associated factor (BAF) complexes, belonging to the ISWI and SWI/SNF families, respectively, are involved in various types of DNA repair. Suppression of several BAF factors makes U2OS cells significantly sensitive to X-rays, UV and especially to cisplatin, and these BAF factors contribute to the accumulation of repair proteins at various types of DNA damage and to DNA repair. Recent cancer genome sequencing and expression analysis has shown that BAF factors are frequently mutated or, more frequently, silenced in various types of cancer cells. Thus, those cancer cells are potentially X-ray- and especially cisplatin-sensitive, suggesting a way of optimizing current cancer therapy. Recent single-stem cell analysis suggests that mutations and epigenetic changes influence stem cell functionality leading to cellular ageing. Genetic and epigenetic changes in the BAF factors diminish DNA repair as well as transcriptional regulation activities, and DNA repair defects in turn negatively influence NR and transcriptional regulation. Thus, they build negative feedback loops, which accelerate both cellular senescence and transformation as common and rare cellular events, respectively, causing cellular ageing.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. © 2017 The Author(s).

  9. VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair.

    PubMed

    Waschek, J A

    2013-06-01

    Inflammatory processes play both regenerative and destructive roles in multiple sclerosis, stroke, CNS trauma, amyotrophic lateral sclerosis and aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Endogenous defence mechanisms against these pathologies include those that are directly neuroprotective, and those that modulate the expression of inflammatory mediators in microglia, astrocytes, and invading inflammatory cells. While a number of mechanisms and molecules have been identified that can directly promote neuronal survival, less is known about how the brain protects itself from harmful inflammation, and further, how it co-opts the healing function of the immune system to promote CNS repair. The two closely related neuroprotective peptides, vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP), which are up-regulated in neurons and immune cells after injury and/or inflammation, are known to protect neurons, but also exert powerful in vivo immunomodulatory actions, which are primarily anti-inflammatory. These peptide actions are mediated by high-affinity receptors expressed not only on neurons, but also astrocytes, microglia and peripheral inflammatory cells. Well-established immunomodulatory actions of these peptides are to inhibit macrophage and microglia production and release of inflammatory mediators such as TNF-α and IFN-γ, and polarization of T-cell responses away from Th1 and Th17, and towards a Th2 phenotype. More recent studies have revealed that these peptides can also promote the production of both natural and inducible subsets of regulatory T-cells. The neuroprotective and immunomodulatory actions of VIP and PACAP suggest that receptors for these peptides may be therapeutic targets for neurodegenerative and neuroinflammatory diseases and other forms of CNS injury. Published 2013.. This article is a U.S. Government work and is in the public domain in the USA.

  10. VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair

    PubMed Central

    Waschek, JA

    2013-01-01

    Inflammatory processes play both regenerative and destructive roles in multiple sclerosis, stroke, CNS trauma, amyotrophic lateral sclerosis and aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Endogenous defence mechanisms against these pathologies include those that are directly neuroprotective, and those that modulate the expression of inflammatory mediators in microglia, astrocytes, and invading inflammatory cells. While a number of mechanisms and molecules have been identified that can directly promote neuronal survival, less is known about how the brain protects itself from harmful inflammation, and further, how it co-opts the healing function of the immune system to promote CNS repair. The two closely related neuroprotective peptides, vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP), which are up-regulated in neurons and immune cells after injury and/or inflammation, are known to protect neurons, but also exert powerful in vivo immunomodulatory actions, which are primarily anti-inflammatory. These peptide actions are mediated by high-affinity receptors expressed not only on neurons, but also astrocytes, microglia and peripheral inflammatory cells. Well-established immunomodulatory actions of these peptides are to inhibit macrophage and microglia production and release of inflammatory mediators such as TNF-α and IFN-γ, and polarization of T-cell responses away from Th1 and Th17, and towards a Th2 phenotype. More recent studies have revealed that these peptides can also promote the production of both natural and inducible subsets of regulatory T-cells. The neuroprotective and immunomodulatory actions of VIP and PACAP suggest that receptors for these peptides may be therapeutic targets for neurodegenerative and neuroinflammatory diseases and other forms of CNS injury. PMID:23517078

  11. Cigarette Smoke Modulates Repair and Innate Immunity following Injury to Airway Epithelial Cells

    PubMed Central

    Daniel, Nadia M.; van der Vlugt, Luciën E. P. M.; van Schadewijk, Annemarie; Taube, Christian; Hiemstra, Pieter S.

    2016-01-01

    Cigarette smoking is the main risk factor associated with chronic obstructive pulmonary disease (COPD), and contributes to COPD development and progression by causing epithelial injury and inflammation. Whereas it is known that cigarette smoke (CS) may affect the innate immune function of airway epithelial cells and epithelial repair, this has so far not been explored in an integrated design using mucociliary differentiated airway epithelial cells. In this study, we examined the effect of whole CS exposure on wound repair and the innate immune activity of mucociliary differentiated primary bronchial epithelial cells, upon injury induced by disruption of epithelial barrier integrity or by mechanical wounding. Upon mechanical injury CS caused a delayed recovery in the epithelial barrier integrity and wound closure. Furthermore CS enhanced innate immune responses, as demonstrated by increased expression of the antimicrobial protein RNase 7. These differential effects on epithelial repair and innate immunity were both mediated by CS-induced oxidative stress. Overall, our findings demonstrate modulation of wound repair and innate immune responses of injured airway epithelial cells that may contribute to COPD development and progression. PMID:27829065

  12. Increasing age and tear size reduce rotator cuff repair healing rate at 1 year.

    PubMed

    Rashid, Mustafa S; Cooper, Cushla; Cook, Jonathan; Cooper, David; Dakin, Stephanie G; Snelling, Sarah; Carr, Andrew J

    2017-09-07

    Background and purpose - There is a need to understand the reasons why a high proportion of rotator cuff repairs fail to heal. Using data from a large randomized clinical trial, we evaluated age and tear size as risk factors for failure of rotator cuff repair. Patients and methods - Between 2007 and 2014, 65 surgeons from 47 hospitals in the National Health Service (NHS) recruited 447 patients with atraumatic rotator cuff tendon tears to the United Kingdom Rotator Cuff Trial (UKUFF) and 256 underwent rotator cuff repair. Cuff integrity was assessed by imaging in 217 patients, at 12 months post-operation. Logistic regression analysis was used to determine the influence of age and intra-operative tear size on healing. Hand dominance, sex, and previous steroid injections were controlled for. Results - The overall healing rate was 122/217 (56%) at 12 months. Healing rate decreased with increasing tear size (small tears 66%, medium tears 68%, large tears 47%, and massive tears 27% healed). The mean age of patients with a healed repair was 61 years compared with 64 years for those with a non-healed repair. Mean age increased with larger tear sizes (small tears 59 years, medium tears 62 years, large tears 64 years, and massive tears 66 years). Increasing age was an independent factor that negatively influenced healing, even after controlling for tear size. Only massive tears were an independent predictor of non-healing, after controlling for age. Interpretation - Although increasing age and larger tear size are both risks for failure of rotator cuff repair healing, age is the dominant risk factor.

  13. Modulation of Wound Healing and Scar Formation by MG53 Protein-mediated Cell Membrane Repair*

    PubMed Central

    Li, Haichang; Duann, Pu; Lin, Pei-Hui; Zhao, Li; Fan, Zhaobo; Tan, Tao; Zhou, Xinyu; Sun, Mingzhai; Fu, Minghuan; Orange, Matthew; Sermersheim, Matthew; Ma, Hanley; He, Duofen; Steinberg, Steven M.; Higgins, Robert; Zhu, Hua; John, Elizabeth; Zeng, Chunyu; Guan, Jianjun; Ma, Jianjie

    2015-01-01

    Cell membrane repair is an important aspect of physiology, and disruption of this process can result in pathophysiology in a number of different tissues, including wound healing, chronic ulcer and scarring. We have previously identified a novel tripartite motif family protein, MG53, as an essential component of the cell membrane repair machinery. Here we report the functional role of MG53 in the modulation of wound healing and scarring. Although MG53 is absent from keratinocytes and fibroblasts, remarkable defects in skin architecture and collagen overproduction are observed in mg53−/− mice, and these animals display delayed wound healing and abnormal scarring. Recombinant human MG53 (rhMG53) protein, encapsulated in a hydrogel formulation, facilitates wound healing and prevents scarring in rodent models of dermal injuries. An in vitro study shows that rhMG53 protects against acute injury to keratinocytes and facilitates the migration of fibroblasts in response to scratch wounding. During fibrotic remodeling, rhMG53 interferes with TGF-β-dependent activation of myofibroblast differentiation. The resulting down-regulation of α smooth muscle actin and extracellular matrix proteins contributes to reduced scarring. Overall, these studies establish a trifunctional role for MG53 as a facilitator of rapid injury repair, a mediator of cell migration, and a modulator of myofibroblast differentiation during wound healing. Targeting the functional interaction between MG53 and TGF-β signaling may present a potentially effective means for promoting scarless wound healing. PMID:26306047

  14. Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology

    PubMed Central

    de Waard, Monique C.; Haasdijk, Elize D.; Brandt, Renata; Vermeij, Marcel; Rijksen, Yvonne; Maas, Alex; van Steeg, Harry; Hoeijmakers, Jan H. J.; van der Horst, Gijsbertus T. J.

    2011-01-01

    Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities

  15. Age-associated changes in regenerative capabilities of mesenchymal stem cell: impact on chronic wounds repair.

    PubMed

    Yao, Bin; Huang, Sha; Gao, Dongyun; Xie, Jiangfan; Liu, Nanbo; Fu, Xiaobing

    2016-12-01

    Mesenchymal stem cells (MSCs) represent an ideal source of autologous cell-based therapy for chronic wounds. Functional characteristics of MSCs may benefit wound healing by exerting their multi-regenerative potential. However, cell ageing resulting from chronic degenerative diseases or donor age could cause inevitable effects on the regenerative abilities of MSCs. A variety of studies have shown the relationship between MSC ageing and age-related dysfunction, but few associate these age-related impacts on MSCs with their ability of repairing chronic wounds, which are common in the elderly population. Here, we discuss the age-associated changes of MSCs and describe the potential impacts on MSC-based therapy for chronic wounds. Furthermore, critical evaluation of the current literatures is necessary for understanding the underlying mechanisms of MSC ageing and raising the corresponding concerns on considering their possible use for chronic wound repair. © 2015 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  16. The convergence of fracture repair and stem cells: interplay of genes, aging, environmental factors and disease.

    PubMed

    Hadjiargyrou, Michael; O'Keefe, Regis J

    2014-11-01

    The complexity of fracture repair makes it an ideal process for studying the interplay between the molecular, cellular, tissue, and organ level events involved in tissue regeneration. Additionally, as fracture repair recapitulates many of the processes that occur during embryonic development, investigations of fracture repair provide insights regarding skeletal embryogenesis. Specifically, inflammation, signaling, gene expression, cellular proliferation and differentiation, osteogenesis, chondrogenesis, angiogenesis, and remodeling represent the complex array of interdependent biological events that occur during fracture repair. Here we review studies of bone regeneration in genetically modified mouse models, during aging, following environmental exposure, and in the setting of disease that provide insights regarding the role of multipotent cells and their regulation during fracture repair. Complementary animal models and ongoing scientific discoveries define an increasing number of molecular and cellular targets to reduce the morbidity and complications associated with fracture repair. Last, some new and exciting areas of stem cell research such as the contribution of mitochondria function, limb regeneration signaling, and microRNA (miRNA) posttranscriptional regulation are all likely to further contribute to our understanding of fracture repair as an active branch of regenerative medicine. © 2014 American Society for Bone and Mineral Research.

  17. Helicobacter pylori infection modulates the expression of miRNAs associated with DNA mismatch repair pathway.

    PubMed

    Santos, Juliana C; Brianti, Mitsue T; Almeida, Victor R; Ortega, Manoela M; Fischer, Wolfgang; Haas, Rainer; Matheu, Ander; Ribeiro, Marcelo L

    2017-04-01

    Genetic and epigenetic inactivation of DNA mismatch repair (MMR) genes might lead to modifications in cancer-related gene expression and cancer development. Recently, it has been shown that the infection by Helicobacter pylori, the major causative agent of gastric cancer, induces DNA damage and inhibits MMR DNA repair. Also, it has been reported that microRNAs (miRs) have an important role in regulating genomic stability and MMR DNA repair. Thus, the aim of this study was to identify miRs regulating MMR pathway in H. pylori-associated gastric carcinogenesis. To address this question, a gastric epithelial cell line and AGS cancer gastric cells were infected with several H. pylori strains. MMR gene expression and miRs correlating with H. pylori strain infection were evaluated. The results showed that H. pylori infection significantly down-regulated the expression of all selected MMR genes. Also, H. pylori infection modulated the expression of several miRs (including miR-150-5p, miR-155-5p, and miR-3163), after 4, 8, and 12 h of infection. Computational prediction of candidate miRs and their predicted MMR targeting sites were obtained from TargetScan, mirDB, and MetaCore. The generated data indicated that the selected miRs (miR-150-5p, miR-155-5p, and miR-3163) could possibly target and modulate MMR genes (POLD3, MSH2, and MSH3, respectively). The target validation was performed using mimics and luciferase gene reporter assays. Briefly, this study shows that H. pylori impairs MMR DNA repair pathway and identifies miRs that regulate MMR gene expression in gastric cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Performance of weld repairs on service-aged 2{1/4}Cr-1Mo girth weldments utilizing conventional postweld heat treatment and temper-bead repair techniques

    SciTech Connect

    Gandy, D.W.; Viswanathan, R.; Findlan, S.J.

    1996-06-01

    Weld repair of service-damaged piping and header girth weldments has generated considerable interest within the fossil power plant arena over the past few years. The interest has stemmed in part from recent revisions to the National Board Inspection Code regarding welding repair of Cr-Mo steels and from the fact that many domestic utility power plants are nearing the end of their projected design life. EPRI is addressing a number of concerns expressed by utilities surrounding weld repair under a joint EPRI/utility program RP3484-01. The program is focused on procuring service-aged piping and header girth weldments, quantifying the level of damage associated with those weldments, performing weld repairs within the girth weldment region, testing the repair weldment mechanically and metallurgically, and comparing the increase or decrease in remaining life associated with the weld repair. This paper discusses four industry case histories along with two piping girth weld repairs performed under the EPRI program: (1) a repair performed with conventional postweld heat treatment and (2) a repair performed employing temper-bead welding repair technology.

  19. Effects of surface conditioning on repair bond strengths of non-aged and aged microhybrid, nanohybrid, and nanofilled composite resins.

    PubMed

    Rinastiti, Margareta; Özcan, Mutlu; Siswomihardjo, Widowati; Busscher, Henk J

    2011-10-01

    This study evaluates effects of aging on repair bond strengths of microhybrid, nanohybrid, and nanofilled composite resins and characterizes the interacting surfaces after aging. Disk-shaped composite specimens were assigned to one of three aging conditions: (1) thermocycling (5,000 ×, 5-55 °C), (2) storage in water at 37 °C for 6 months, or (3) immersion in citric acid at 37 °C, pH 3 for 1 week; a non-aged group acted as the control. Two surface conditionings were selected: intermediate adhesive resin application (IAR-application) and chairside silica coating followed by silanization and its specific IAR-application (SC-application). Composite resins, of the same kind as their substrate, were adhered onto the substrates, and repair shear bond strengths were determined, followed by failure type evaluation. Filler particle exposure was determined by X-ray photoelectron spectroscopy and surface roughness analyzed using scanning electron and atomic force microscopy. Surface roughness increased in all composite resins after aging, but filler particle exposure at the surface only increased after thermocycling and citric acid immersion. Composite resin type, surface conditioning, and aging method significantly influenced the repair bond strengths (p < 0.05, three-way analysis of variance) with the least severe effects of water storage. Repair bond strengths in aged composite resins after IAR-application were always lower in non-aged ones, while SC-application led to higher bond strengths than IAR-application after thermocycling and water storage. In addition, SC-application led to more cohesive failures than after IAR-application, regardless the aging method.

  20. Sympathetic modulation of sensory nerve activity with age: human and rodent skin models.

    PubMed

    Khalil, Z; LeVasseur, S; Merhi, M; Helme, R D

    1997-11-01

    1. Sensory nerves serve an afferent role and mediate neurogenic components of inflammation and tissue repair via an axon reflex release of sensory peptides at sites of injury. Dysfunction of these nerves with age could contribute to delayed tissue healing. 2. Complementary animal and human skin models were used in the present studies to investigate changes in the modulation of sensory nerve function by sympathetic efferents during ageing. Laser Doppler flowmetry was used to monitor neurogenic skin vascular responses. 3. The animal model used skin of the hind footpad of anaesthetized rats combined with electrical stimulation of the sciatic nerve, while the human model comprised capsaicin electrophoresis to the volar surface of the forearm. Sympathetic modulation was effected by systemic phentolamine pretreatment in animals and local application in the human model. 4. The results obtained from the human model confirmed the reported decline in sensory nerve function and showed no change in sympathetic modulation with age. The results from the animal model confirm and expand results obtained from the human model. 5. The use of low (5 Hz) and high (15 Hz) frequency electrical stimulation (20 V, 2 ms for 1 min) revealed a preferential response of aged sensory nerves to low-frequency electrical stimulation parameters with differential sympathetic modulation that is dependent on the frequency of stimulation.

  1. Mesenchymal stromal cells; role in tissue repair, drug discovery and immune modulation.

    PubMed

    English, Karen; Mahon, Bernard P; Wood, Kathryn J

    2014-01-01

    Mesenchymal stromal cells (MSCs) participate in repair of damaged tissues, possess the potential to serve as a useful tool in the drug discovery field and exert immunosuppressive effects as demonstrated by their ability to modulate the immune response. Herein, the roles played by MSC differentiation and/or production of trophic factors involved in tissue repair are discussed. MSCs offer the opportunity to probe targets that conventional or differentiated cell lines do not express; thus providing a more refined system that allows identification of novel therapeutics. However, there are difficulties associated with drug discovery assays to which MSCs are not exempt. The immunosuppressive potential of MSCs has already been utilised in clinical trials where MSCs have been used to treat patients with graft- versus- host disease (GvHD) and autoimmune diseases. Another possible therapeutic application of MSCs lies in the field of transplantation tolerance. Although the capacity of MSCs to modulate immune responses has received much attention, the role of MSCs in transplantation tolerance is as yet unclear. In this review, we discuss the evidence for MSC induction of a state of tolerance in the transplantation setting.

  2. SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair.

    PubMed

    Vazquez, Berta N; Thackray, Joshua K; Simonet, Nicolas G; Kane-Goldsmith, Noriko; Martinez-Redondo, Paloma; Nguyen, Trang; Bunting, Samuel; Vaquero, Alejandro; Tischfield, Jay A; Serrano, Lourdes

    2016-07-15

    Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N-terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7-knockout mice suffer from partial embryonic lethality and a progeroid-like phenotype. Consistently, SIRT7-deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1-dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double-strand breaks (DSBs), thereby influencing the efficiency of non-homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7-mediated H3K18 deacetylation and the maintenance of genome integrity. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  3. [The correlations between aging of the human body, oxidative stress and reduced efficiency of repair systems].

    PubMed

    Michalak, Aleksandra; Krzeszowiak, Jakub; Markiewicz-Górka, Iwona

    2014-12-15

    The article presents an current knowledge overview about the importance of oxidative stress and reduced efficiency of repair processes during the aging process of the human body. Oxidative damage to cellular macromolecules (proteins, lipids, nucleic acids), are formed under the influence of reactive oxygen species (ROS). They are the part of important mechanism which is responsible for the process of aging and the development of many diseases. The most important effects result from DNA damage, due to the mutations formation, which can lead to the development of tumors. However, a well-functioning repair systems (i.a. homologous recombination) remove the damage and prevent harmful changes in the cells. Lipid peroxidation products also cause oxidative modification of nucleic acids (and proteins). Proteins and fats also have repair systems, but much simpler than those responsible for the repair of nucleic acids. Unfortunately, with increasing age, they are more weakened, which contributes to increase numbers of cell damage, and consequently development of diseases specific to old age: cancer, neurodegenerative diseases or atherosclerosis.

  4. Modulation of wound healing and scar formation by MG53 protein-mediated cell membrane repair.

    PubMed

    Li, Haichang; Duann, Pu; Lin, Pei-Hui; Zhao, Li; Fan, Zhaobo; Tan, Tao; Zhou, Xinyu; Sun, Mingzhai; Fu, Minghuan; Orange, Matthew; Sermersheim, Matthew; Ma, Hanley; He, Duofen; Steinberg, Steven M; Higgins, Robert; Zhu, Hua; John, Elizabeth; Zeng, Chunyu; Guan, Jianjun; Ma, Jianjie

    2015-10-02

    Cell membrane repair is an important aspect of physiology, and disruption of this process can result in pathophysiology in a number of different tissues, including wound healing, chronic ulcer and scarring. We have previously identified a novel tripartite motif family protein, MG53, as an essential component of the cell membrane repair machinery. Here we report the functional role of MG53 in the modulation of wound healing and scarring. Although MG53 is absent from keratinocytes and fibroblasts, remarkable defects in skin architecture and collagen overproduction are observed in mg53(-/-) mice, and these animals display delayed wound healing and abnormal scarring. Recombinant human MG53 (rhMG53) protein, encapsulated in a hydrogel formulation, facilitates wound healing and prevents scarring in rodent models of dermal injuries. An in vitro study shows that rhMG53 protects against acute injury to keratinocytes and facilitates the migration of fibroblasts in response to scratch wounding. During fibrotic remodeling, rhMG53 interferes with TGF-β-dependent activation of myofibroblast differentiation. The resulting down-regulation of α smooth muscle actin and extracellular matrix proteins contributes to reduced scarring. Overall, these studies establish a trifunctional role for MG53 as a facilitator of rapid injury repair, a mediator of cell migration, and a modulator of myofibroblast differentiation during wound healing. Targeting the functional interaction between MG53 and TGF-β signaling may present a potentially effective means for promoting scarless wound healing. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Role of metabolic rate and DNA-repair in Drosophila aging Implications for the mitochondrial mutation theory of aging

    NASA Technical Reports Server (NTRS)

    Miquel, J.; Binnard, R.; Fleming, J. E.

    1983-01-01

    The notion that injury to mitochondrial DNA is a cause of intrinsic aging was tested by correlating the different respiration rates of several wild strains of Drosophila melanogaster with the life-spans. Respiration rate and aging in a mutant of D. melanogaster deficient in postreplication repair were also investigated. In agreement with the rate of living theory, there was an inverse relation between oxygen consumption and median life-span in flies having normal DNA repair. The mutant showed an abnormally low life-span as compared to the controls and also exhibited significant deficiency in mating fitness and a depressed metabolic rate. Therefore, the short life-span of the mutant may be due to the congenital condition rather than to accelerated aging.

  6. Role of metabolic rate and DNA-repair in Drosophila aging Implications for the mitochondrial mutation theory of aging

    NASA Technical Reports Server (NTRS)

    Miquel, J.; Binnard, R.; Fleming, J. E.

    1983-01-01

    The notion that injury to mitochondrial DNA is a cause of intrinsic aging was tested by correlating the different respiration rates of several wild strains of Drosophila melanogaster with the life-spans. Respiration rate and aging in a mutant of D. melanogaster deficient in postreplication repair were also investigated. In agreement with the rate of living theory, there was an inverse relation between oxygen consumption and median life-span in flies having normal DNA repair. The mutant showed an abnormally low life-span as compared to the controls and also exhibited significant deficiency in mating fitness and a depressed metabolic rate. Therefore, the short life-span of the mutant may be due to the congenital condition rather than to accelerated aging.

  7. Aging and photo-aging DNA repair phenotype of skin cells-evidence toward an effect of chronic sun-exposure.

    PubMed

    Prunier, Chloé; Masson-Genteuil, Gwénaëlle; Ugolin, Nicolas; Sarrazy, Fanny; Sauvaigo, Sylvie

    2012-08-01

    Several studies have demonstrated the deleterious effect of aging on the capacity of cells to repair their DNA. However, current existing assays aimed at measuring DNA repair address only a specific repair step dedicated to the correction of a specific DNA lesion type. Consequently they provide no information regarding the repair pathways that handle other types of lesions. In addition to aging, consequences of photo-exposure on these repair processes remain elusive. In this study we evaluated the consequence of aging and of chronic and/or acute photo-exposure on DNA repair in human skin fibroblasts using a multiplexed approach, which provided detailed information on several repair pathways at the same time. The resulting data were analyzed with adapted statistics/bioinformatics tools. We showed that, irrespective of the repair pathway considered, excision/synthesis was less efficient in non-exposed cells from elderly compared to cells from young adults and that photo-exposure disrupted this very clear pattern. Moreover, it was evidenced that chronic sun-exposure induced changes in DNA repair properties. Finally, the identification of a specific signature at the level of the NER pathway in cells repeatedly exposed to sun revealed a cumulative effect of UVB exposure and chronic sun irradiation. The uses of bioinformatics tools in this study was essential to fully take advantage of the large sum of data obtained with our multiplexed DNA repair assay and unravel the effects of environmental exposure on DNA repair pathways.

  8. Performance of repair welds on service-aged 2-1/4Cr-1Mo girth weldments

    SciTech Connect

    Viswanathan, R.; Gandy, D.; Findlan, S.

    1997-11-01

    This paper discusses the results of evaluations performed on service-aged piping using both conventional postweld heat treatments and temperbead repair techniques. The two repair weldments were accomplished on two 2-1/4Cr-1Mo pipe girth weldments which were removed from a utility hot reheat piping system in the fall of 1992 after 161,000 h of operation at 1,000 F (538 C). Each repair was performed around one-half of the diameter of a pipe girth weldment, while the remaining half of the girth weldment was left in the service-aged condition. Post-repair metallurgical and mechanical test results indicated that both weld repairs produced improved remaining lives when compared to the service-aged girth weldments. Since the two ex-service weldments that were utilized in weld repairs exhibited different stress rupture strengths to start with, the performance of temper bead and postweld heat-treated (PWHT) repair could not be compared directly. It was clear, however, that life extension periods exceeding 30 yr could be achieved by temperbead repairs, with improved toughness and with no loss of stress rupture ductility, tensile strength, or yield strength. The temperbead repair improved the toughness of the service-aged weldment, while the postweld heat-treated repair lowered the HAZ toughness.

  9. NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging

    PubMed Central

    Bonsignore, Lindsay A.; Tooley, John G.; Van Hoose, Patrick M.; Wang, Eugenia; Cheng, Alan; Cole, Marsha P.; Tooley, Christine E. Schaner

    2015-01-01

    Though defective genome maintenance and DNA repair have long been know to promote phenotypes of premature aging, the role protein methylation plays in these processes is only now emerging. We have recently identified the first N-terminal methyltransferase, NRMT1, which regulates protein-DNA interactions and is necessary for both accurate mitotic division and nucleotide excision repair. To demonstrate if complete loss of NRMT1 subsequently resulted in developmental or aging phenotypes, we constructed the first NRMT1 knockout (Nrmt1−/−) mouse. The majority of these mice die shortly after birth. However, the ones that survive exhibit decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration; phenotypes characteristic of other mouse models deficient in DNA repair. The livers from Nrmt1−/− mice produce less reactive oxygen species (ROS) than wild type controls, and Nrmt1−/− mouse embryonic fibroblasts show a decreased capacity for handling oxidative damage. This indicates that decreased mitochondrial function may benefit Nrmt1−/− mice and protect them from excess internal ROS and subsequent DNA damage. These studies position the NRMT1 knockout mouse as a useful new system for studying the effects of genomic instability and defective DNA damage repair on organismal and tissue-specific aging. PMID:25843235

  10. NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging.

    PubMed

    Bonsignore, Lindsay A; Tooley, John G; Van Hoose, Patrick M; Wang, Eugenia; Cheng, Alan; Cole, Marsha P; Schaner Tooley, Christine E

    2015-03-01

    Though defective genome maintenance and DNA repair have long been known to promote phenotypes of premature aging, the role protein methylation plays in these processes is only now emerging. We have recently identified the first N-terminal methyltransferase, NRMT1, which regulates protein-DNA interactions and is necessary for both accurate mitotic division and nucleotide excision repair. To demonstrate if complete loss of NRMT1 subsequently resulted in developmental or aging phenotypes, we constructed the first NRMT1 knockout (Nrmt1(-/-)) mouse. The majority of these mice die shortly after birth. However, the ones that survive, exhibit decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration; phenotypes characteristic of other mouse models deficient in DNA repair. The livers from Nrmt1(-/-) mice produce less reactive oxygen species (ROS) than wild type controls, and Nrmt1(-/-) mouse embryonic fibroblasts show a decreased capacity for handling oxidative damage. This indicates that decreased mitochondrial function may benefit Nrmt1(-/-) mice and protect them from excess internal ROS and subsequent DNA damage. These studies position the NRMT1 knockout mouse as a useful new system for studying the effects of genomic instability and defective DNA damage repair on organismal and tissue-specific aging.

  11. Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice

    PubMed Central

    de Waard, Monique C.; Zuiderveen Borgesius, Nils; Comley, Laura H.; Haasdijk, Elize D.; Rijksen, Yvonne; Ridwan, Yanto; Zondag, Gerben; Hoeijmakers, Jan H. J.; Elgersma, Ype; Gillingwater, Thomas H.

    2010-01-01

    Degeneration of motor neurons contributes to senescence-associated loss of muscle function and underlies human neurodegenerative conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors contributing to motor neuron vulnerability and degenerative phenotypes in vivo are therefore important for our understanding of the neuromuscular system in health and disease. Here, we analyzed neurodegenerative abnormalities in the spinal cord of progeroid Ercc1Δ/− mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1Δ/− mice develop age-dependent motor abnormalities, and have a shortened life span of 6–7 months. Pathologically, Ercc1Δ/− mice develop widespread astrocytosis and microgliosis, and motor neuron loss and denervation of skeletal muscle fibers. Degenerating motor neurons in many occasions expressed genotoxic-responsive transcription factors p53 or ATF3, and in addition, displayed a range of Golgi apparatus abnormalities. Furthermore, Ercc1Δ/− motor neurons developed perikaryal and axonal intermediate filament abnormalities reminiscent of cytoskeletal pathology observed in aging spinal cord. Our findings support the notion that accumulation of DNA damage and genotoxic stress may contribute to neuronal aging and motor neuron vulnerability in human neuromuscular disorders. Electronic supplementary material The online version of this article (doi:10.1007/s00401-010-0715-9) contains supplementary material, which is available to authorized users. PMID:20602234

  12. Modulating mTOR in aging and health.

    PubMed

    Johnson, Simon C; Sangesland, Maya; Kaeberlein, Matt; Rabinovitch, Peter S

    2015-01-01

    The physiological responses to nutrient availability play a central role in aging and disease. Genetic and pharmacological studies have identified highly conserved cellular signaling pathways that influence aging by regulating the interface between nutrient and hormone cues and cellular growth and maintenance. Among these pathways, the mechanistic target of rapamycin (mTOR) has been most reproducibly shown to modulate aging in evolutionarily diverse organisms as reduction in mTOR activity extends life span from yeast to rodents. mTOR has been shown to play a role in a broad range of diseases, and is of particular interest to human health and aging due to the availability of clinically approved pharmacological agents targeting the mTOR complexes and other components of the mTOR signaling network. Characterizing the role of mTOR in aging and health promises to provide new avenues for intervention in human aging and disease through modulation of this signaling pathway.

  13. Repair bond strength in aged methacrylate- and silorane-based composites.

    PubMed

    Bacchi, Atais; Consani, Rafael Leonardo; Sinhoreti, Mario Alexandre; Feitosa, Victor Pinheiro; Cavalcante, Larissa Maria; Pfeifer, Carmem Silva; Schneider, Luis Felipe

    2013-10-01

    To evaluate the tensile bond strength at repaired interfaces of aged dental composites, either dimethacrylate- or silorane-based, when subjected to different surface treatments. The composites used were Filtek P60 (methacrylate-based, 3M ESPE) and Filtek P90 (silorane-based, 3M ESPE), of which 50 slabs were stored for 6 months at 37°C. The surface of adhesion was abraded with a 600-grit silicone paper and the slabs repaired with the respective composite, according to the following surface treatment protocols: G1: no treatment; G2: adhesive application; G3: silane + adhesive; G4: sandblasting (Al2O3) + adhesive; G5: sandblasting (Al2O3) + silane + adhesive. After 24-h storage in distilled water at 37°C, tensile bond strength (TBS) was determined in a universal testing machine (Instron 4411) at a crosshead speed of 0.5 mm/min. The original data were submitted to two-way ANOVA and Tukey's test (α = 5%). The methacrylate-based composite presented a statistically significantly higher repair potential than did the silorane-based resin (p = 0.0002). Of the surface treatments for the silorane-based composite, aluminum-oxide air abrasion and adhesive (18.5 ± 3.3MPa) provided higher bond strength than only adhesive application or the control group without surface treatment. For Filtek P60, the control without treatment presented lower repair strength than all other groups with surface treatments, which were statistically similar to each other. The interaction between the factors resin composite and surface treatment was significant (p = 0.002). For aged silorane-based materials, repairs were considered successful after sandblasting (Al2O3) and adhesive application. For methacrylate resin, repair was successful with all surface treatments tested.

  14. Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration

    PubMed Central

    Painter, Michio W.; Brosius Lutz, Amanda; Cheng, Yung-Chih; Latremoliere, Alban; Duong, Kelly; Miller, Christine M.; Posada, Sean; Cobos, Enrique J.; Zhang, Alice X.; Wagers, Amy J.; Havton, Leif A.; Barres, Ben; Omura, Takao

    2014-01-01

    SUMMARY The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month old mice exhibit an impairment of functional recovery after nerve injury compared to 2-month old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro nor in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired de-differentiation, myelin clearance and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance. PMID:25033179

  15. Triple nanoemulsion potentiates the effects of topical treatments with microencapsulated retinol and modulates biological processes related to skin aging.

    PubMed

    Afornali, Alessandro; Vecchi, Rodrigo de; Stuart, Rodrigo Makowiecky; Dieamant, Gustavo; Oliveira, Luciana Lima de; Brohem, Carla Abdo; Feferman, Israel Henrique Stokfisz; Fabrício, Lincoln Helder Zambaldi; Lorencini, Márcio

    2013-01-01

    The sum of environmental and genetic factors affects the appearance and function of the skin as it ages. The identification of molecular changes that take place during skin aging provides biomarkers and possible targets for therapeutic intervention. Retinoic acid in different formulations has emerged as an alternative to prevent and repair age-related skin damage. To understand the effects of different retinoid formulations on the expression of genes associated with biological processes that undergo changes during skin aging. Ex-vivo skin samples were treated topically with different retinoid formulations. The modulation of biological processes associated with skin aging was measured by Reverse Transcription quantitative PCR (RT-qPCR). A formulation containing microencapsulated retinol and a blend of active ingredients prepared as a triple nanoemulsion provided the best results for the modulation of biological, process-related genes that are usually affected during skin aging. This association proved to be therapeutically more effective than tretinoin or microencapsulated retinol used singly.

  16. Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair.

    PubMed

    Borgesius, Nils Z; de Waard, Monique C; van der Pluijm, Ingrid; Omrani, Azar; Zondag, Gerben C M; van der Horst, Gijsbertus T J; Melton, David W; Hoeijmakers, Jan H J; Jaarsma, Dick; Elgersma, Ype

    2011-08-31

    Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1(Δ/-) mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.

  17. NDR1 modulates the UV-induced DNA-damage checkpoint and nucleotide excision repair

    SciTech Connect

    Park, Jeong-Min; Choi, Ji Ye; Yi, Joo Mi; Chung, Jin Woong; Leem, Sun-Hee; Koh, Sang Seok; Kang, Tae-Hong

    2015-06-05

    Nucleotide excision repair (NER) is the sole mechanism of UV-induced DNA lesion repair in mammals. A single round of NER requires multiple components including seven core NER factors, xeroderma pigmentosum A–G (XPA–XPG), and many auxiliary effector proteins including ATR serine/threonine kinase. The XPA protein helps to verify DNA damage and thus plays a rate-limiting role in NER. Hence, the regulation of XPA is important for the entire NER kinetic. We found that NDR1, a novel XPA-interacting protein, modulates NER by modulating the UV-induced DNA-damage checkpoint. In quiescent cells, NDR1 localized mainly in the cytoplasm. After UV irradiation, NDR1 accumulated in the nucleus. The siRNA knockdown of NDR1 delayed the repair of UV-induced cyclobutane pyrimidine dimers in both normal cells and cancer cells. It did not, however, alter the expression levels or the chromatin association levels of the core NER factors following UV irradiation. Instead, the NDR1-depleted cells displayed reduced activity of ATR for some set of its substrates including CHK1 and p53, suggesting that NDR1 modulates NER indirectly via the ATR pathway. - Highlights: • NDR1 is a novel XPA-interacting protein. • NDR1 accumulates in the nucleus in response to UV irradiation. • NDR1 modulates NER (nucleotide excision repair) by modulating the UV-induced DNA-damage checkpoint response.

  18. Direct and indirect roles of RECQL4 in modulating base excision repair capacity.

    PubMed

    Schurman, Shepherd H; Hedayati, Mohammad; Wang, ZhengMing; Singh, Dharmendra K; Speina, Elzbieta; Zhang, Yongqing; Becker, Kevin; Macris, Margaret; Sung, Patrick; Wilson, David M; Croteau, Deborah L; Bohr, Vilhelm A

    2009-09-15

    RECQL4 is a human RecQ helicase which is mutated in approximately two-thirds of individuals with Rothmund-Thomson syndrome (RTS), a disease characterized at the cellular level by chromosomal instability. BLM and WRN are also human RecQ helicases, which are mutated in Bloom and Werner's syndrome, respectively, and associated with chromosomal instability as well as premature aging. Here we show that primary RTS and RECQL4 siRNA knockdown human fibroblasts accumulate more H(2)O(2)-induced DNA strand breaks than control cells, suggesting that RECQL4 may stimulate repair of H(2)O(2)-induced DNA damage. RTS primary fibroblasts also accumulate more XRCC1 foci than control cells in response to endogenous or induced oxidative stress and have a high basal level of endogenous formamidopyrimidines. In cells treated with H(2)O(2), RECQL4 co-localizes with APE1, and FEN1, key participants in base excision repair. Biochemical experiments indicate that RECQL4 specifically stimulates the apurinic endonuclease activity of APE1, the DNA strand displacement activity of DNA polymerase beta, and incision of a 1- or 10-nucleotide flap DNA substrate by Flap Endonuclease I. Additionally, RTS cells display an upregulation of BER pathway genes and fail to respond like normal cells to oxidative stress. The data herein support a model in which RECQL4 regulates both directly and indirectly base excision repair capacity.

  19. Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging

    PubMed Central

    Singh, Dharmendra Kumar; Ahn, Byungchan

    2009-01-01

    The maintenance of the stability of genetic material is an essential feature of every living organism. Organisms across all kingdoms have evolved diverse and highly efficient repair mechanisms to protect the genome from deleterious consequences of various genotoxic factors that might tend to destabilize the integrity of the genome in each generation. One such group of proteins that is actively involved in genome surveillance is the RecQ helicase family. These proteins are highly conserved DNA helicases, which have diverse roles in multiple DNA metabolic processes such as DNA replication, recombination and DNA repair. In humans, five RecQ helicases have been identified and three of them namely, WRN, BLM and RecQL4 have been linked to genetic diseases characterized by genome instability, premature aging and cancer predisposition. This helicase family plays important roles in various DNA repair pathways including protecting the genome from illegitimate recombination during chromosome segregation in mitosis and assuring genome stability. This review mainly focuses on various roles of human RecQ helicases in the process of recombination-based DNA repair to maintain genome stability and physiological consequences of their defects in the development of cancer and premature aging. PMID:19083132

  20. Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging.

    PubMed

    Singh, Dharmendra Kumar; Ahn, Byungchan; Bohr, Vilhelm A

    2009-06-01

    The maintenance of the stability of genetic material is an essential feature of every living organism. Organisms across all kingdoms have evolved diverse and highly efficient repair mechanisms to protect the genome from deleterious consequences of various genotoxic factors that might tend to destabilize the integrity of the genome in each generation. One such group of proteins that is actively involved in genome surveillance is the RecQ helicase family. These proteins are highly conserved DNA helicases, which have diverse roles in multiple DNA metabolic processes such as DNA replication, recombination and DNA repair. In humans, five RecQ helicases have been identified and three of them namely, WRN, BLM and RecQL4 have been linked to genetic diseases characterized by genome instability, premature aging and cancer predisposition. This helicase family plays important roles in various DNA repair pathways including protecting the genome from illegitimate recombination during chromosome segregation in mitosis and assuring genome stability. This review mainly focuses on various roles of human RecQ helicases in the process of recombination-based DNA repair to maintain genome stability and physiological consequences of their defects in the development of cancer and premature aging.

  1. DNA repair diseases: What do they tell us about cancer and aging?

    PubMed

    Menck, Carlos Fm; Munford, Veridiana

    2014-03-01

    The discovery of DNA repair defects in human syndromes, initially in xeroderma pigmentosum (XP) but later in many others, led to striking observations on the association of molecular defects and patients' clinical phenotypes. For example, patients with syndromes resulting from defective nucleotide excision repair (NER) or translesion synthesis (TLS) present high levels of skin cancer in areas exposed to sunlight. However, some defects in NER also lead to more severe symptoms, such as developmental and neurological impairment and signs of premature aging. Skin cancer in XP patients is clearly associated with increased mutagenesis and genomic instability, reflecting the defective repair of DNA lesions. By analogy, more severe symptoms observed in NER-defective patients have also been associated with defective repair, likely involving cell death after transcription blockage of damaged templates. Endogenously induced DNA lesions, particularly through oxidative stress, have been identified as responsible for these severe pathologies. However, this association is not that clear and alternative explanations have been proposed. Despite high levels of exposure to intense sunlight, patients from tropical countries receive little attention or care, which likely also reflects the lack of understanding of how DNA damage causes cancer and premature aging.

  2. Repairing the Aged Parkinsonian Striatum: Lessons from the Lab and Clinic

    PubMed Central

    Mercado, Natosha M; Collier, Timothy J; Freeman, Thomas; Steece-Collier, Kathy

    2016-01-01

    The primary risk factor associated with Parkinson's disease (PD) is advanced age. While there are symptomatic therapies for PD, efficacy of these eventually wane and/or side-effects develop over time. An alternative experimental therapy that has received a great deal of attention over the past several decades has been neural transplantation aimed at replacing nigral dopamine (DA) neurons that degenerate in PD. However, in PD patients and parkinsonian rats, advanced age is associated with inferior benefit following intrastriatal grafting of embryonic DA neurons. Traditionally it has been thought that decreased therapeutic benefit results from the decreased survival of grafted DA neurons and the accompanying poor reinnervation observed in the aged host. However, recent clinical and preclinical data suggest that factors inherent to the aged striatum per se limit successful brain repair. In this short communication, we focus discussion on the implications of our recent grafting study in aged parkinsonian rats, with additional emphasis on a recent clinical report of the outcome of cell therapy in an aged PD patient with long-term (24 years) survival of DA neuron grafts. To address aging as a limiting factor in successful brain repair, we use the example of cell transplantation as a means to interrogate the environment of the aged striatum and identify factors that may, or may not, respond to interventions aimed at improving the prospects for adequate repair of the aged brain. We offer discussion of how these recent reports, in the context of other historical grafting studies, might provide new insight into specific risk factors that have potential to negatively impact all DA cell or terminal replacement strategies for clinical use in PD. PMID:28111608

  3. Repairing the Aged Parkinsonian Striatum: Lessons from the Lab and Clinic.

    PubMed

    Mercado, Natosha M; Collier, Timothy J; Freeman, Thomas; Steece-Collier, Kathy

    2016-12-01

    The primary risk factor associated with Parkinson's disease (PD) is advanced age. While there are symptomatic therapies for PD, efficacy of these eventually wane and/or side-effects develop over time. An alternative experimental therapy that has received a great deal of attention over the past several decades has been neural transplantation aimed at replacing nigral dopamine (DA) neurons that degenerate in PD. However, in PD patients and parkinsonian rats, advanced age is associated with inferior benefit following intrastriatal grafting of embryonic DA neurons. Traditionally it has been thought that decreased therapeutic benefit results from the decreased survival of grafted DA neurons and the accompanying poor reinnervation observed in the aged host. However, recent clinical and preclinical data suggest that factors inherent to the aged striatum per se limit successful brain repair. In this short communication, we focus discussion on the implications of our recent grafting study in aged parkinsonian rats, with additional emphasis on a recent clinical report of the outcome of cell therapy in an aged PD patient with long-term (24 years) survival of DA neuron grafts. To address aging as a limiting factor in successful brain repair, we use the example of cell transplantation as a means to interrogate the environment of the aged striatum and identify factors that may, or may not, respond to interventions aimed at improving the prospects for adequate repair of the aged brain. We offer discussion of how these recent reports, in the context of other historical grafting studies, might provide new insight into specific risk factors that have potential to negatively impact all DA cell or terminal replacement strategies for clinical use in PD.

  4. Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review).

    PubMed

    Bertin, G; Averbeck, D

    2006-11-01

    Cadmium is an important toxic environmental heavy metal. Occupational and environmental pollution with cadmium results mainly from mining, metallurgy industry and manufactures of nickel-cadmium batteries, pigments and plastic stabilizers. Important sources of human intoxication are cigarette smoke as well as food, water and air contaminations. In humans, cadmium exposures have been associated with cancers of the prostate, lungs and testes. Acute exposures are responsible for damage to these organs. Chronic intoxication is associated with obstructive airway disease, emphysema, irreversible renal failure, bone disorders and immuno-suppression. At the cellular level, cadmium affects proliferation, differentiation and causes apoptosis. It has been classified as a carcinogen by the International Agency for Research on Cancer (IARC). However, it is weakly genotoxic. Indirect effects of cadmium provoke generation of reactive oxygen species (ROS) and DNA damage. Cadmium modulates also gene expression and signal transduction, reduces activities of proteins involved in antioxidant defenses. Several studies have shown that it interferes with DNA repair. The present review focuses on the effects of cadmium in mammalian cells with special emphasis on the induction of damage to DNA, membranes and proteins, the inhibition of different types of DNA repair and the induction of apoptosis. Current data and hypotheses on the mechanisms involved in cadmium genotoxicity and carcinogenesis are outlined.

  5. Repair Bond Strength of Aged Resin Composite after Different Surface and Bonding Treatments

    PubMed Central

    Wendler, Michael; Belli, Renan; Panzer, Reinhard; Skibbe, Daniel; Petschelt, Anselm; Lohbauer, Ulrich

    2016-01-01

    The aim of this study was to compare the effect of different mechanical surface treatments and chemical bonding protocols on the tensile bond strength (TBS) of aged composite. Bar specimens were produced using a nanohybrid resin composite and aged in distilled water for 30 days. Different surface treatments (diamond bur, phosphoric acid, silane, and sandblasting with Al2O3 or CoJet Sand), as well as bonding protocols (Primer/Adhesive) were used prior to application of the repair composite. TBS of the specimens was measured and the results were analyzed using analysis of variance (ANOVA) and the Student–Newman–Keuls test (α = 0.05). Mechanically treated surfaces were characterized under SEM and by profilometry. The effect of water aging on the degree of conversion was measured by means of FTIR-ATR spectroscopy. An important increase in the degree of conversion was observed after aging. No significant differences in TBS were observed among the mechanical surface treatments, despite variations in surface roughness profiles. Phosphoric acid etching significantly improved repair bond strength values. The cohesive TBS of the material was only reached using resin bonding agents. Application of an intermediate bonding system plays a key role in achieving reliable repair bond strengths, whereas the kind of mechanical surface treatment appears to play a secondary role. PMID:28773669

  6. The role of age and comorbidities in postoperative outcome of mitral valve repair

    PubMed Central

    Bonnet, Vincent; Boisselier, Clément; Saplacan, Vladimir; Belin, Annette; Gérard, Jean-Louis; Fellahi, Jean-Luc; Hanouz, Jean-Luc; Fischer, Marc-Olivier

    2016-01-01

    Abstract The average age of patients undergoing mitral valve repair is increasing each year. This retrospective study aimed to compare postoperative complications of mitral valve repair (known to be especially high-risk) between 2 age groups: under and over the age of 80. Patients who underwent mitral valve repair were divided into 2 groups: group 1 (<80 years old) and group 2 (≥80 years old). Baseline characteristics, pre- and postoperative hemodynamic data, surgical characteristics, and postoperative follow-up data until hospital discharge were collected. A total of 308 patients were included: 264 in group 1 (age 63 ± 13 years) and 44 in group 2 (age 83 ± 2 years). Older patients had more comorbidities (atrial fibrillation, history of cardiac decompensation, systemic hypertension, pulmonary hypertension, and chronic kidney disease) and they presented more postoperative complications (50.0% vs 33.7%; P = 0.043), with a longer hospital stay (8.9 ± 6.9 vs 6.6 ± 4.6 days; P = 0.005). To assess the burden of age, a propensity score was awarded to postoperative complications. Active smoking, chronic pulmonary disease, chronic kidney disease, associated ischemic heart disease, obesity, and cardio pulmonary by-pass duration were described as independent risk factors. When matched on this propensity score, there was no difference in morbidity or mortality between group 1 and group 2. Older patients suffered more postoperative complications, which were related to their comorbidities and not only to their age. PMID:27336886

  7. Comparison of arthroscopic rotator cuff repair in healthy patients over and under 65 years of age.

    PubMed

    Osti, Leonardo; Papalia, Rocco; Del Buono, Angelo; Denaro, Vincenzo; Maffulli, Nicola

    2010-12-01

    We compared the outcomes of arthroscopically repaired rotator cuff tears in 28 patients older than 65 years (the over 65 group: median age 70 years) with a control group of 28 patients younger than 65 years (the under 65 group: median age 57 years). The groups were similar in regard to sex distribution, surgical technique, and post-operative rehabilitation programmes, but different in age. After careful arthroscopic evaluation of the full-thickness rotator cuff tear, rotator cuff repair and biceps tenotomy were performed in all patients. Pre- and post-operatively, each patient was evaluated for range of motion, shoulder score (UCLA), and SF-36 self-administered questionnaire. Comparing pre- versus post-operative status at a minimum 24 months follow-up, forward elevation, internal and external rotation, modified UCLA rating system scores, and SF-36 scores improved significantly in both groups, with no significant difference between the groups. At the last follow-up, strength improved significantly in both groups, with non-significant intergroup difference. The Popeye sign was detected in 13/28 (46%) of the patients in the over 65 group and in 11/28 (39%) in the under 65 group (χ = 0.29) with non-significant difference between the two groups. In selected active patients older than 65, arthroscopic rotator cuff repair associated with biceps tenotomy (when necessary) can yield clinical and related quality of life outcomes similar to those of patients younger than 65 years.

  8. Cyclin A2 promotes DNA repair in the brain during both development and aging

    PubMed Central

    Gygli, Patrick E.; Chang, Joshua C.; Gokozan, Hamza N.; Catacutan, Fay P.; Schmidt, Theresa A.; Kaya, Behiye; Goksel, Mustafa; Baig, Faisal S.; Chen, Shannon; Griveau, Amelie; Michowski, Wojciech; Wong, Michael; Palanichamy, Kamalakannan; Sicinski, Piotr; Nelson, Randy J.; Czeisler, Catherine; Otero, José J.

    2016-01-01

    Various stem cell niches of the brain have differential requirements for Cyclin A2. Cyclin A2 loss results in marked cerebellar dysmorphia, whereas forebrain growth is retarded during early embryonic development yet achieves normal size at birth. To understand the differential requirements of distinct brain regions for Cyclin A2, we utilized neuroanatomical, transgenic mouse, and mathematical modeling techniques to generate testable hypotheses that provide insight into how Cyclin A2 loss results in compensatory forebrain growth during late embryonic development. Using unbiased measurements of the forebrain stem cell niche, we parameterized a mathematical model whereby logistic growth instructs progenitor cells as to the cell-types of their progeny. Our data was consistent with prior findings that progenitors proliferate along an auto-inhibitory growth curve. The growth retardation in CCNA2-null brains corresponded to cell cycle lengthening, imposing a developmental delay. We hypothesized that Cyclin A2 regulates DNA repair and that CCNA2-null progenitors thus experienced lengthened cell cycle. We demonstrate that CCNA2-null progenitors suffer abnormal DNA repair, and implicate Cyclin A2 in double-strand break repair. Cyclin A2's DNA repair functions are conserved among cell lines, neural progenitors, and hippocampal neurons. We further demonstrate that neuronal CCNA2 ablation results in learning and memory deficits in aged mice. PMID:27425845

  9. Involvement of oxidatively damaged DNA and repair in cancer development and aging

    PubMed Central

    Tudek, Barbara; Winczura, Alicja; Janik, Justyna; Siomek, Agnieszka; Foksinski, Marek; Oliński, Ryszard

    2010-01-01

    DNA damage and DNA repair may mediate several cellular processes, like replication and transcription, mutagenesis and apoptosis and thus may be important factors in the development and pathology of an organism, including cancer. DNA is constantly damaged by reactive oxygen species (ROS) and reactive nitrogen species (RNS) directly and also by products of lipid peroxidation (LPO), which form exocyclic adducts to DNA bases. A wide variety of oxidatively-generated DNA lesions are present in living cells. 8-oxoguanine (8-oxoGua) is one of the best known DNA lesions due to its mutagenic properties. Among LPO-derived DNA base modifications the most intensively studied are ethenoadenine and ethenocytosine, highly miscoding DNA lesions considered as markers of oxidative stress and promutagenic DNA damage. Although at present it is impossible to directly answer the question concerning involvement of oxidatively damaged DNA in cancer etiology, it is likely that oxidatively modified DNA bases may serve as a source of mutations that initiate carcinogenesis and are involved in aging (i.e. they may be causal factors responsible for these processes). To counteract the deleterious effect of oxidatively damaged DNA, all organisms have developed several DNA repair mechanisms. The efficiency of oxidatively damaged DNA repair was frequently found to be decreased in cancer patients. The present work reviews the basis for the biological significance of DNA damage, particularly effects of 8-oxoGua and ethenoadduct occurrence in DNA in the aspect of cancer development, drawing attention to the multiplicity of proteins with repair activities. PMID:20589166

  10. One-year outcomes following repair of thoracoabdominal aneurysms with the multilayer flow modulator: report from the STRATO trial.

    PubMed

    Vaislic, Claude D; Fabiani, Jean Noël; Chocron, Sidney; Robin, Jacques; Costache, Victor S; Villemot, Jean-Pierre; Alsac, Jean Marc; Leprince, Pascal N; Unterseeh, Thierry; Portocarrero, Eric; Glock, Yves; Rousseau, Hervé

    2014-02-01

    To evaluate endovascular repair of type II and III thoracoabdominal aortic aneurysms (TAAA) using the Multilayer Flow Modulator (MFM) in patients with contraindications for open surgery and fenestrated stent-grafts. In this prospective, multicenter, nonrandomized trial (EudraCT registration: 2009-013678-42; ClinicalTrials.gov identifier NCT01756911), 23 patients (19 men; mean age 75.8 years) with Crawford type II (43.5%) and III (56.5%) TAAA (mean diameter 6.5 cm) were treated with the MFM between April 2010 and February 2011. The primary efficacy outcome measure was stable aneurysm thrombosis with associated branch vessel patency at 12 months; the primary safety endpoint was 30-day and 12-month all-cause mortality. The rate of technical success was 100%. In 20 patients with computed tomography scans at 12 months, the primary efficacy outcome was met in 15 patients. The rate of primary patency of covered branch vessels was 96% (53/55); 1 patient with 2 occluded visceral branches underwent successful surgical reintervention. Endoleaks were identified in 5 patients (3 attachment site and 2 at device overlap), 4 of whom underwent reintervention (3 additional MFMs and 1 stent-graft implanted). At 12 months, aneurysm diameter was stable in 18 of 20 patients; the mean ratio of residual aneurysm flow volume to total volume had decreased by 28.9%, and the mean ratio of thrombus volume to total lumen volume had increased by 21.3% (n=17). There were no cases of device migration, loss of device integrity, spinal cord ischemia, or aneurysm rupture. At 1 year, endovascular repair with the MFM appears to be safe and effective while successfully maintaining branch vessel patency. Follow-up is ongoing.

  11. The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition.

    PubMed

    Mosyak, Lidia; Wood, Andrew; Dwyer, Brian; Buddha, Madhavan; Johnson, Mark; Aulabaugh, Ann; Zhong, Xiaotian; Presman, Eleonora; Benard, Susan; Kelleher, Kerry; Wilhelm, James; Stahl, Mark L; Kriz, Ron; Gao, Ying; Cao, Zixuan; Ling, Huai-Ping; Pangalos, Menelas N; Walsh, Frank S; Somers, William S

    2006-11-24

    Nogo receptor (NgR)-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1. Interactions between Lingo-1 and NgR, along with a complementary co-receptor, result in neurite and axonal collapse. In addition, the inhibitory role of Lingo-1 is particularly important in regulation of oligodendrocyte differentiation and myelination, suggesting that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Here we report on the crystal structure of the ligand-binding ectodomain of human Lingo-1 and show it has a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. The structure, together with biophysical analysis of its solution properties, reveals that in the crystals and in solution Lingo-1 persistently associates with itself to form a stable tetramer and that it is its LRR-Ig-composite fold that drives such assembly. Specifically, in the crystal structure protomers of Lingo-1 associate in a ring-shaped tetramer, with each LRR domain filling an open cleft in an adjacent protomer. The tetramer buries a large surface area (9,200 A2) and may serve as an efficient scaffold to simultaneously bind and assemble the NgR complex components during activation on a membrane. Potential functional binding sites that can be identified on the ectodomain surface, including the site of self-recognition, suggest a model for protein assembly on the membrane.

  12. The Protein Oxidation Repair Enzyme Methionine Sulfoxide Reductase A Modulates Aβ Aggregation and Toxicity In Vivo

    PubMed Central

    Minniti, Alicia N.; Arrazola, Macarena S.; Bravo-Zehnder, Marcela; Ramos, Francisca; Inestrosa, Nibaldo C.

    2015-01-01

    Abstract Aims: To examine the role of the enzyme methionine sulfoxide reductase A-1 (MSRA-1) in amyloid-β peptide (Aβ)-peptide aggregation and toxicity in vivo, using a Caenorhabditis elegans model of the human amyloidogenic disease inclusion body myositis. Results: MSRA-1 specifically reduces oxidized methionines in proteins. Therefore, a deletion of the msra-1 gene was introduced into transgenic C. elegans worms that express the Aβ-peptide in muscle cells to prevent the reduction of oxidized methionines in proteins. In a constitutive transgenic Aβ strain that lacks MSRA-1, the number of amyloid aggregates decreases while the number of oligomeric Aβ species increases. These results correlate with enhanced synaptic dysfunction and mislocalization of the nicotinic acetylcholine receptor ACR-16 at the neuromuscular junction (NMJ). Innovation: This approach aims at modulating the oxidation of Aβ in vivo indirectly by dismantling the methionine sulfoxide repair system. The evidence presented here shows that the absence of MSRA-1 influences Aβ aggregation and aggravates locomotor behavior and NMJ dysfunction. The results suggest that therapies which boost the activity of the Msr system could have a beneficial effect in managing amyloidogenic pathologies. Conclusion: The absence of MSRA-1 modulates Aβ-peptide aggregation and increments its deleterious effects in vivo. Antioxid. Redox Signal. 22, 48–62. PMID:24988428

  13. Repair of full-thickness rotator cuff tears in patients aged younger than 55 years.

    PubMed

    MacKechnie, Michael A K; Chahal, Jaskarndip; Wasserstein, David; Theodoropoulos, John S; Henry, Patrick; Dwyer, Tim

    2014-10-01

    The purpose of this study was to conduct a systematic review of the available evidence regarding clinical outcomes after open or arthroscopic repair of full-thickness rotator cuff tears in young patients. Medline, PubMed, and Embase were reviewed to find all studies examining full-thickness rotator cuff repairs in patients aged younger than 55 years and with a minimum of 1 year of follow-up. We found 7 studies that met the inclusion criteria. The mean patient age was 41.7 years (range, 16.2 to 54 years), and the mean time from injury was 66.1 months. Eighty-one percent of the included patients had a traumatic tear. The rotator cuff repair was supplemented by acromioplasty in 96.6% of patients, distal clavicle resection in 34.6%, and biceps tenodesis in 16.1%. Postoperative American Shoulder and Elbow Surgeons Standardized Shoulder Assessment was the most commonly reported outcome score, with a mean postoperative score of 82.0 (4 studies). Improvement was shown in all studies that reported on postoperative strength. All studies that assessed pain showed an improvement in the postoperative setting. Overall, 82% of the shoulders had satisfactory results. Full-thickness rotator cuff tears in patients aged younger than 55 years are mostly traumatic in origin and respond well to open and arthroscopic rotator cuff repair, as shown by good patient-reported outcomes, significant pain relief, improvement in strength, and high satisfaction postoperatively. Level IV, systematic review of Level IV studies. Copyright © 2014 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

  14. The role of aging and DNA repair in chronic disease. Final progress report, December 1, 1985--September 29, 1993

    SciTech Connect

    Grossman, L.

    1993-11-01

    We carried out a molecular epidemiological study of the DNA repair of photochemical damage as a risk factor in basal cell carcinoma (BCC). In that clinic-based control study of 88 cases and 135 cancer-free control it was found that DNA repair in the controls declined linearly at a rate of 0.61% per year over a 30-60 year age group. However, repair in younger BCC cases, significantly less than their age-matched controls, did not decline at the same rate so that the repair differences between the cases and the controls disappeared as the cases grew older. Besides this age effect, the odds are high (5:1) that an individual with low repair overexposed to sunlight will have basal cell carcinoma. That these odds increase to 10:1 for females compared to male subjects led to the observation that repair may be sensitive to hormonal control. Because of the ease of BCC diagnosis it is possible to demonstrate significantly that the level of DNA repair directly influences the multiplicity of tumors. Further, both those cases and controls with a family history of BCC invariably have reduced levels of DNA repair (p<0-05).

  15. Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice.

    PubMed

    Diderich, Karin E M; Nicolaije, Claudia; Priemel, Matthias; Waarsing, Jan H; Day, Judd S; Brandt, Renata M C; Schilling, Arndt F; Botter, Sander M; Weinans, Harrie; van der Horst, Gijsbertus T J; Hoeijmakers, Jan H J; van Leeuwen, Johannes P T M

    2012-08-01

    Trichothiodystrophy (TTD) is a rare, autosomal recessive nucleotide excision repair (NER) disorder caused by mutations in components of the dual functional NER/basal transcription factor TFIIH. TTD mice, carrying a patient-based point mutation in the Xpd gene, strikingly resemble many features of the human syndrome and exhibit signs of premature aging. To examine to which extent TTD mice resemble the normal process of aging, we thoroughly investigated the bone phenotype. Here, we show that female TTD mice exhibit accelerated bone aging from 39 weeks onwards as well as lack of periosteal apposition leading to reduced bone strength. Before 39 weeks have passed, bones of wild-type and TTD mice are identical excluding a developmental defect. Albeit that bone formation is decreased, osteoblasts in TTD mice retain bone-forming capacity as in vivo PTH treatment leads to increased cortical thickness. In vitro bone marrow cell cultures showed that TTD osteoprogenitors retain the capacity to differentiate into osteoblasts. However, after 13 weeks of age TTD females show decreased bone nodule formation. No increase in bone resorption or the number of osteoclasts was detected. In conclusion, TTD mice show premature bone aging, which is preceded by a decrease in mesenchymal stem cells/osteoprogenitors and a change in systemic factors, identifying DNA damage and repair as key determinants for bone fragility by influencing osteogenesis and bone metabolism.

  16. Age stratified, perioperative, and one-year mortality after abdominal aortic aneurysm repair: a statewide experience.

    PubMed

    Rigberg, David A; Zingmond, David S; McGory, Marcia L; Maggard, Melinda A; Agustin, Michelle; Lawrence, Peter F; Ko, Clifford Y

    2006-02-01

    The purpose of this study was to determine the in-hospital, 30-day, and 365-day mortality for the open repair of abdominal aortic aneurysms (AAAs), when stratified by age, in the general population. Age stratification could provide clinicians with information more applicable to an individual patient than overall mortality figures. In a retrospective analysis, data were obtained from the California Office of Statewide Health Planning and Development (OSHPD) for the years 1995 to 1999. Out-of-hospital mortality was determined via linkage to the state death registry. All patients undergoing AAA repair as coded by International Classification of Diseases, 9th Revision (ICD-9) procedure code 38.44 and diagnosis codes 441.4 (intact) and 441.3/441.5 (ruptured) in California were identified. Patients <50 years of age were excluded. We determined in-hospital, 30-day, and 365-day mortality, and stratified our findings by patient age. Multivariate logistic regression was used to determine predictors of mortality in the intact and ruptured AAA cohorts. We identified 12,406 patients (9,778 intact, 2,628 ruptured). Mean patient age was 72.4 +/- 7.2 years (intact) and 73.9 +/- 8.2 (ruptured). Men comprised 80.9% of patients, and 90.8% of patients were white. Overall, intact AAA patient mortality was 3.8% in-hospital, 4% at 30 days, and 8.5% at 365 days. There was a steep increase in mortality with increasing age, such that 365-day mortality increased from 2.9% for patients 51 to 60 years old to 15% for patients 81 to 90 years old. Mortality from day 31 to 365 was greater than both in-hospital and 30-day mortality for all but the youngest intact AAA patients. Perioperative (in-hospital and 30-day) mortality for ruptured cases was 45%, and mortality at 1 year was 54%. There is continued mortality after the open repair of AAAs during postoperative days 31 to 365 that, for many patients, is greater than the perioperative death rate. This mortality increases dramatically with age for

  17. Insulin modulates inflammatory and repair responses to elastase-induced emphysema in diabetic rats.

    PubMed

    Di Petta, Antonio; Greco, Karin V; Castro, Eveline O; Lopes, Fernanda D T Q S; Martins, Milton A; Capelozzi, Vera L; Moreira, Luiz F P; Sannomiya, Paulina

    2011-12-01

    As pulmonary emphysema and diabetes mellitus are common diseases, concomitance of both is correspondingly expected to occur frequently. To examine whether insulin influences the development of inflammation in the alveolar septa, diabetic male Wistar rats (alloxan, 42 mg/kg, i.v., n = 37) and matching controls (n = 31) were used. Ten days after alloxan injection, diabetic and control rats were instilled with physiologic saline solution containing porcine pancreatic elastase (PPE, 0.25 IU/0.2 ml, right lung) or saline only (left lung). The following analyses were performed: (i) number of leucocytes in the bronchoalveolar lavage (BAL) fluid of the animals, 6 h after PPE/saline instillation (early time point); and (ii) mean alveolar diameter (μm) and quantification of elastic and collagen fibres (%) 50 days after PPE/saline instillation (late time point). Relative to controls, alloxan-induced diabetic rats showed a 42% reduction in the number of neutrophils in BAL fluid, a 20% increase in the mean alveolar diameter and a 33% decrease in elastic fibre density in the alveolar septa. Treatment of diabetic rats with 4 IU neutral protamine Hagedorn (NPH) insulin, 2 h before elastase instillation, restored the number of neutrophils in the BAL fluid. The mean alveolar diameter and elastic fibre content in alveolar septa matched the values observed in control rats if diabetic rats were treated with 4 IU NPH insulin 2 h before instillation followed by 2 IU/day for the next 50 days. Density of collagen fibres did not differ between the various groups. Thus, the data presented suggest that insulin modulates the inflammatory and repair responses in elastase-induced emphysema, and assures normal repair and tissue remodelling.

  18. Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: Molecules to patients

    PubMed Central

    Niedernhofer, Laura J.; Bohr, Vilhelm A.; Sander, Miriam; Kraemer, Kenneth H.

    2012-01-01

    A workshop1 to share, consider and discuss the latest developments in understanding xeroderma pigmentosum and other human diseases caused by defects in nucleotide excision repair (NER) of DNA damage was held on September 21–24, 2010 in Virginia. It was attended by approximately 100 researchers and clinicians, as well as several patients and representatives of patient support groups. This was the third in a series of workshops with similar design and goals: to emphasize discussion and interaction among participants as well as open exchange of information and ideas. The participation of patients, their parents and physicians was an important feature of this and the preceding two workshops. Topics discussed included the natural history and clinical features of the diseases, clinical and laboratory diagnosis of these rare diseases, therapeutic strategies, mouse models of neurodegeneration, molecular analysis of accelerated aging, impact of transcriptional defects and mitochondrial dysfunction on neurodegeneration, and biochemical insights into mechanisms of NER and base excision repair. PMID:21708183

  19. Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: molecules to patients.

    PubMed

    Niedernhofer, Laura J; Bohr, Vilhelm A; Sander, Miriam; Kraemer, Kenneth H

    2011-01-01

    A workshop(1) to share, consider and discuss the latest developments in understanding xeroderma pigmentosum and other human diseases caused by defects in nucleotide excision repair (NER) of DNA damage was held on September 21-24, 2010 in Virginia. It was attended by approximately 100 researchers and clinicians, as well as several patients and representatives of patient support groups. This was the third in a series of workshops with similar design and goals: to emphasize discussion and interaction among participants as well as open exchange of information and ideas. The participation of patients, their parents and physicians was an important feature of this and the preceding two workshops. Topics discussed included the natural history and clinical features of the diseases, clinical and laboratory diagnosis of these rare diseases, therapeutic strategies, mouse models of neurodegeneration, molecular analysis of accelerated aging, impact of transcriptional defects and mitochondrial dysfunction on neurodegeneration, and biochemical insights into mechanisms of NER and base excision repair.

  20. A mouse model of accelerated liver aging due to a defect in DNA repair

    PubMed Central

    Gregg, Siobhán Q.; Gutiérrez, Verónica; Robinson, Andria Rasile; Woodell, Tyler; Nakao, Atsunori; Ross, Mark A.; Michalopoulos, George K.; Rigatti, Lora; Rothermel, Carrie E.; Kamileri, Irene; Garinis, George; Stolz, Donna Beer; Niedernhofer, Laura J.

    2011-01-01

    The liver changes with age leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging-related liver changes. One potential opportunity is murine models of human progerias, or diseases of accelerated aging. Ercc1−/Δ mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine if hepatic changes that occur with normal aging occur prematurely in Ercc1−/Δ mice, we systematically compared liver from 5 month-old, progeroid Ercc1−/Δ mice to old (24–36 month) wild-type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in Ercc1−/Δ mice than in old WT mice. Liver enzymes were significantly elevated in serum of Ercc1−/Δ mice and old WT mice, while albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of Ercc1−/Δ liver following partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in Ercc1−/Δ and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein as well as increased hepatocellular senescence. There was a highly significant correlation in genome-wide transcriptional changes between old WT and 16 but not 5 week-old Ercc1−/Δ mice emphasizing that the Ercc1−/Δ mice acquire an aging profile in early adulthood. Conclusion There are strong functional, regulatory and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging-related hepatic changes. PMID:21953681

  1. Diet restriction delays accelerated aging and genomic stress in DNA repair deficient mice

    PubMed Central

    Vermeij, W.P.; Dollé, M.E.T.; Reiling, E.; Jaarsma, D.; Payan-Gomez, C.; Bombardieri, C.R.; Wu, H.; Roks, A.J.M.; Botter, S.M.; van der Eerden, B.C.; Youssef, S.A.; Kuiper, R.V.; Nagarajah, B.; van Oostrom, C.T.; Brandt, R.M.C.; Barnhoorn, S.; Imholz, S.; Pennings, J.L.A.; de Bruin, A.; Gyenis, Á.; Pothof, J.; Vijg, J.; van Steeg, H.; Hoeijmakers, J.H.J.

    2016-01-01

    DNA repair-deficient Ercc1Δ/− mice show numerous accelerated aging features limiting lifespan to 4–6 month1–4. Simultaneously they exhibit a ‘survival response’, which suppresses growth and enhances maintenance, resembling the anti-aging response induced by dietary restriction (DR)1,5. Here we report that subjecting these progeroid, dwarf mutants to 30% DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated aging, e.g. DR animals retained 50% more neurons and maintained full motoric function, even far beyond the lifespan of ad libitum (AL) animals. Repair-deficient, progeroid Xpg−/− mice, a Cockayne syndrome model6, responded similarly, extending this observation to other repair mutants. The DR response in Ercc1Δ/− mice closely resembled DR in wild type animals. Interestingly, AL Ercc1Δ/− liver showed preferential extinction of expression of long genes, a phenomenon we also observe in several normal aging tissues. This is consistent with accumulation of stochastic, transcription-blocking lesions, affecting long genes more than short ones. DR largely prevented declining transcriptional output and reduced γH2AX DNA damage foci, indicating that DR preserves genome function by alleviating DNA damage. Our findings establish Ercc1Δ/− mice as powerful model for interventions sustaining health, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general. PMID:27556946

  2. Carcinogenically relevant split dose repair increased with age in rat skin model.

    NASA Astrophysics Data System (ADS)

    Burns, Fredric; Tang, Moon-Shong Eric; Wu, Feng; Uddin, Ahmed

    2012-07-01

    These experiments utilize cancer induction to evaluate cancer-relevant repair during the interval between dose fractions. Low LET electron radiation(LET ~ 0.34 keV/u) were utilized in experiments that involved exposing rat dorsal skin to 2 equal 8 Gy dose fractions separated at various intervals from 0.25 h to 24 h. Cancer onset was established for 80 weeks after the exposures and only histologically verified cancers were included in the analysis. This experiment involved a total of 540 rats and 880 induced cancers. In the youngest rats (irradiated at 28 days of age) the cancer yield declined with a halftime of approximately 3.5 hrs. In 113 day old rats the cancer yield halftime was shortened to 1.3 hrs. In the oldest rats (182 days of age), the halftime could not be established quantitatively, because it was less than the shortest interval (15 min) utilized in the protocol (best estimate ~5 min). In the oldest rats the cancer yields for all fractionated exposures dropped essentially to the expected level of 2 single fractions, below which theoretically no further reduction is possible. The follow-up times for obtaining cancer yields were the same for all exposure groups in spite of the differing ages at exposure. These results indicate that repair of carcinogenically-relevant damage accelerates with age of the rat. No information is available on the possible mechanistic basis for this finding, although the model might be useful for delineating which of the many postulated split dose repair pathways is the correct one. The finding indicates that older rats should be less susceptible to the carcinogenic action of single doses of low LET radiation in comparison to younger rats, which has been verified in separate studies.

  3. Photobiomodulation therapy action in wound repair skin induced in aged rats old: time course of biomarkers inflammatory and repair.

    PubMed

    Fiorio, Franciane Barbieri; Dos Santos, Solange Almeida; de Melo Rambo, Caroline Sobral; Dalbosco, Camila Guerra; Serra, Andrey Jorge; de Melo, Brunno Lemes; Leal-Junior, Ernesto Cesar Pinto; de Carvalho, Paulo de Tarso Camillo

    2017-07-05

    Previous studies have discussed an inverse correlation between age and wound healing, because it relates to the association of aging with a gradual decrease in healing capacity. Treatment with photobiomodulation therapy (PBMT) improves wound healing by inducing increases in mitotic activity, numbers of fibroblasts, collagen synthesis, and neovascularization. Therefore, this study aimed to evaluate the effects of PBMT in cutaneous wound healing in aged rats. A punch biopsy of 8 mm in diameter was performed to produce a skin wound. The study included 45 male rats, of which 15 were young (30 days) and 30 were elderly (500 days). The 45 animals were distributed into 3 experimental groups, which were subjected to skin wounds and 1 aged group received PBMT, with a 30-mW laser beam (power density of 1.07 W/cm(2)), beam area of 0.028 cm(2), and λ660 nm produced through active phosphide Gallium-Aluminum-Indio (InGaAIP). The PBMT application took the form of a single-point transcutaneous method, with a total energy of 2 joules per wound site, energy density of 72 J/cm(2), and time of 1 min and 7 s. Analysis was performed to verify the effect of PBMT on the quantity of collagen I and III, metalloproteinase 3 and 9 (MMP-3 and MMP-9), tissue inhibitor of metalloproteinase-2 (TIMP-2) and of vascular endothelial growth factor (VEGF) at the wound site by immunohistochemistry, cytokine-induced neutrophil chemoattractant (CINC)-1, by enzyme-linked immunosorbent assay (ELISA) and interleukin (IL)-6 real-time polymerase chain reaction (RT-PCR). That we conclude LLLT is effective in the modulation of inflammatory mediators IL-6, CINC-1, VEGF, MMP-3, MMP-9 and TIMP-2 as well as increased collagen production in aged animals during different phases of the tissue regeneration process. However, the effects of PBMT obtained in the aged animals (aged LLLT group) suggest that new dosimetries should be tested to achieve better results.

  4. Autologous tendon-derived cell-seeded nanofibrous scaffolds improve rotator cuff repair in an age-dependent fashion.

    PubMed

    Huegel, Julianne; Kim, Dong Hwa; Cirone, James M; Pardes, Adam M; Morris, Tyler R; Nuss, Courtney A; Mauck, Robert L; Soslowsky, Louis J; Kuntz, Andrew F

    2017-06-01

    Rotator cuff tendon tears are one of the most common shoulder pathologies, especially in the aging population. Due to a poor healing response and degenerative changes associated with aging, rotator cuff repair failure remains common. Although cell-based therapies to augment rotator cuff repair appear promising, it is unknown whether the success of such a therapy is age-dependent. We hypothesized that autologous cell therapy would improve tendon-to-bone healing across age groups, with autologous juvenile cells realizing the greatest benefit. In this study, juvenile, adult, and aged rats underwent bilateral supraspinatus tendon repair with augmentation of one shoulder with autologous tendon-derived cell-seeded polycaprolactone scaffolds. At 8 weeks, shoulders treated with cells in both juvenile and aged animals exhibited increased cellularity, increased collagen organization, and improved mechanical properties. No changes between treated and control limbs were seen in adult rats. These findings suggest that cell delivery during supraspinatus repair initiates earlier matrix remodeling in juvenile and aged animals. This may be due to the relative "equilibrium" of adult tendon tissue with regards to catabolic and anabolic processes, contrasted with actively growing juvenile tendons and degenerative aged tendons. This study demonstrates the potential for autologous cell-seeded scaffolds to improve repairs in both the juvenile and aged population. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1250-1257, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  5. Comparing the effects of age on amplitude modulation and frequency modulation detection.

    PubMed

    Wallaert, Nicolas; Moore, Brian C J; Lorenzi, Christian

    2016-06-01

    Frequency modulation (FM) and amplitude modulation (AM) detection thresholds were measured at 40 dB sensation level for young (22-28 yrs) and older (44-66 yrs) listeners with normal audiograms for a carrier frequency of 500 Hz and modulation rates of 2 and 20 Hz. The number of modulation cycles, N, varied between 2 and 9. For FM detection, uninformative AM at the same rate as the FM was superimposed to disrupt excitation-pattern cues. For both groups, AM and FM detection thresholds were lower for the 2-Hz than for the 20-Hz rate, and AM and FM detection thresholds decreased with increasing N. Thresholds were higher for older than for younger listeners, especially for FM detection at 2 Hz, possibly reflecting the effect of age on the use of temporal-fine-structure cues for 2-Hz FM detection. The effect of increasing N was similar across groups for both AM and FM. However, at 20 Hz, older listeners showed a greater effect of increasing N than younger listeners for both AM and FM. The results suggest that ageing reduces sensitivity to both excitation-pattern and temporal-fine-structure cues for modulation detection, but more so for the latter, while sparing temporal integration of these cues at low modulation rates.

  6. Differential Modulation of Nitric Oxide Synthases in Aging: Therapeutic Opportunities

    PubMed Central

    Cau, Stefany B. A.; Carneiro, Fernando S.; Tostes, Rita C.

    2012-01-01

    Vascular aging is the term that describes the structural and functional disturbances of the vasculature with advancing aging. The molecular mechanisms of aging-associated endothelial dysfunction are complex, but reduced nitric oxide (NO) bioavailability and altered vascular expression and activity of NO synthase (NOS) enzymes have been implicated as major players. Impaired vascular relaxation in aging has been attributed to reduced endothelial NOS (eNOS)-derived NO, while increased inducible NOS (iNOS) expression seems to account for nitrosative stress and disrupted vascular homeostasis. Although eNOS is considered the main source of NO in the vascular endothelium, neuronal NOS (nNOS) also contributes to endothelial cells-derived NO, a mechanism that is reduced in aging. Pharmacological modulation of NO generation and expression/activity of NOS isoforms may represent a therapeutic alternative to prevent the progression of cardiovascular diseases. Accordingly, this review will focus on drugs that modulate NO bioavailability, such as nitrite anions and NO-releasing non-steroidal anti-inflammatory drugs, hormones (dehydroepiandrosterone and estrogen), statins, resveratrol, and folic acid, since they may be useful to treat/to prevent aging-associated vascular dysfunction. The impact of these therapies on life quality in elderly and longevity will be discussed. PMID:22737132

  7. One-year aging effects on microtensile bond strengths of composite and repairs with different surface treatments.

    PubMed

    Souza, Marcela Oliveira de; Leitune, Vicente Castelo Branco; Rodrigues, Stéfani Becker; Samuel, Susana Maria Werner; Collares, Fabrício Mezzomo

    2017-01-05

    The present study aimed to evaluate effects of different surface treatments and aging of composite cylinders on bond strength of composite resin repair. Thirty-two composite cylinders were produced and divided into four groups according to type of surface treatment and storage time of composite cylinder and repair. Cylinder surface of control group (Gcontrol) received no treatment before composite repair. Other groups were sandblasted with aluminum oxide (GAl2O3), followed by silane (GAl2O3sil) or adhesive (GAl2O3ad). Composite cylinders were stored in artificial saliva for either 24 hours or 1 year. Repairs were performed and stored in artificial saliva for 24 hours or 1 year and repair strength was evaluated using microtensile bond strength test. Data were submitted to Student's t test, two-way ANOVA, and post hoc test for storage time and treatment (α = 0.05). Gcontrol group showed lower values of aging of composite cylinder and storage time of repair (24 hours or 1 year for both) compared with other groups (p < 0.05). GAl2O3ad and GAl2O3sil groups did not exhibit decreased microtensile bond strength with aged repairs (1 year; p > 0.05). Polymer degradation was significant for composite cylinders during the first year of storage in Gcontrol, GAl2O3, and GAl2O3ad groups (p < 0.05). In GAl2O3sil group, storage time of composite cylinders was not significant (p > 0.05). Aging of composite resin influenced bond strength of restoration repair for up to 1 year. Sandblasting with Al2O3, followed by application of silane layer, produced high bond strength after composite or repair aging.

  8. The zebrafish as a gerontology model in nervous system aging, disease, and repair.

    PubMed

    Van Houcke, Jessie; De Groef, Lies; Dekeyster, Eline; Moons, Lieve

    2015-11-01

    Considering the increasing number of elderly in the world's population today, developing effective treatments for age-related pathologies is one of the biggest challenges in modern medical research. Age-related neurodegeneration, in particular, significantly impacts important sensory, motor, and cognitive functions, seriously constraining life quality of many patients. Although our understanding of the causal mechanisms of aging has greatly improved in recent years, animal model systems still have much to tell us about this complex process. Zebrafish (Danio rerio) have gained enormous popularity for this research topic over the past decade, since their life span is relatively short but, like humans, they are still subject to gradual aging. In addition, the extensive characterization of its well-conserved molecular and cellular physiology makes the zebrafish an excellent model to unravel the underlying mechanisms of aging, disease, and repair. This review provides a comprehensive overview of the progress made in zebrafish gerontology, with special emphasis on nervous system aging. We review the evidence that classic hallmarks of aging can also be recognized within this small vertebrate, both at the molecular and cellular level. Moreover, we illustrate the high level of similarity with age-associated human pathologies through a survey of the functional deficits that arise as zebrafish age.

  9. DNA Mismatch Repair System: Repercussions in Cellular Homeostasis and Relationship with Aging

    PubMed Central

    Conde-Pérezprina, Juan Cristóbal; León-Galván, Miguel Ángel; Konigsberg, Mina

    2012-01-01

    The mechanisms that concern DNA repair have been studied in the last years due to their consequences in cellular homeostasis. The diverse and damaging stimuli that affect DNA integrity, such as changes in the genetic sequence and modifications in gene expression, can disrupt the steady state of the cell and have serious repercussions to pathways that regulate apoptosis, senescence, and cancer. These altered pathways not only modify cellular and organism longevity, but quality of life (“health-span”). The DNA mismatch repair system (MMR) is highly conserved between species; its role is paramount in the preservation of DNA integrity, placing it as a necessary focal point in the study of pathways that prolong lifespan, aging, and disease. Here, we review different insights concerning the malfunction or absence of the DNA-MMR and its impact on cellular homeostasis. In particular, we will focus on DNA-MMR mechanisms regulated by known repair proteins MSH2, MSH6, PMS2, and MHL1, among others. PMID:23213348

  10. NADPH oxidases: key modulators in aging and age-related cardiovascular diseases?

    PubMed Central

    Sahoo, Sanghamitra; Meijles, Daniel N.; Pagano, Patrick J.

    2016-01-01

    Reactive oxygen species (ROS) and oxidative stress have long been linked to aging and diseases prominent in the elderly such as hypertension, atherosclerosis, diabetes and atrial fibrillation (AF). NADPH oxidases (Nox) are a major source of ROS in the vasculature and are key players in mediating redox signalling under physiological and pathophysiological conditions. In this review, we focus on the Nox-mediated ROS signalling pathways involved in the regulation of ‘longevity genes’ and recapitulate their role in age-associated vascular changes and in the development of age-related cardiovascular diseases (CVDs). This review is predicated on burgeoning knowledge that Nox-derived ROS propagate tightly regulated yet varied signalling pathways, which, at the cellular level, may lead to diminished repair, the aging process and predisposition to CVDs. In addition, we briefly describe emerging Nox therapies and their potential in improving the health of the elderly population. PMID:26814203

  11. Immune modulation to improve tissue engineering outcomes for cartilage repair in the osteoarthritic joint.

    PubMed

    Fahy, Niamh; Farrell, Eric; Ritter, Thomas; Ryan, Aideen E; Murphy, J Mary

    2015-02-01

    Osteoarthritis (OA), the most common form of arthritis, is a disabling degenerative joint disease affecting synovial joints and is associated with cartilage destruction, inflammation of the synovial membrane, and subchondral bone remodeling. Inflammation of the synovial membrane may arise secondary to degenerative processes in articular cartilage (AC), or may be a primary occurrence in OA pathogenesis. However, synovial inflammation plays a key role in the pathogenesis and disease progression of OA through the production of pro-inflammatory mediators, and is associated with cartilage destruction and pain. The triggers that initiate activation of the immune response in OA are unknown, but crosstalk between osteoarthritic chondrocytes, cartilage degradation products, and the synovium may act to perpetuate this response. Increasing evidence has emerged highlighting an important role for pro-inflammatory mediators and infiltrating inflammatory cell populations in the progression of the disease. Tissue engineering strategies hold great potential for the repair of damaged AC in an osteoarthritic joint. However, an in-depth understanding of how OA-associated inflammation impacts chondrocyte and progenitor cell behavior is required to achieve efficient cartilage regeneration in a catabolic osteoarthritic environment. In this review, we will discuss the role of inflammation in OA, and investigate novel immune modulation strategies that may prevent disease progression and facilitate successful cartilage regeneration for the treatment of OA.

  12. Immune Modulation to Improve Tissue Engineering Outcomes for Cartilage Repair in the Osteoarthritic Joint

    PubMed Central

    Fahy, Niamh; Farrell, Eric; Ritter, Thomas; Ryan, Aideen E.

    2015-01-01

    Osteoarthritis (OA), the most common form of arthritis, is a disabling degenerative joint disease affecting synovial joints and is associated with cartilage destruction, inflammation of the synovial membrane, and subchondral bone remodeling. Inflammation of the synovial membrane may arise secondary to degenerative processes in articular cartilage (AC), or may be a primary occurrence in OA pathogenesis. However, synovial inflammation plays a key role in the pathogenesis and disease progression of OA through the production of pro-inflammatory mediators, and is associated with cartilage destruction and pain. The triggers that initiate activation of the immune response in OA are unknown, but crosstalk between osteoarthritic chondrocytes, cartilage degradation products, and the synovium may act to perpetuate this response. Increasing evidence has emerged highlighting an important role for pro-inflammatory mediators and infiltrating inflammatory cell populations in the progression of the disease. Tissue engineering strategies hold great potential for the repair of damaged AC in an osteoarthritic joint. However, an in-depth understanding of how OA-associated inflammation impacts chondrocyte and progenitor cell behavior is required to achieve efficient cartilage regeneration in a catabolic osteoarthritic environment. In this review, we will discuss the role of inflammation in OA, and investigate novel immune modulation strategies that may prevent disease progression and facilitate successful cartilage regeneration for the treatment of OA. PMID:24950588

  13. Modulation of DNA Damage and Repair Pathways by Human Tumour Viruses

    PubMed Central

    Hollingworth, Robert; Grand, Roger J

    2015-01-01

    With between 10% and 15% of human cancers attributable to viral infection, there is great interest, from both a scientific and clinical viewpoint, as to how these pathogens modulate host cell functions. Seven human tumour viruses have been identified as being involved in the development of specific malignancies. It has long been known that the introduction of chromosomal aberrations is a common feature of viral infections. Intensive research over the past two decades has subsequently revealed that viruses specifically interact with cellular mechanisms responsible for the recognition and repair of DNA lesions, collectively known as the DNA damage response (DDR). These interactions can involve activation and deactivation of individual DDR pathways as well as the recruitment of specific proteins to sites of viral replication. Since the DDR has evolved to protect the genome from the accumulation of deleterious mutations, deregulation is inevitably associated with an increased risk of tumour formation. This review summarises the current literature regarding the complex relationship between known human tumour viruses and the DDR and aims to shed light on how these interactions can contribute to genomic instability and ultimately the development of human cancers. PMID:26008701

  14. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

    PubMed Central

    Perry, John R.B.; Hsu, Yi-Hsiang; Chasman, Daniel I.; Johnson, Andrew D.; Elks, Cathy; Albrecht, Eva; Andrulis, Irene L.; Beesley, Jonathan; Berenson, Gerald S.; Bergmann, Sven; Bojesen, Stig E.; Bolla, Manjeet K.; Brown, Judith; Buring, Julie E.; Campbell, Harry; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Corre, Tanguy; Couch, Fergus J.; Cox, Angela; Czene, Kamila; D'adamo, Adamo Pio; Davies, Gail; Deary, Ian J.; Dennis, Joe; Easton, Douglas F.; Engelhardt, Ellen G.; Eriksson, Johan G.; Esko, Tõnu; Fasching, Peter A.; Figueroa, Jonine D.; Flyger, Henrik; Fraser, Abigail; Garcia-Closas, Montse; Gasparini, Paolo; Gieger, Christian; Giles, Graham; Guenel, Pascal; Hägg, Sara; Hall, Per; Hayward, Caroline; Hopper, John; Ingelsson, Erik; Kardia, Sharon L.R.; Kasiman, Katherine; Knight, Julia A.; Lahti, Jari; Lawlor, Debbie A.; Magnusson, Patrik K.E.; Margolin, Sara; Marsh, Julie A.; Metspalu, Andres; Olson, Janet E.; Pennell, Craig E.; Polasek, Ozren; Rahman, Iffat; Ridker, Paul M.; Robino, Antonietta; Rudan, Igor; Rudolph, Anja; Salumets, Andres; Schmidt, Marjanka K.; Schoemaker, Minouk J.; Smith, Erin N.; Smith, Jennifer A.; Southey, Melissa; Stöckl, Doris; Swerdlow, Anthony J.; Thompson, Deborah J.; Truong, Therese; Ulivi, Sheila; Waldenberger, Melanie; Wang, Qin; Wild, Sarah; Wilson, James F; Wright, Alan F.; Zgaga, Lina; Ong, Ken K.; Murabito, Joanne M.; Karasik, David; Murray, Anna

    2014-01-01

    The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility. PMID:24357391

  15. Outcomes after quadriceps tendon repair in patients over 80 years of age

    PubMed Central

    Ellanti, Prasad; Moriarty, Andrew; Nagle, Matthew; McCarthy, Tom

    2016-01-01

    Summary Background Quadriceps tendon (QT) ruptures are uncommon and mostly occur in those who are 50–60 years of age. Timely surgical repair can result in a good functional outcome, however, little is known about the outcome in the older patient. Methods A retrospective review of all QT ruptures between 2009 and 2014 was conducted. Patients over the age of 80 were included. Those with penetrating trauma or partial ruptures were excluded. A chart review was undertaken to gather demographic and operative details. The patients were contacted by phone or by mail to have Lysholm and Rougraff scores completed. Results Of the 32 QT ruptures identified, 6 (19%) patients were eligible for inclusion in our study. They were predominantly (83%) males with a mean age of 81.38 years. The mean follow up was 54 months. The mean Lysholm score at last follow up was 84.8/100, which falls within the range of a good outcome. The mean Rougraff score was 21.3/25, which is an excellent outcome. All patients felt they were close to their premorbid level of mobility. Conclusion Good outcomes can be expected with QT repair in older patients, resulting in restoration of the pre-injury level of mobility. Level of evidence: Level V case series. PMID:27900296

  16. Age-related dystrophic changes in corneal endothelium from DNA repair-deficient mice.

    PubMed

    Roh, Danny S; Du, Yiqin; Gabriele, Michelle L; Robinson, Andria R; Niedernhofer, Laura J; Funderburgh, James L

    2013-12-01

    The corneal endothelium (CE) is a single layer of cells lining the posterior face of the cornea providing metabolic functions essential for maintenance of corneal transparency. Adult CE cells lack regenerative potential, and the number of CE cells decreases throughout life. To determine whether endogenous DNA damage contributes to the age-related spontaneous loss of CE, we characterized CE in Ercc1(-/Δ) mice, which have impaired capacity to repair DNA damage and age prematurely. Eyes from 4.5- to 6-month-old Ercc1(-/Δ) mice, age-matched wild-type (WT) littermates, and old WT mice (24- to 34-month-old) were compared by spectral domain optical coherence tomography and corneal confocal microscopy. Histopathological changes in CE were further identified in paraffin tissue sections, whole-mount immunostaining, and scanning electron and transmission electron microscopy. The CE of old WT mice displayed polymorphism and polymegathism, polyploidy, decreased cell density, increased cell size, increases in Descemet's thickness, and the presence of posterior projections originating from the CE toward the anterior chamber, similar to changes documented for aging human corneas. Similar changes were observed in young adult Ercc1(-/Δ) mice CE, demonstrating spontaneous premature aging of the CE of these DNA repair-deficient mice. CD45(+) immune cells were associated with the posterior surface of CE from Ercc1(-/Δ) mice and the tissue expressed increased IL-1α, Cxcl2, and TNFα, pro-inflammatory proteins associated with senescence-associated secretory phenotype. These data provide strong experimental evidence that DNA damage can promote aging of the CE and that Ercc1(-/Δ) mice offer a rapid and accurate model to study CE pathogenesis and therapy.

  17. Aging Affects Neural Synchronization to Speech-Related Acoustic Modulations

    PubMed Central

    Goossens, Tine; Vercammen, Charlotte; Wouters, Jan; van Wieringen, Astrid

    2016-01-01

    As people age, speech perception problems become highly prevalent, especially in noisy situations. In addition to peripheral hearing and cognition, temporal processing plays a key role in speech perception. Temporal processing of speech features is mediated by synchronized activity of neural oscillations in the central auditory system. Previous studies indicate that both the degree and hemispheric lateralization of synchronized neural activity relate to speech perception performance. Based on these results, we hypothesize that impaired speech perception in older persons may, in part, originate from deviances in neural synchronization. In this study, auditory steady-state responses that reflect synchronized activity of theta, beta, low and high gamma oscillations (i.e., 4, 20, 40, and 80 Hz ASSR, respectively) were recorded in young, middle-aged, and older persons. As all participants had normal audiometric thresholds and were screened for (mild) cognitive impairment, differences in synchronized neural activity across the three age groups were likely to be attributed to age. Our data yield novel findings regarding theta and high gamma oscillations in the aging auditory system. At an older age, synchronized activity of theta oscillations is increased, whereas high gamma synchronization is decreased. In contrast to young persons who exhibit a right hemispheric dominance for processing of high gamma range modulations, older adults show a symmetrical processing pattern. These age-related changes in neural synchronization may very well underlie the speech perception problems in aging persons. PMID:27378906

  18. Age does not affect the outcome after digital nerve repair in children - A retrospective long term follow up.

    PubMed

    Rosberg, Hans-Eric; Hazer Rosberg, Derya Burcu; Birkisson, Illugi; Dahlin, Lars B

    2017-09-01

    Digital nerve injuries in children are not common, but they are considered to have an excellent prognosis, compared to adults, after nerve injury and repair. In studies including both children and adults age have been found to have an effect on outcome after nerve repair. We investigated in a retrospective follow up study the long-time result after digital nerve injury and repair in children, 1-16 years of age (n = 38), and evaluate if age influences outcome. A group with young children, 1-10 years of age (n = 18), was compared with a group with older children, 11-16 years of age (n = 20). A clinical evaluation to evaluate sensation and grip strength was performed and questionnaires were used [Disability of the Arm, Shoulder and Hand (DASH), Cold Sensitivity Severity Scale (CISS), VAS-function and VAS-cosmetic] in median 40 months (range 12-131 months) after the injury and repair. All patient regained normal sensation. No correlations between age and monofilaments were found. Twenty children (52%) reported some problems with cold intolerance (i.e. CISS), but no other abnormal disability was found (i.e. DASH, VAS); again with no differences between the two groups. Children have an excellent long-term recovery after a digital nerve repair and without any influence of age. Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

  19. Pipe inspection and repair system

    NASA Technical Reports Server (NTRS)

    Schempf, Hagen (Inventor); Mutschler, Edward (Inventor); Chemel, Brian (Inventor); Boehmke, Scott (Inventor); Crowley, William (Inventor)

    2004-01-01

    A multi-module pipe inspection and repair device. The device includes a base module, a camera module, a sensor module, an MFL module, a brush module, a patch set/test module, and a marker module. Each of the modules may be interconnected to construct one of an inspection device, a preparation device, a marking device, and a repair device.

  20. Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age.

    PubMed

    Vaidya, Amita; Mao, Zhiyong; Tian, Xiao; Spencer, Brianna; Seluanov, Andrei; Gorbunova, Vera

    2014-07-01

    Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs), we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ) pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site-specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ) events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age.

  1. Effect of estrogens on base excision repair in brain and liver mitochondria of aged female rats.

    PubMed

    Leclère, R; Torregrosa-Muñumer, R; Kireev, R; García, C; Vara, E; Tresguerres, J A F; Gredilla, R

    2013-08-01

    Changes in the endocrine system have been suggested to act as signaling factors in the regulation of age-related events. Among the different hormones that have been linked to the aging process, estrogens have been widely investigated. They have been associated with inflammatory and oxidative processes and several investigations have established a relationship between the protective effects of estrogens and the mitochondrial function. Mitochondrial DNA is subjected to continuous oxidative attack by free radicals, and the base excision repair (BER) pathway is the main DNA repair route present in mitochondria. We have investigated the effect of estrogen levels on some of the key enzymes of BER in brain and liver mitochondria. In both tissues, depletion of estrogens led to an increased mitochondrial AP endonuclease (mtAPE1) activity, while restoration of estrogen levels by exogenous supplementation resulted in restitution of control APE1 activity only in liver. Moreover, in hepatic mitochondria, changes in estrogen levels affected the processing of oxidative lesions but not deaminations. Our results suggest that changes in mtAPE1 activity are related to specific translocation of the enzyme from the cytosol into the mitochondria probably due to oxidative stress changes as a consequence of changes in estrogen levels.

  2. Priming of microglia in a DNA-repair deficient model of accelerated aging.

    PubMed

    Raj, Divya D A; Jaarsma, Dick; Holtman, Inge R; Olah, Marta; Ferreira, Filipa M; Schaafsma, Wandert; Brouwer, Nieske; Meijer, Michel M; de Waard, Monique C; van der Pluijm, Ingrid; Brandt, Renata; Kreft, Karim L; Laman, Jon D; de Haan, Gerald; Biber, Knut P H; Hoeijmakers, Jan H J; Eggen, Bart J L; Boddeke, Hendrikus W G M

    2014-09-01

    Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state.

  3. Modulation of Macrophage Activity During Fracture Repair has Differential Effects in Young Adult and Elderly Mice

    PubMed Central

    Slade Shantz, Jesse Alan; Yu, Yan-Yiu; Andres, Wells; Miclau, Theodore; Marcucio, Ralph

    2014-01-01

    Objectives Advanced age is a factor associated with altered fracture healing. Delays in healing may increase the incidence of complications in the elderly, who are less able to tolerate long periods of immobilization and activity restrictions. The following study sought to determine if fracture repair could be enhanced in elderly animals by inhibiting macrophage activation, blocking the M-CSF receptor c-fms, and inhibiting monocyte trafficking using CC chemokine receptor-2 (CCR2) knockout mice. Methods Closed, unstable tibial shaft fractures were produced in mice aged four, 12 and 78 weeks. Mice were then fed a diet containing PLX3397 or a control diet from days 1–10 post-injury. Fractures were similarly made in CCR2−/− mice aged 78 weeks. The fracture callus was collected during fracture healing and was assessed for its size and the presence of macrophages, both of which were evaluated using the Mann-Whitney U test. Results PLX3397 treatment resulted in a decrease in the number of macrophages in the fracture callus at Day 5. Calluses in juvenile mice trended towards being smaller compared to elderly mice (p=0.08). There was also a trend toward larger callus size and increased bone formation in PLX3397-treated elderly animals compared to those of the control animals (p=0.12). Similar increases in bone formation (p=0.013) and decreases in cartilage within the callus (p=0.03) were seen at Day 10 in CCR2−/− mice. Conclusions The inhibition of macrophages in elderly mice may lead to an acceleration of fracture healing. Altering macrophage activation after fracture may represent a therapeutic strategy for preventing delayed healing and nonunion in the elderly. PMID:24378434

  4. Age-related decline in oligodendrogenesis retards white matter repair in mice

    PubMed Central

    Miyamoto, Nobukazu; Pham, Loc-Duyen D.; Hayakawa, Kazuhide; Matsuzaki, Toshinori; Seo, Ji Hae; Magnain, Caroline; Ayata, Cenk; Kim, Kyu-Won; Boas, David; Lo, Eng H.; Arai, Ken

    2013-01-01

    Background/Purpose Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask if compared to young brains, white matter regions in older brains may be more vulnerable in part due to decreased rates of compensatory oligodendrogenesis after injury. Methods A mouse model of prolonged cerebral hypoperfusion was prepared by bilateral common carotid artery stenosis in 2-month and 8-month old mice. Matching in vitro studies were performed by subjecting oligodendrocyte precursor cells (OPCs) to sub-lethal 7-day CoCl2 treatment to induce chemical hypoxic stress. Results Baseline myelin density in the corpus callosum was similar in 2-month and 8-month old mice. But after induction of prolonged cerebral hypoperfusion, older mice showed more severe white matter injury together with worse deficits in working memory. The numbers of newborn oligodendrocytes and their precursors were increased by cerebral hypoperfusion in young mice, whereas these endogenous responses were significantly dampened in older mice. Defects in CREB signaling may be involved because activating CREB with the type-III phosphodiesterase inhibitor cilostazol in older mice restored the differentiation of OPCs, alleviated myelin loss and improved cognitive dysfunction during cerebral hypoperfusion. Cell culture systems confirmed that cilostazol promoted the differentiation of OPCs. Conclusions An age-related decline in CREB-mediated oligodendrogenesis may compromise endogenous white matter repair mechanisms, and therefore, drugs that activate CREB signaling provide a potential therapeutic approach for treating white matter injury in aging brains. PMID:23881957

  5. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.

    PubMed

    Vermeij, W P; Dollé, M E T; Reiling, E; Jaarsma, D; Payan-Gomez, C; Bombardieri, C R; Wu, H; Roks, A J M; Botter, S M; van der Eerden, B C; Youssef, S A; Kuiper, R V; Nagarajah, B; van Oostrom, C T; Brandt, R M C; Barnhoorn, S; Imholz, S; Pennings, J L A; de Bruin, A; Gyenis, Á; Pothof, J; Vijg, J; van Steeg, H; Hoeijmakers, J H J

    2016-09-15

    Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1(∆/-)) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg(-/-) (also known as Ercc5(-/-)) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1(∆/-) mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1(∆/-) mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1(∆/-) mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.

  6. Aged blood factors decrease cellular responses associated with delayed gingival wound repair

    PubMed Central

    Morgan, Alejandra; Díaz, Catalina; Morales, Diego; Jaña, Fabián; Gómez, Alvaro; Silva, Alonso; Briceño, Fernanda; Oyarzún, Alejandro; Maldonado, Felipe; Cerda, Oscar; Smith, Patricio C.

    2017-01-01

    Aging is a gradual biological process characterized by a decrease in cell and organism functions. Gingival wound healing is one of the impaired processes found in old rats. Here, we studied the in vivo wound healing process using a gingival repair rat model and an in vitro model using human gingival fibroblast for cellular responses associated to wound healing. To do that, we evaluated cell proliferation of both epithelial and connective tissue cells in gingival wounds and found decreased of Ki67 nuclear staining in old rats when compared to their young counterparts. We next evaluated cellular responses of primary gingival fibroblast obtained from young subjects in the presence human blood serum of individuals of different ages. Eighteen to sixty five years old masculine donors were classified into 3 groups: “young” from 18 to 22 years old, “middle-aged” from 30 to 48 years old and “aged” over 50 years old. Cell proliferation, measured through immunofluorescence for Ki67 and flow cytometry for DNA content, was decreased when middle-aged and aged serum was added to gingival fibroblast compared to young serum. Myofibroblastic differentiation, measured through alpha-smooth muscle actin (α-SMA), was stimulated with young but not middle-aged or aged serum both the protein levels and incorporation of α-SMA into actin stress fibers. High levels of PDGF, VEGF, IL-6R were detected in blood serum from young subjects when compared to middle-aged and aged donors. In addition, the pro-inflammatory cytokines MCP-1 and TNF were increased in the serum of aged donors. In old rat wound there is an increased of staining for TNF compared to young wound. Moreover, healthy gingiva (non injury) shows less staining compared to a wound site, suggesting a role in wound healing. Moreover, serum from middle-aged and aged donors was able to stimulate cellular senescence in young cells as determined by the expression of senescence associated beta-galactosidase and histone H2A

  7. Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms

    PubMed Central

    Edifizi, Diletta; Schumacher, Björn

    2015-01-01

    DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice and C. elegans has shed new light on the mechanisms through which developing and aging animals respond to persistent DNA damage. The various NER mouse mutants have served as important disease models for Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), while the traceable genetics of C. elegans have allowed the mechanistic delineation of the distinct outcomes of genome instability in metazoan development and aging. Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. The insulin-like growth factor signaling (IIS) effector transcription factor DAF-16 could indeed overcome DNA damage-driven developmental growth delay and functional deterioration even when DNA damage persists. Longevity assurance mechanisms might thus delay DNA damage-driven aging by raising the threshold when accumulating DNA damage becomes detrimental for physiological tissue functioning. PMID:26287260

  8. Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms.

    PubMed

    Edifizi, Diletta; Schumacher, Björn

    2015-08-13

    DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice and C. elegans has shed new light on the mechanisms through which developing and aging animals respond to persistent DNA damage. The various NER mouse mutants have served as important disease models for Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), while the traceable genetics of C. elegans have allowed the mechanistic delineation of the distinct outcomes of genome instability in metazoan development and aging. Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. The insulin-like growth factor signaling (IIS) effector transcription factor DAF-16 could indeed overcome DNA damage-driven developmental growth delay and functional deterioration even when DNA damage persists. Longevity assurance mechanisms might thus delay DNA damage-driven aging by raising the threshold when accumulating DNA damage becomes detrimental for physiological tissue functioning.

  9. Cardiosphere-Derived Cells Facilitate Heart Repair by Modulating M1/M2 Macrophage Polarization and Neutrophil Recruitment

    PubMed Central

    Hasan, Al Shaimaa; Luo, Lan; Yan, Chen; Zhang, Tian-Xia; Urata, Yoshishige; Goto, Shinji; Mangoura, Safwat A.; Abdel-Raheem, Mahmoud H.; Zhang, Shouhua; Li, Tao-Sheng

    2016-01-01

    Cardiosphere-derived cells (CDCs), one of the promising stem cell sources for myocardial repair, have been tested in clinical trials and resulted in beneficial effects; however, the relevant mechanisms are not fully understood. In this study, we examined the hypothesis that CDCs favor heart repair by switching the macrophages from a pro-inflammatory phenotype (M1) into a regulatory anti-inflammatory phenotype (M2). Macrophages from mice were cultured with CDCs-conditioned medium or with fibroblasts-conditioned medium as a control. Immunostaining showed that CDCs-conditioned medium significantly enhanced the expression of CD206 (a marker for M2 macrophages), but decreased the expression of CD86 (a marker for M1 macrophages) 3 days after culture. For animal studies, we used an acute myocardial infarction model of mice. We injected CDCs, fibroblasts, or saline only into the border zone of infarction. Then we collected the heart tissues for histological analysis 5 and 14 days after treatment. Compared with control animals, CDCs treatment significantly decreased M1 macrophages and neutrophils but increased M2 macrophages in the infarcted heart. Furthermore, CDCs-treated mice had reduced infarct size and fewer apoptotic cells compared to the controls. Our data suggest that CDCs facilitate heart repair by modulating M1/M2 macrophage polarization and neutrophil recruitment, which may provide a new insight into the mechanisms of stem cell-based myocardial repair. PMID:27764217

  10. Ndrg3 gene regulates DSB repair during meiosis through modulation the ERK signal pathway in the male germ cells

    PubMed Central

    Pan, Hongjie; Zhang, Xuan; Jiang, Hanwei; Jiang, Xiaohua; Wang, Liu; Qi, Qi; Bi, Yuan; Wang, Jian; Shi, Qinghua; Li, Runsheng

    2017-01-01

    The N-myc downstream regulated gene (NDRG) family consists of 4 members, NDRG-1, -2, -3, -4. Physiologically, we found Ndrg3, a critical gene which led to homologous lethality in the early embryo development, regulated the male meiosis in mouse. The expression of Ndrg3 was enhanced specifically in germ cells, and reached its peak level in the pachytene stage spermatocyte. Haplo-insufficiency of Ndrg3 gene led to sub-infertility during the male early maturation. In the Ndrg3+/− germ cells, some meiosis events such as DSB repair and synaptonemal complex formation were impaired. Disturbances on meiotic prophase progression and spermatogenesis were observed. In mechanism, the attenuation of pERK1/2 signaling was detected in the heterozygous testis. With our primary spermatocyte culture system, we found that lactate promoted DSB repair via ERK1/2 signaling in the male mouse germ cells in vitro. Deficiency of Ndrg3 gene attenuated the activation of ERK which further led to the aberrancy of DSB repair in the male germ cells in mouse. Taken together, we reported that Ndrg3 gene modulated the lactate induced ERK pathway to facilitate DSB repair in male germ cells, which further regulated meiosis and subsequently fertility in male mouse. PMID:28290521

  11. Ndrg3 gene regulates DSB repair during meiosis through modulation the ERK signal pathway in the male germ cells.

    PubMed

    Pan, Hongjie; Zhang, Xuan; Jiang, Hanwei; Jiang, Xiaohua; Wang, Liu; Qi, Qi; Bi, Yuan; Wang, Jian; Shi, Qinghua; Li, Runsheng

    2017-03-14

    The N-myc downstream regulated gene (NDRG) family consists of 4 members, NDRG-1, -2, -3, -4. Physiologically, we found Ndrg3, a critical gene which led to homologous lethality in the early embryo development, regulated the male meiosis in mouse. The expression of Ndrg3 was enhanced specifically in germ cells, and reached its peak level in the pachytene stage spermatocyte. Haplo-insufficiency of Ndrg3 gene led to sub-infertility during the male early maturation. In the Ndrg3(+/-) germ cells, some meiosis events such as DSB repair and synaptonemal complex formation were impaired. Disturbances on meiotic prophase progression and spermatogenesis were observed. In mechanism, the attenuation of pERK1/2 signaling was detected in the heterozygous testis. With our primary spermatocyte culture system, we found that lactate promoted DSB repair via ERK1/2 signaling in the male mouse germ cells in vitro. Deficiency of Ndrg3 gene attenuated the activation of ERK which further led to the aberrancy of DSB repair in the male germ cells in mouse. Taken together, we reported that Ndrg3 gene modulated the lactate induced ERK pathway to facilitate DSB repair in male germ cells, which further regulated meiosis and subsequently fertility in male mouse.

  12. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD

    PubMed Central

    Ferenbach, David A.; Bonventre, Joseph V.

    2015-01-01

    Acute kidney injury is an increasingly common complication of hospital admission and is associated with high levels of morbidity and mortality. A hypotensive, septic, or toxic insult can initiate a cascade of events, resulting in impaired microcirculation, activation of inflammatory pathways and tubular cell injury or death. These processes ultimately result in acutely impaired kidney function and initiation of a repair response. This Review explores the various mechanisms responsible for the initiation and propagation of acute kidney injury, the prototypic mechanisms by which a substantially damaged kidney can regenerate its normal architecture, and how the adaptive processes of repair can become maladaptive. These mechanisms, which include G2/M cell-cycle arrest, cell senescence, profibrogenic cytokine production, and activation of pericytes and interstitial myofibroblasts, contribute to the development of progressive fibrotic kidney disease. The end result is a state that mimics accelerated kidney ageing. These mechanisms present important opportunities for the design of targeted therapeutic strategies to promote adaptive renal recovery and minimize progressive fibrosis and chronic kidney disease after acute insults. PMID:25643664

  13. Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

    PubMed Central

    Guedj, Avital; Geiger-Maor, Anat; Galun, Eithan; Amsalem, Hagai; Rachmilewitz, Jacob

    2016-01-01

    Aging is associated with progressive decline in cell function and with increased damage to macromolecular components. DNA damage, in the form of double-strand breaks (DSBs), increases with age and in turn, contributes to the aging process and age-related diseases. DNA strand breaks triggers a set of highly orchestrated signaling events known as the DNA damage response (DDR), which coordinates DNA repair. However, whether the accumulation of DNA damage with age is a result of decreased repair capacity, remains to be determined. In our study we showed that with age there is a decline in the resolution of foci containing γH2AX and pKAP-1 in diethylnitrosamine (DEN)-treated mouse livers, already evident at a remarkably early age of 6-months. Considerable age-dependent differences in global gene expression profiles in mice livers after exposure to DEN, further affirmed these age related differences in the response to DNA damage. Functional analysis identified p53 as the most overrepresented pathway that is specifically enhanced and prolonged in 6-month-old mice. Collectively, our results demonstrated an early decline in DNA damage repair that precedes ‘old age’, suggesting this may be a driving force contributing to the aging process rather than a phenotypic consequence of old age. PMID:27922819

  14. A generalised maintenance policy with age-dependent minimal repair cost for a system subject to shocks under periodic overhaul

    NASA Astrophysics Data System (ADS)

    Sheu, Shey-Huei; Li, Suh-Huey; Chang, Chin-Chih

    2012-06-01

    A system is subject to shocks that arrive according to a non-homogeneous Poisson process. As shocks occur, the system has two types of failures: type 1 failure (minor failure) is removed by a minimal repair, whereas type 2 failure (catastrophic failure) is removed by overhaul or replacement. The cost of minimal repair depends on age. A system is overhauled when the occurrence of a type 2 failure or at age T, whichever occurs first. At the N-th overhaul, the system is replaced rather than overhauled. A maintenance policy for determining optimal number of overhauls and optimal interval between overhauls which incorporate minimal repairs, overhauls and replacement is proposed. Under such a policy, an approach which using the concept of virtual age is adopted. It is shown that there exists a unique optimal policy which minimises the expected cost rate under certain conditions. Various cases are considered.

  15. Fall prevention modulates decisional saccadic behavior in aging

    PubMed Central

    Coubard, Olivier A.

    2012-01-01

    As society ages and frequency of falls increases in older adults, counteracting motor decline is a challenging issue for developed countries. Physical activity based on aerobic and strength training as well as motor activity based on skill learning both help benefit balance and reduce the risk of falls, as assessed by clinical or laboratory measures. However, how such programs influence motor control is a neglected issue. This study examined the effects of fall prevention (FP) training on saccadic control in older adults. Saccades were recorded in 12 participants aged 64–91 years before and after 2.5 months training in FP. Traditional analysis of saccade timing and dynamics was performed together with a quantitative analysis using the LATER model, enabling us to examine the underlying motor control processes. Results indicated that FP reduced the rate of anticipatory and express saccades in inappropriate directions and enhanced that of express saccades in the appropriate direction, resulting in decreased latency and higher left-right symmetry of motor responses. FP reduced within-participant variability of saccade duration, amplitude, and peak velocity. LATER analysis suggested that FP modulates decisional thresholds, extending our knowledge of motor training influence on central motor control. We introduce the Threshold Interval Modulation with Early Release-Rate of rIse Deviation with Early Release (TIMER-RIDER) model to account for the results. PMID:22807914

  16. Adults with repaired tetralogy: low mortality but high morbidity up to middle age.

    PubMed

    Dennis, Mark; Moore, Ben; Kotchetkova, Irina; Pressley, Lynne; Cordina, Rachael; Celermajer, David S

    2017-01-01

    Survival of patients with repaired tetralogy of Fallot (rToF) into young adulthood is very good. Concerns exist, however, over long-term morbidity and mortality as these subjects reach middle age. We aimed to assess survival and the prevalence of complications in patients with rToF seen in our Adult Congenital Heart Disease (ACHD) service. One hundred and sixty-eight consecutive patients with 'simple rToF', aged over 16 years, followed up at our tertiary-level ACHD service in Sydney, Australia since 2000, were included. We documented mortality and analysed the prospectively defined composite end points of (a) 'Serious adverse events', including death, heart failure hospitalisation and/or documented ventricular arrhythmia and (b) 'Adverse events' inclusive of the above and endocarditis, atrial arrhythmia, defibrillator and/or pacemaker implantation. Mean age at the last follow-up was 34±12 years, and 55% were men. There were 10 (6%) deaths, and 26 patients (16%) experienced a 'serious adverse event'. Fifty-one patients (30%) experienced an 'adverse event' and 29 patients had atrial arrhythmias. One hundred and one (61%) patients had at least one pulmonary valve replacement. By age 40 years, 93% were free of serious adverse events, and 83% were free of any adverse event. By age 50 years, only 56% had not had an adverse event. Older age and history of atrial arrhythmia were predictive of serious adverse events. Survival into mid-adulthood in patients with rToF is very good; however, a substantial number of survivors have adverse events by the age of 50 years.

  17. Learning to integrate versus inhibiting information is modulated by age.

    PubMed

    Cappelletti, Marinella; Pikkat, Helen; Upstill, Emily; Speekenbrink, Maarten; Walsh, Vincent

    2015-02-04

    Cognitive training aiming at improving learning is often successful, but what exactly underlies the observed improvements and how these differ across the age spectrum are currently unknown. Here we asked whether learning in young and older people may reflect enhanced ability to integrate information required to perform a cognitive task or whether it may instead reflect the ability to inhibit task-irrelevant information for successful task performance. We trained 30 young and 30 aging human participants on a numerosity discrimination task known to engage the parietal cortex and in which cue-integration and inhibitory abilities can be distinguished. We coupled training with parietal, motor, or sham transcranial random noise stimulation, known for modulating neural activity. Numerosity discrimination improved after training and was maintained long term, especially in the training + parietal stimulation group, regardless of age. Despite the quantitatively similar improvement in the two age groups, the content of learning differed remarkably: aging participants improved more in inhibitory abilities, whereas younger subjects improved in cue-integration abilities. Moreover, differences in the content of learning were reflected in different transfer effects to untrained but related abilities: in the younger group, improvements in cue integration paralleled improvements in continuous quantity (time and space), whereas in the elderly group, improvements in numerosity-based inhibitory abilities generalized to other measures of inhibition and corresponded to a decline in space discrimination, possibly because conflicting learning resources are used in numerosity and continuous quantity processing. These results indicate that training can enhance different, age-dependent cognitive processes and highlight the importance of identifying the exact processes underlying learning for effective training programs.

  18. Rupture of Abdominal Aortic Aneurysms in Patients Under Screening Age and Elective Repair Threshold.

    PubMed

    Laine, M T; Vänttinen, T; Kantonen, I; Halmesmäki, K; Weselius, E M; Laukontaus, S; Salenius, J; Aho, P S; Venermo, M

    2016-04-01

    The objective of this study was to identify the proportion of abdominal aortic aneurysm ruptures that occur before the screening age or threshold diameter for operative repair is reached. The study was a retrospective analysis of RAAA patients including all RAAA patients admitted to Helsinki (HUH) and Tampere University Hospitals (TaUH) during 2002-2013. The data for age, gender, and comorbidities were collected from vascular registry and patient records. Computed tomography images taken at the time of admission were used for the measurement of maximum anteroposterior (AP) aneurysm diameter at the time of rupture. Age and diameter data were compared with risk factors. A total of 585 patients diagnosed with RAAA were admitted to the two hospitals during the 12 year period. The mean age at the time of rupture was 73.6 years (SD 9.5, range 42-96 years). 18.3% of patients were under 65: 21.4% of men and 3.0% of women. Men were on average 8 years younger than women. The odds ratio (OR) for rupture before 65 years of age for smokers was 2.1 compared with non-smokers, and 28.4% of smokers were under 65 at the time of rupture. Of all RAAA patients, 327 had a computed tomography scan confirming rupture. The mean AP diameter of the aneurysm was 75.6 mm (SD 15.8, range 32-155 mm). The mean size was significantly lower in women than in men (70.5 vs. 76.8, p = .005). The data from this study show that a fifth of men would not make it to the screening age of 65 before AAA rupture, the proportion being even larger in active smokers. The data from this study also supports the previous finding that aneurysm size at the time of rupture is significantly smaller in women. Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  19. Th2 cells are essential for modulation of vascular repair by allogeneic endothelial cells

    PubMed Central

    Methe, Heiko; Nanasato, Mamoru; Spognardi, Anna-Maria; Groothuis, Adam; Edelman, Elazer R.

    2009-01-01

    Background Endothelial cells (EC) embedded within three-dimensional matrices (MEEC) when placed in the vascular adventitia control lumenal inflammation and intimal hyperplasia. Matrix-embedding alters endothelial immunogenicity in vitro. T helper (Th) driven host immunity is a major impediment for of allogeneic grafts. We therefore aimed to identify if modulation of T helper balance would affect immune compatibility and endothelial regulation of vascular repair in vivo. Methods Pigs (n=4/group) underwent balloon injury of both carotid arteries and were left alone (group 1) or received perivascular implants of porcine MEEC (group 2), a 12 days course of cyclosporine A (CsA) (group 3), or a combination of MEEC and CsA (group 4). Host immune reactivity (EC-specific antibodies, activation of splenocytes) was analyzed after 28 and 90 days in 2 pigs/group respectively. Results MEEC treatment alone induced formation of EC-specific IgG1-antibodies (41±6 mean fluorescence intensity (MFI)) and differentiation of host splenocytes into Th2, but not Th1, cytokine-producing cells (IL-4: 242±102, IL-10: 273±114 number of spots). Concomitant CsA-therapy reduced the frequency of IgG1-antibodies (25±2 MFI; p<0.02) and Th2-cytokine producing splenocytes upon MEEC treatment (IL-4: 157±19, IL-10: 124±26 number of spots; p< 0.05). MEEC significantly inhibited luminal occlusion 28 and 90 days after balloon injury compared to untreated controls (12±7 vs. 68±14%; p<0.001) but to a lesser extent in the face of immunomodulation with concomitant CsA-treatment (34±13%; p<0.02 vs. group 2). Conclusions MEEC do not induce a significant Th1-driven immune response expected from alloimplants, but do enhance differentiation of splenocytes into Th2-cytokine producing cells. Reduction in this Th2 response reduces the vasoregulatory effects of allogeneic EC after injury. PMID:20036161

  20. Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy

    PubMed Central

    Leguisamo, Natalia M.; Gloria, Helena C.; Kalil, Antonio N.; Martins, Talita V.; Azambuja, Daniel B.

    2017-01-01

    Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients’ clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC. PMID:28903334

  1. Do patient age and sex influence tendon cell biology and clinical/radiographic outcomes after rotator cuff repair?

    PubMed

    Pauly, Stephan; Stahnke, Katharina; Klatte-Schulz, Franka; Wildemann, Britt; Scheibel, Markus; Greiner, Stefan

    2015-03-01

    Many clinical and radiographic studies suggest that patient age and sex have an influence on rotator cuff (RC) repair outcomes. However, these findings result from retrospective statistical analyses and cannot provide a causal answer. To analyze whether age and sex influence the biological potential at the time of RC repair or midterm clinical and radiographic outcomes. Also assessed was the effect of the biological potential on intraindividual clinical/radiographic results. Cohort study; Level of evidence, 2. A total of 40 patients underwent arthroscopic RC repair. At the time of surgery (t = 0), supraspinatus tendon biopsy specimens were obtained, cultivated, and assessed for their biological potential, particularly (1) cell growth and (2) collagen type I production. After a follow-up at 24 months (t = 1), all patients were assessed by clinical scores (Constant score, subjective shoulder value, American Shoulder and Elbow Surgeons [ASES] score, and Western Ontario Rotator Cuff Index [WORC] score) and underwent magnetic resonance imaging to determine RC integrity. The data were examined for age- and sex-related differences and to identify the correlation between biological potential (t = 0) and clinical/radiographic outcome (t = 1). The follow-up rate for the imaging and clinical evaluation was 100%. Age, but not sex, influenced the biological tendon cell parameters at t = 0. However, there was no effect of age or sex on the clinical and radiographic results at t = 1. Furthermore, no correlation was observed between the initial biological parameters and later clinical outcomes or radiographic RC integrity. Finally, there was no significant difference between intact and nonhealed repairs in terms of the respective clinical scores. Age, but not sex, was found to have a negative effect on RC tendon cell biology. However, neither sex nor, in particular, a higher age influenced repair outcomes after 24 months. © 2015 The Author(s).

  2. Modulation of Saccharomyces Cerevisiae DNA Double-Strand Break Repair by Srs2 and Rad51

    PubMed Central

    Milne, G. T.; Ho, T.; Weaver, D. T.

    1995-01-01

    RAD52 function is required for virtually all DNA double-strand break repair and recombination events in Saccharomyces cerevisiae. To gain greater insight into the mechanism of RAD52-mediated repair, we screened for genes that suppress partially active alleles of RAD52 when mutant or overexpressed. Described here is the isolation of a phenotypic null allele of SRS2 that suppressed multiple alleles of RAD52 (rad52B, rad52D, rad52-1 and KlRAD52) and RAD51 (KlRAD51) but failed to suppress either a rad52δ or a rad51δ. These results indicate that SRS2 antagonizes RAD51 and RAD52 function in recombinational repair. The mechanism of suppression of RAD52 alleles by srs2 is distinct from that which has been previously described for RAD51 overexpression, as both conditions were shown to act additively with respect to the rad52B allele. Furthermore, overexpression of either RAD52 or RAD51 enhanced the recombination-dependent sensitivity of an srs2δ RAD52 strain, suggesting that RAD52 and RAD51 positively influence recombinational repair mechanisms. Thus, RAD52-dependent recombinational repair is controlled both negatively and positively. PMID:7768432

  3. Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases.

    PubMed

    Sallam, Nada; Laher, Ismail

    2016-01-01

    Despite the wealth of epidemiological and experimental studies indicating the protective role of regular physical activity/exercise training against the sequels of aging and cardiovascular diseases, the molecular transducers of exercise/physical activity benefits are not fully identified but should be further investigated in more integrative and innovative approaches, as they bear the potential for transformative discoveries of novel therapeutic targets. As aging and cardiovascular diseases are associated with a chronic state of oxidative stress and inflammation mediated via complex and interconnected pathways, we will focus in this review on the antioxidant and anti-inflammatory actions of exercise, mainly exerted on adipose tissue, skeletal muscles, immune system, and cardiovascular system by modulating anti-inflammatory/proinflammatory cytokines profile, redox-sensitive transcription factors such as nuclear factor kappa B, activator protein-1, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, antioxidant and prooxidant enzymes, and repair proteins such as heat shock proteins, proteasome complex, oxoguanine DNA glycosylase, uracil DNA glycosylase, and telomerase. It is important to note that the effects of exercise vary depending on the type, intensity, frequency, and duration of exercise as well as on the individual's characteristics; therefore, the development of personalized exercise programs is essential.

  4. Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases

    PubMed Central

    Sallam, Nada

    2016-01-01

    Despite the wealth of epidemiological and experimental studies indicating the protective role of regular physical activity/exercise training against the sequels of aging and cardiovascular diseases, the molecular transducers of exercise/physical activity benefits are not fully identified but should be further investigated in more integrative and innovative approaches, as they bear the potential for transformative discoveries of novel therapeutic targets. As aging and cardiovascular diseases are associated with a chronic state of oxidative stress and inflammation mediated via complex and interconnected pathways, we will focus in this review on the antioxidant and anti-inflammatory actions of exercise, mainly exerted on adipose tissue, skeletal muscles, immune system, and cardiovascular system by modulating anti-inflammatory/proinflammatory cytokines profile, redox-sensitive transcription factors such as nuclear factor kappa B, activator protein-1, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, antioxidant and prooxidant enzymes, and repair proteins such as heat shock proteins, proteasome complex, oxoguanine DNA glycosylase, uracil DNA glycosylase, and telomerase. It is important to note that the effects of exercise vary depending on the type, intensity, frequency, and duration of exercise as well as on the individual's characteristics; therefore, the development of personalized exercise programs is essential. PMID:26823952

  5. One month of contemporary dance modulates fractal posture in aging.

    PubMed

    Coubard, Olivier A; Ferrufino, Lena; Nonaka, Tetsushi; Zelada, Oscar; Bril, Blandine; Dietrich, Gilles

    2014-01-01

    Understanding the human aging of postural control and how physical or motor activity improves balance and gait is challenging for both clinicians and researchers. Previous studies have evidenced that physical and sporting activity focusing on cardiovascular and strength conditioning help older adults develop their balance and gait and/or decrease their frequency of falls. Motor activity based on motor-skill learning has also been put forward as an alternative to develop balance and/or prevent falls in aging. Specifically dance has been advocated as a promising program to boost motor control. In this study, we examined the effects of contemporary dance (CD) on postural control of older adults. Upright stance posturography was performed in 38 participants aged 54-89 years before and after the intervention period, during which one half of the randomly assigned participants was trained to CD and the other half was not trained at all (no dance, ND). CD training lasted 4 weeks, 3 times a week. We performed classical statistic scores of postural signal and dynamic analyses, namely signal diffusion analysis (SDA), recurrence quantification analysis (RQA), and detrended fluctuation analysis (DFA). CD modulated postural control in older trainees, as revealed in the eyes closed condition by a decrease in fractal dimension and an increase in DFA alpha component in the mediolateral plane. The ND group showed an increase in length and mean velocity of postural signal, and the eyes open a decrease in RQA maximal diagonal line in the anteroposterior plane and an increase in DFA alpha component in the mediolateral plane. No change was found in SDA in either group. We suggest that such a massed practice of CD reduced the quantity of exchange between the subject and the environment by increasing their postural confidence. Since CD has low-physical but high-motor impact, we conclude that it may be recommended as a useful program to rehabilitate posture in aging.

  6. One month of contemporary dance modulates fractal posture in aging

    PubMed Central

    Coubard, Olivier A.; Ferrufino, Lena; Nonaka, Tetsushi; Zelada, Oscar; Bril, Blandine; Dietrich, Gilles

    2013-01-01

    Understanding the human aging of postural control and how physical or motor activity improves balance and gait is challenging for both clinicians and researchers. Previous studies have evidenced that physical and sporting activity focusing on cardiovascular and strength conditioning help older adults develop their balance and gait and/or decrease their frequency of falls. Motor activity based on motor-skill learning has also been put forward as an alternative to develop balance and/or prevent falls in aging. Specifically dance has been advocated as a promising program to boost motor control. In this study, we examined the effects of contemporary dance (CD) on postural control of older adults. Upright stance posturography was performed in 38 participants aged 54–89 years before and after the intervention period, during which one half of the randomly assigned participants was trained to CD and the other half was not trained at all (no dance, ND). CD training lasted 4 weeks, 3 times a week. We performed classical statistic scores of postural signal and dynamic analyses, namely signal diffusion analysis (SDA), recurrence quantification analysis (RQA), and detrended fluctuation analysis (DFA). CD modulated postural control in older trainees, as revealed in the eyes closed condition by a decrease in fractal dimension and an increase in DFA alpha component in the mediolateral plane. The ND group showed an increase in length and mean velocity of postural signal, and the eyes open a decrease in RQA maximal diagonal line in the anteroposterior plane and an increase in DFA alpha component in the mediolateral plane. No change was found in SDA in either group. We suggest that such a massed practice of CD reduced the quantity of exchange between the subject and the environment by increasing their postural confidence. Since CD has low-physical but high-motor impact, we conclude that it may be recommended as a useful program to rehabilitate posture in aging. PMID:24611047

  7. Nuclear Technology. Course 28: Welding Inspection. Module 28-9, Weld Repair Control.

    ERIC Educational Resources Information Center

    Espy, John

    This ninth in a series of ten modules for a course titled Welding Inspection describes the purposes, essential elements, and application of a weld control program. The module follows a typical format that includes the following sections: (1) introduction, (2) module prerequisites, (3) objectives, (4) notes to instructor/student, (5) subject…

  8. Long non-coding RNAs as novel expression signatures modulate DNA damage and repair in cadmium toxicology

    PubMed Central

    Zhou, Zhiheng; Liu, Haibai; Wang, Caixia; Lu, Qian; Huang, Qinhai; Zheng, Chanjiao; Lei, Yixiong

    2015-01-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in a variety of physiological and pathophysiological processes. Our study was to investigate whether lncRNAs as novel expression signatures are able to modulate DNA damage and repair in cadmium(Cd) toxicity. There were aberrant expression profiles of lncRNAs in 35th Cd-induced cells as compared to untreated 16HBE cells. siRNA-mediated knockdown of ENST00000414355 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA-damage related genes (ATM, ATR and ATRIP), while increased the expressions of DNA-repair related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1). Cadmium increased ENST00000414355 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000414355 expression and urinary/blood Cd concentrations, and there were significant correlations of lncRNA-ENST00000414355 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. These results indicate that some lncRNAs are aberrantly expressed in Cd-treated 16HBE cells. lncRNA-ENST00000414355 may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity. PMID:26472689

  9. Long non-coding RNAs as novel expression signatures modulate DNA damage and repair in cadmium toxicology

    NASA Astrophysics Data System (ADS)

    Zhou, Zhiheng; Liu, Haibai; Wang, Caixia; Lu, Qian; Huang, Qinhai; Zheng, Chanjiao; Lei, Yixiong

    2015-10-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in a variety of physiological and pathophysiological processes. Our study was to investigate whether lncRNAs as novel expression signatures are able to modulate DNA damage and repair in cadmium(Cd) toxicity. There were aberrant expression profiles of lncRNAs in 35th Cd-induced cells as compared to untreated 16HBE cells. siRNA-mediated knockdown of ENST00000414355 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA-damage related genes (ATM, ATR and ATRIP), while increased the expressions of DNA-repair related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1). Cadmium increased ENST00000414355 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000414355 expression and urinary/blood Cd concentrations, and there were significant correlations of lncRNA-ENST00000414355 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. These results indicate that some lncRNAs are aberrantly expressed in Cd-treated 16HBE cells. lncRNA-ENST00000414355 may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity.

  10. Influence of repair welding of aged 18Ni 250 maraging steel weldments on tensile and fracture properties

    SciTech Connect

    Sinha, P.P.; Arumugham, S.; Nagarajan, K.V. . Materials and Metallurgy Group)

    1993-08-01

    The effects of repair welding on tensile strength and fracture toughness of aged weldments of 18 Ni 250-grade maraging steel have been studied. It has been established that aged weldments in the steel can be repaired and approximately 95% of the tensile strength of the initial welds could be achieved by postrepair aging treatment. Also, the repairs had practically no effect on the fracture toughness (K[sub IC]) of the weldment. These results have been discussed in terms of microstructural conditions in the various affected and unaffected zones of the initial weld. One important inference that emerges from the mechanical properties-microstructural correlation in the study is that (K[sub IC]) of the weld is independent of the gross microstructural features of the dendritic size and shapes in the ranges observed in this study. It has, however, been cautioned that the above statement is not valid in cases in which heavy segregation occurs along the interdendritic boundaries resulting in heavily banded microstructure. This can result from faulty weld parameters such as excessive heat input. A second aging to recover the mechanical properties of the repaired zone has additional beneficial effects on tensile strengths and helps in maintaining fracture toughness to the original level of the initial weld.

  11. Age and exposure to arsenic alter base excision repair transcript levels in mice.

    PubMed

    Osmond, Megan J; Kunz, Bernard A; Snow, Elizabeth T

    2010-09-01

    Arsenic (As) induces DNA-damaging reactive oxygen species. Most oxidative DNA damage is countered by base excision repair (BER), the capacity for which may be reduced in older animals. We examined whether age and consumption of As in lactational milk or drinking water influences BER gene transcript levels in mice. Lactating mothers and 24-week-old mice were exposed (24 h or 2 weeks) to As (2 or 50 p.p.m.) in drinking water. Lung tissue was harvested from adults, neonates (initially 1 week old) feeding from lactating mothers and untreated animals 1-26 weeks old. Transcripts encoding BER proteins were quantified. BER transcript levels decreased precipitously with age in untreated mice but increased in neonates whose mothers were exposed to 50 p.p.m. As for 24 h or 2 weeks. Treatment of 24-week-old mice with 2 or 50 p.p.m. As for 2 weeks decreased all transcript levels measured. Exposure to As attenuated the age-related transcript level decline for only one BER gene. We conclude that aging is associated with a rapid reduction of BER transcript levels in mice, which may contribute to decreased BER activity in older animals. Levels of As that can alter gene expression are transmitted to neonatal mice in lactational milk produced by mothers drinking water containing As, raising concerns about breastfeeding in countries having As-contaminated groundwater. Reduction of BER transcript levels in 24-week-old mice exposed to As for 2 weeks suggests As may potentiate sensitivity to itself in older animals.

  12. Triple nanoemulsion potentiates the effects of topical treatments with microencapsulated retinol and modulates biological processes related to skin aging *

    PubMed Central

    Afornali, Alessandro; de Vecchi, Rodrigo; Stuart, Rodrigo Makowiecky; Dieamant, Gustavo; de Oliveira, Luciana Lima; Brohem, Carla Abdo; Feferman, Israel Henrique Stokfisz; Fabrício, Lincoln Helder Zambaldi; Lorencini, Márcio

    2013-01-01

    BACKGROUND The sum of environmental and genetic factors affects the appearance and function of the skin as it ages. The identification of molecular changes that take place during skin aging provides biomarkers and possible targets for therapeutic intervention. Retinoic acid in different formulations has emerged as an alternative to prevent and repair age-related skin damage. OBJECTIVES To understand the effects of different retinoid formulations on the expression of genes associated with biological processes that undergo changes during skin aging. METHODS Ex-vivo skin samples were treated topically with different retinoid formulations. The modulation of biological processes associated with skin aging was measured by Reverse Transcription quantitative PCR (RT-qPCR). RESULTS A formulation containing microencapsulated retinol and a blend of active ingredients prepared as a triple nanoemulsion provided the best results for the modulation of biological, process-related genes that are usually affected during skin aging. CONCLUSION This association proved to be therapeutically more effective than tretinoin or microencapsulated retinol used singly. PMID:24474102

  13. Oxygen-induced changes in mitochondrial DNA and DNA repair enzymes in aging rat lens.

    PubMed

    Zhang, Yi; Ouyang, Shan; Zhang, Lan; Tang, Xianling; Song, Zhen; Liu, Ping

    2010-01-01

    The treatment of patients with hyperbaric oxygen (HBO), vitrectomy and loss of vitreous gel during aging is associated with a high risk of subsequent development of nuclear cataract. Many studies proved that oxidation is the key reason of nuclear cataract. Reactive oxygen species (ROS) are formed in mitochondria as a by-product of normal metabolism and as a consequence of exposure to environmental compounds. Therefore, mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage. Oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases and aging. However, the effect of mtDNA damage to the lens has not been studied. The goals of the study were to identify if there was increased mtDNA damage in lens when the eye were exposed to hyperoxic or hypoxic conditions and also to evaluate the changes in gene expression of mtDNA base excision repair (mtBER) enzymes. Our data have shown that the damage of mtDNA, the expression of mtBER enzymes and the level of 8-OHdG in lens increased after inspired hyperoxia, which is likely associated with oxidative stress. However, there was no effect to mtDNA and mtBER enzymes in lens after inspired hypoxia. Nuclear cataract appeared rapidly at 14 month old rats in hyperoxia group, and lens kept transparency in other groups.

  14. "Oxygen supply" as modulator of aging processes: hypoxia and hyperoxia models for aging studies.

    PubMed

    Cataldi, Amelia; Di Giulio, Camillo

    2009-07-01

    Cell growth is regulated by several factors, including oxygen supply, which influence cell metabolism. Aging is characterized by decreased oxygen supply to tissue, a reduction of tissue PO(2) and of the activity of several enzymes and metabolic factors. The oxygen-gradient diffusion at capillary tissue level is essential for the cellular survival, while the homeostasis of the oxygen in the arterial blood is mediated by reflexes sensitive to oxygen decrease and by release of several factors. Aging is correlated with a reduction of cells' oxygen supply concomitant to a parallel decrease in oxygen demand by tissues. Both chronic hypoxia or hyperoxia are considered as stresses. Indeed, in both conditions, free radical species, which damage structural and functional components of the membrane, are generated. ROS (reactive oxygen species) are physiological products of aerobic life and their accumulation affects aging. Because hypoxia per se modulates mitochondria activity, influencing oxygen consumption, hypoxia and aging could share some link. Moreover, the observation that in hypoxia or hyperoxia there is an accumulation of lipofucsine as a general reaction to stress is consistent with the accumulation of such components during aging. Correlation between hypoxia-hyperoxia and life-span remains open until we solve the question of how and why do cells sense oxygen. In other words, to better understand aging we need to know what O(2) species are being sensed by cells. In conclusion, hypoxia and hyperoxia represent an experimental model adequate for studying aging processes.

  15. Modulation of cellular response to anticancer treatment by caffeine: inhibition of cell cycle checkpoints, DNA repair and more.

    PubMed

    Sabisz, Michal; Skladanowski, Andrzej

    2008-08-01

    Caffeine and other methylxanthines produce multiple physiologic effects throughout the human body, many of these effects could potentially modulate the activity of anticancer therapy. Caffeine may directly interfere with drug transport to tumor cells by formation of mixed stacking complexes with polyaromatic drugs. If formed in cells, these complexes may also prevent of intercalating drugs from DNA binding and, in this way, lower their antitumor activity. Since many of potent carcinogens are polyaromatic compounds, formation of stacking complexes with carcinogens could be associated with anti-genotoxic activity of caffeine and its use in cancer chemoprevention. Caffeine has also been reported to inhibit ATM and ATR kinases which leads to the disruption of multiple DNA damage-responsive cell cycle checkpoints and greatly sensitizes tumor cells to antitumor agents which induce genotoxic stress. Caffeine may inhibit repair of DNA lesions through a direct interference with DNA-PK activity and other repair enzymes. A number of in vitro and in vivo studies demonstrated that caffeine modulates both innate and adaptive immune responses via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase. Finally, another group of effects induced by caffeine is mediated through its inhibitory action on adenosine receptors. This may modulate the stability of HIF1 alpha as well as VEGF and interleukin-8 expression in tumor cells, which could have a direct impact on neovascularization of human tumors. In this review, we present different molecular mechanisms by which caffeine and other methylxanthines may directly or indirectly modulate the effect of antitumor treatment in tumor cells and in cancer patients.

  16. Energetic Coupling Between Clustered Lesions Modulated by Intervening Triplet Repeat Bulge Loops: Allosteric Implications for DNA Repair and Triplet Repeat Expansion

    PubMed Central

    Völker, Jens; Plum, G.Eric; Klump, Horst H.; Breslauer, Kenneth J.

    2013-01-01

    Clusters of closely spaced oxidative DNA lesions present challenges to the cellular repair machinery. When located in opposing strands, base excision repair (BER) of such lesions can lead to double strand DNA breaks (DSB). Activation of BER and DSB repair pathways has been implicated in inducing enhanced expansion of triplet repeat sequences. We show here that energy coupling between distal lesions (8oxodG and/or abasic sites) in opposing DNA strands can be modulated by a triplet repeat bulge loop located between the lesion sites. We find this modulation to be dependent on the identity of the lesions (8oxodG versus abasic site) and the positions of the lesions (upstream versus downstream) relative to the intervening bulge loop domain. We discuss how such bulge loop-mediated lesion cross talk might influence repair processes, while favoring DNA expansion, the genotype of triplet repeat diseases. PMID:19890964

  17. Age modulates attitudes to whole body donation among medical students.

    PubMed

    Perry, Gary F; Ettarh, Raj R

    2009-01-01

    Managing a whole body donor program is necessary for facilitating a traditional dissection-based anatomy curriculum in medicine and health sciences. Factors which influence body donations to medical science can therefore affect dissection-based anatomy teaching. In order to determine whether age influences the attitudes of medical students to donations, this study surveyed, by Likert-type questionnaires, first-year graduate-entry medical students attending a dissection-based anatomy course. In contrast to attitudes among younger traditional-entry medical students, initial support for whole body donation by an unrelated stranger (83.8%), a family member (43.2%) or by the respondent (40.5%) did not decrease among graduate-entry medical students after exposure to dissection although there was a significant shift in strength of support for donation by stranger. This suggests that older medical students do not readily modify their pre-established attitudes to the idea of whole body donation after exposure and experience with dissection. Initial ambivalence among respondents to the idea of donation by family member was followed by opposition to this type of donation. These findings demonstrate that age modulates the influences on a priori attitudes to whole body donation that exposure to dissection causes in younger medical students.

  18. Small Engine Repair Modules (Workbook) = Reparacion de Motores Pequenos (Guia de Trabajo)

    ERIC Educational Resources Information Center

    New York State Dept. of Correctional Services, Albany.

    This package contains an English-Language set of task procedure sheets dealing with small-engine repair and a Spanish translation of the same material. Addressed in the individual sections of the manual are the following aspects of engine tune-up, reconditioning, and troubleshooting: servicing air cleaners; cleaning gas tanks, fuel lines, and fuel…

  19. Low-level infrared laser modulates muscle repair and chromosome stabilization genes in myoblasts.

    PubMed

    da Silva Neto Trajano, Larissa Alexsandra; Stumbo, Ana Carolina; da Silva, Camila Luna; Mencalha, Andre Luiz; Fonseca, Adenilson S

    2016-08-01

    Infrared laser therapy is used for skeletal muscle repair based on its biostimulative effect on satellite cells. However, shortening of telomere length limits regenerative potential in satellite cells, which occurs after each cell division cycle. Also, laser therapy could be more effective on non-physiologic tissues. This study evaluated low-level infrared laser exposure effects on mRNA expression from muscle injury repair and telomere stabilization genes in myoblasts in normal and stressful conditions. Laser fluences were those used in clinical protocols. C2C12 myoblast cultures were exposed to low-level infrared laser (10, 35, and 70 J/cm(2)) in standard or normal (10 %) and reduced (2 %) fetal bovine serum concentrations; total RNA was extracted for mRNA expression evaluation from muscle injury repair (MyoD and Pax7) and chromosome stabilization (TRF1 and TRF2) genes by real time quantitative polymerization chain reaction. Data show that low-level infrared laser increases the expression of MyoD and Pax7 in 10 J/cm(2) fluence, TRF1 expression in all fluences, and TRF2 expression in 70 J/cm(2) fluence in both 10 and 2 % fetal bovine serum. Low-level infrared laser increases mRNA expression from genes related to muscle repair and telomere stabilization in myoblasts in standard or normal and stressful conditions.

  20. Nucleotide excision repair efficiency in quiescent human fibroblasts is modulated by circadian clock

    PubMed Central

    Bee, Leonardo; Marini, Selena; Pontarin, Giovanna; Ferraro, Paola; Costa, Rodolfo; Albrecht, Urs; Celotti, Lucia

    2015-01-01

    The efficiency of Nucleotide Excision Repair (NER)process is crucial for maintaining genomic integrity because in many organisms, including humans, it represents the only system able to repair a wide range of DNA damage. The aim of the work was to investigate whether the efficiency of the repair of photoproducts induced by UV-light is affected by the circadian phase at which irradiation occurred. NER activity has been analyzed in human quiescent fibroblasts (in the absence of the cell cycle effect), in which circadian rhythmicity has been synchronized with a pulse of dexamethasone. Our results demonstrate that both DNA damage induction and repair efficiency are strictly dependent on the phase of the circadian rhythm at which the cells are UV-exposed. Furthermore, the differences observed between fibroblasts irradiated at different circadian times (CTs) are abolished when the clock is obliterated. In addition, we observe that chromatin structure is regulated by circadian rhythmicity. Maximal chromatin relaxation occurred at the same CT when photoproduct formation and removal were highest. Our data suggest that the circadian clock regulates both the DNA sensitivity to UV damage and the efficiency of NER by controlling chromatin condensation mainly through histone acetylation. PMID:25662220

  1. Small Engine Repair Modules (Workbook) = Reparacion de Motores Pequenos (Guia de Trabajo)

    ERIC Educational Resources Information Center

    New York State Dept. of Correctional Services, Albany.

    This package contains an English-Language set of task procedure sheets dealing with small-engine repair and a Spanish translation of the same material. Addressed in the individual sections of the manual are the following aspects of engine tune-up, reconditioning, and troubleshooting: servicing air cleaners; cleaning gas tanks, fuel lines, and fuel…

  2. ADJUSTMENT, MAINTENANCE, AND REPAIR OF SMALL GASOLINE ENGINES. AGRICULTURAL MACHINERY--SERVICE OCCUPATIONS, MODULE NUMBER 12.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Center for Vocational and Technical Education.

    ONE OF A SERIES DESIGNED TO HELP TEACHERS PREPARE POSTSECONDARY STUDENTS FOR THE AGRICULTURAL MACHINERY SERVICE OCCUPATIONS AS PARTS MEN, MECHANICS, MECHANIC'S HELPERS, OR SERVICE SUPERVISORS, THIS GUIDE AIMS TO DEVELOP STUDENT COMPETENCY IN THE ADJUSTMENT, MAINTENANCE, AND REPAIR OF SMALL GASOLINE ENGINES. IT WAS DEVELOPED BY A NATIONAL TASK…

  3. ADJUSTMENT, MAINTENANCE, AND REPAIR OF CROP HARVESTING MACHINERY. AGRICULTURAL MACHINERY--SERVICE OCCUPATIONS, MODULE NUMBER 11.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Center for Vocational and Technical Education.

    ONE OF A SERIES DESIGNED FOR HELPING TEACHERS PREPARE POSTSECONDARY-LEVEL STUDENTS FOR AGRICULTURAL MACHINERY SERVICE OCCUPATIONS AS PARTS MEN, MECHANICS, MECHANIC'S HELPERS, AND SERVICE SUPERVISORS, THIS GUIDE AIMS TO DEVELOP STUDENT COMPETENCY IN ADJUSTING, REPAIRING, AND MAINTAINING CROP HARVESTING MACHINERY. SUGGESTIONS FOR INTRODUCTION OF THE…

  4. EGFR Modulates DNA Synthesis and Repair through Tyr Phosphorylation of Histone H4

    PubMed Central

    Chou, Ruey-Hwang; Wang, Ying-Nai; Hsieh, Yi-Hsien; Li, Long-Yuan; Xia, Weiya; Chang, Wei-Chao; Chang, Ling-Chu; Cheng, Chien-Chia; Lai, Chien-Chen; Hsu, Jennifer L.; Chang, Wei-Jung; Chiang, Shu-Ya; Lee, Hong-Jen; Liao, Hsin-Wei; Chuang, Pei-Huan; Chen, Hui-Yu; Wang, Hung-Ling; Kuo, Sheng-Chu; Chen, Chung-Hsuan; Yu, Yung-Luen; Hung, Mien-Chie

    2014-01-01

    Summary Posttranslational modifications of histones play fundamental roles in many biological functions. Specifically, histone H4-K20 methylation is critical in DNA synthesis and repair. However, little is known about how these functions are regulated by the upstream stimuli. Here, we identify a tyrosine phosphorylation site at Y72 of histone H4, which facilitates recruitment of histone methyltransferases (HMTases), SET8 and SUV4-20H, to enhance its K20 methylation, thereby promoting DNA synthesis and repair. Phosphorylation-defective histone H4 mutant is deficient in K20 methylation, leading to reduced DNA synthesis, delayed cell cycle progression, and decreased DNA repair ability. Disrupting the interaction between epidermal growth factor receptor (EGFR) and histone H4 by Y72 peptide significantly reduced tumor growth. Furthermore, EGFR expression clinically correlates with histone H4-Y72 phosphorylation, H4-K20 mono-methylation, and the Ki-67 proliferation marker. These findings uncover a mechanism by which EGFR transduces signal to chromatin to regulate DNA synthesis and repair. PMID:25073158

  5. Aerobic endurance capacity affects spatial memory and SIRT1 is a potent modulator of 8-oxoguanine repair

    PubMed Central

    Sarga, Linda; Hart, Nikolett; Koch, Lauren; Britton, Steve; Hajas, Gyorgy; Boldogh, Istvan; Ba, Xuequing; Radak, Zsolt

    2013-01-01

    Regular exercise promotes brain function via a wide range of adaptive responses, including the increased expression of antioxidant and oxidative DNA damage-repairing systems. Accumulation of oxidized DNA base lesions and strand breaks is etiologically linked to for example aging processes and age-associated diseases. Here we tested whether exercise training has an impact on brain function, extent of neurogenesis, and expression of 8-oxoguanine DNA glycosylase-1 (Ogg1) and SIRT1 (silent mating type information regulation 2 homolog). To do so, we utilized strains of rats with low- and high- running capacity (LCR and HCR) and examined learning and memory, DNA synthesis, expression, and posttranslational modification of Ogg1 hippocampal cells. Our results showed that rats with higher aerobic/running capacity had better spatial memory, and expressed less Ogg1, when compared to LCR rats. Furthermore, exercise increased SIRT1 expression and decreased acetylated Ogg1 (AcOgg1) levels, a post-translational modification important for efficient repair of 8-oxoG. Our data on cell cultures revealed that nicotinamide, a SIRT1-specific inhibitor, caused the greatest increase in the acetylation of Ogg1, a finding further supported by our other observations that silencing SIRT1 also markedly increased the levels of AcOgg1. These findings imply that high-running capacity is associated with increased hippocampal function, and SIRT1 level/activity and inversely correlates with AcOgg1 levels and thereby the repair of genomic 8-oxoG. PMID:23973402

  6. Nutritional modulation of age-related macular degeneration.

    PubMed

    Weikel, Karen A; Chiu, Chung-Jung; Taylor, Allen

    2012-08-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. It affects 30-50 million individuals and clinical hallmarks of AMD are observed in at least one third of persons over the age of 75 in industrialized countries (Gehrs et al., 2006). Costs associated with AMD are in excess of $340 billion US (American-Health-Assistance-Foundation, 2012). The majority of AMD patients in the United States are not eligible for clinical treatments (Biarnes et al., 2011; Klein et al., 2011). Preventive interventions through dietary modulation are attractive strategies because many studies suggest a benefit of micro- and macronutrients with respect to AMD, as well as other age-related debilities, and with few, if any, adverse effects (Chiu, 2011). Preservation of vision would enhance quality of life for millions of elderly people, and alleviate the personal and public health financial burden of AMD (Frick et al., 2007; Wood et al., 2011). Observational studies indicate that maintaining adequate levels of omega-3 fatty acids (i.e. with 2 servings/week of fish) or a low glycemic index diet may be particularly beneficial for early AMD and that higher levels of carotenoids may be protective, most probably, against neovascular AMD. Intervention trials are needed to better understand the full effect of these nutrients and/or combinations of nutrients on retinal health. Analyses that describe effects of a nutrient on onset and/or progress of AMD are valuable because they indicate the value of a nutrient to arrest AMD at the early stages. This comprehensive summary provides essential information about the value of nutrients with regard to diminishing risk for onset or progress of AMD and can serve as a guide until data from ongoing intervention trials are available.

  7. Nutritional Modulation of Age-Related Macular Degeneration

    PubMed Central

    Weikel, Karen A; Taylor, Allen

    2012-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. It affects 30–50 million individuals and clinical hallmarks of AMD are observed in at least one third of persons over the age of 75 in industrialized countries (Gehrs et al., 2006). Costs associated with AMD are in excess of $340 billion US (American-Health-Assistance-Foundation, 2012). The majority of AMD patients in the United States are not eligible for clinical treatments (Biarnes et al., 2011; Klein et al., 2011). Preventive interventions through dietary modulation are attractive strategies because many studies suggest a benefit of micro and macronutrients with respect to AMD, as well as other age-related debilities, and with few, if any, adverse effects (Chiu, 2011). Preservation of vision would enhance quality of life for millions of elderly people, and alleviate the personal and public health financial burden of AMD (Frick et al., 2007; Wood et al., 2011). Observational studies indicate that maintaining adequate levels of omega-3 fatty acids (i.e. with 2 servings/wk of fish) or a low glycemic index diet may be particularly beneficial for early AMD and that higher levels of carotenoids may be protective, most probably, against neovascular AMD. Intervention trials are needed to better understand the full effect of these nutrients and/or combinations of nutrients on retinal health. Analyses that describe effects of a nutrient on onset and/or progress of AMD are valuable because they indicate the value of a nutrient to arrest AMD at the early stages. This comprehensive summary provides essential information about the value of nutrients with regard to diminishing risk for onset or progress of AMD and can serve as a guide until data from ongoing intervention trials are available. PMID:22503690

  8. DNA repair after gamma radiation and superoxide dismutase activity in lymphocytes from subjects of far advanced age

    SciTech Connect

    Licastro, F.; Chiricolo, M.; Battelli, M.G. . Inst. of General Pathology); Franceschi, C. . Inst. of General Pathology); Tabacchi, P.; Cenci, M.; Barboni, F. . Lab. of Clinical Analysis); Pallenzona, D. . Ist. di Genetica)

    1982-01-01

    DNA repair after gamma radiation was studied in purified T lymphocytes from young and aged subjects. Two different assays were employed. In the first, T lymphocytes were stimulated with phytohemagglutinin (PHA) for 72 h and then treated with hydroxyurea, irradiated with 30 K rads and pulsed with (/sup 3/H)thymidine (TdR) for 4 h. In the second, T lymphocytes were first irradiated with graded doses of gamma rays (200-800 rads) and then stimulated with PHA, cultured for 72 h and pulsed with /sup 3/H-TdR for the last 6 h of culture. T lymphocytes from aged subjects showed a lack of DNA repair synthesis in the first assay whereas only minor differences were found in the second assay between the two groups, i.e., a certain degree of radioresistance in aged lymphocytes. Lymphocyte superoxide dismutase activity showed great individual variations in both groups and a slight increase in old subjects.

  9. Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice.

    PubMed

    Nicolaije, Claudia; Diderich, Karin E M; Botter, S M; Priemel, Matthias; Waarsing, Jan H; Day, Judd S; Brandt, Renata M C; Schilling, Arndt F; Weinans, Harrie; Van der Eerden, Bram C; van der Horst, Gijsbertus T J; Hoeijmakers, Jan H J; van Leeuwen, Johannes P T M

    2012-01-01

    Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength.

  10. Dopamine Receptor Genes Modulate Associative Memory in Old Age.

    PubMed

    Papenberg, Goran; Becker, Nina; Ferencz, Beata; Naveh-Benjamin, Moshe; Laukka, Erika J; Bäckman, Lars; Brehmer, Yvonne

    2017-02-01

    Previous research shows that associative memory declines more than item memory in aging. Although the underlying mechanisms of this selective impairment remain poorly understood, animal and human data suggest that dopaminergic modulation may be particularly relevant for associative binding. We investigated the influence of dopamine (DA) receptor genes on item and associative memory in a population-based sample of older adults (n = 525, aged 60 years), assessed with a face-scene item associative memory task. The effects of single-nucleotide polymorphisms of DA D1 (DRD1; rs4532), D2 (DRD2/ANKK1/Taq1A; rs1800497), and D3 (DRD3/Ser9Gly; rs6280) receptor genes were examined and combined into a single genetic score. Individuals carrying more beneficial alleles, presumably associated with higher DA receptor efficacy (DRD1 C allele; DRD2 A2 allele; DRD3 T allele), performed better on associative memory than persons with less beneficial genotypes. There were no effects of these genes on item memory or other cognitive measures, such as working memory, executive functioning, fluency, and perceptual speed, indicating a selective association between DA genes and associative memory. By contrast, genetic risk for Alzheimer disease (AD) was associated with worse item and associative memory, indicating adverse effects of APOE ε4 and a genetic risk score for AD (PICALM, BIN1, CLU) on episodic memory in general. Taken together, our results suggest that DA may be particularly important for associative memory, whereas AD-related genetic variations may influence overall episodic memory in older adults without dementia.

  11. Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair

    SciTech Connect

    Guttmann, David M.; Hart, Lori; Du, Kevin; Seletsky, Andrew; Koumenis, Constantinos

    2013-09-01

    Purpose: To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. Methods and Materials: Clonogenic survival assays, immunoblotting, the proximity ligation assay, and γH2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. Results: Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. Conclusions: These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

  12. Probiotic modulation of dendritic cell function is influenced by ageing.

    PubMed

    You, Jialu; Dong, Honglin; Mann, Elizabeth R; Knight, Stella C; Yaqoob, Parveen

    2014-02-01

    Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, Lactobacillus rhamnosus GG (L.GG) and L. casei Shirota (LcS), on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-β, TNF-α) by old DCs only. LcS induced IL-12 and IFNγ production by DC to a greater degree than other strains, while B. longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR.

  13. Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence.

    PubMed Central

    Whatmore, A M; Cook, N; Hall, G A; Sharpe, S; Rud, E W; Cranage, M P

    1995-01-01

    Experimental evidence from the simian immunodeficiency virus (SIV) model of AIDS has shown that the nef gene is critical in the pathogenesis of AIDS. Consequently, nef is of considerable interest in both antiviral drug and vaccine development. Preliminary findings in two rhesus macaques indicated that a deletion of only 12 bp found in the overlapping nef/3' long terminal repeat (LTR) region (9501 to 9512) of the SIVmacC8 molecular clone was associated with reduced virus isolation frequency. We show that this deletion can be repaired in vivo by a sequence duplication event and that sequence evolution continues until the predicted amino acid sequence of the repair is virtually indistinguishable from that of the virulent wild type. These changes occurred concomitantly with reversion to virulence, evidenced by a high virus isolation frequency and load, decline in anti-p27 antibody, substantial reduction in the CD4/CD8 ratio, and development of opportunistic infections associated with AIDS. These findings clearly illustrate the capacity for repair of small attenuating deletions in primate lentiviruses and also strongly suggest that the region from 9501 to 9512 in the SIV nef/3' LTR region is of biological relevance. In addition, the ability of attenuated virus to revert to virulence raises fundamental questions regarding the nature of superinfection immunity. PMID:7609080

  14. The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair

    PubMed Central

    Bassi, C; Li, Y-T; Khu, K; Mateo, F; Baniasadi, P S; Elia, A; Mason, J; Stambolic, V; Pujana, M A; Mak, T W; Gorrini, C

    2016-01-01

    The acetyltransferase Tip60/Kat5 acetylates both histone and non-histone proteins, and is involved in a variety of biological processes. By acetylating p53, Tip60 controls p53-dependent transcriptional activity and so is implicated as a tumor suppressor. However, many breast cancers with low Tip60 also show p53 mutation, implying that Tip60 has a tumor suppressor function independent of its acetylation of p53. Here, we show in a p53-null mouse model of sporadic invasive breast adenocarcinoma that heterozygosity for Tip60 deletion promotes mammary tumorigenesis. Low Tip60 reduces DNA repair in normal and tumor mammary epithelial cells, both under resting conditions and following genotoxic stress. We demonstrate that Tip60 controls homologous recombination (HR)-directed DNA repair, and that Tip60 levels correlate inversely with a gene expression signature associated with defective HR-directed DNA repair. In human breast cancer data sets, Tip60 mRNA is downregulated, with low Tip60 levels correlating with p53 mutations in basal-like breast cancers. Our findings indicate that Tip60 is a novel breast tumor suppressor gene whose loss results in genomic instability leading to cancer formation. PMID:26915295

  15. FBW7 regulates DNA interstrand cross-link repair by modulating FAAP20 degradation

    PubMed Central

    Wang, Jingming; Jo, Ukhyun; Joo, So Young; Kim, Hyungjin

    2016-01-01

    Mutations that deregulate protein degradation lead to human malignancies. The SCF ubiquitin E3 ligase complex degrades key oncogenic regulators, thereby limiting their oncogenic potential. FBW7 is a substrate recognition subunit of SCFFBW7 and is among the most commonly mutated ubiquitin-proteasome system proteins in cancer. FBW7-mutated cancer cells display increased genome instability, but the molecular mechanism by which FBW7 preserves genome integrity remains elusive. Here, we demonstrate that SCFFBW7 regulates the stability of FAAP20, a critical component of the Fanconi anemia (FA) DNA interstrand cross-link (ICL) repair pathway. Phosphorylation of the FAAP20 degron motif by GSK3β provides a platform for recognition and polyubiquitination of FAAP20 by FBW7, and its subsequent degradation by the proteasome. Accordingly, enhanced GSK3β-FBW7 signaling disrupts the FA pathway. In cells expressing non-phosphorylatable FAAP20 mutant, the turnover of its binding partner, FANCA, is deregulated in the chromatin during DNA ICL repair, and the FA pathway is compromised. We propose that FAAP20 degradation, which is prompted by its phosphorylation, controls the dynamics of the FA core complex required for completing DNA ICL repair. Together, this study provides insights into how FBW7-mediated proteolysis regulates genome stability and how its deregulation is associated with tumorigenesis. PMID:27232758

  16. Molecular ageing of alpha- and Beta-synucleins: protein damage and repair mechanisms.

    PubMed

    Vigneswara, Vasanthy; Cass, Simon; Wayne, Declan; Bolt, Edward L; Ray, David E; Carter, Wayne G

    2013-01-01

    Abnormal α-synuclein aggregates are hallmarks of a number of neurodegenerative diseases. Alpha synuclein and β-synucleins are susceptible to post-translational modification as isoaspartate protein damage, which is regulated in vivo by the action of the repair enzyme protein L-isoaspartyl O-methyltransferase (PIMT). We aged in vitro native α-synuclein, the α-synuclein familial mutants A30P and A53T that give rise to Parkinsonian phenotypes, and β-synuclein, at physiological pH and temperature for a time course of up to 20 days. Resolution of native α-synuclein and β-synuclein by two dimensional techniques showed the accumulation of a number of post-translationally modified forms of both proteins. The levels of isoaspartate formed over the 20 day time course were quantified by exogenous methylation with PIMT using S-Adenosyl-L-[(3)H-methyl]methionine as a methyl donor, and liquid scintillation counting of liberated (3)H-methanol. All α-synuclein proteins accumulated isoaspartate at ∼1% of molecules/day, ∼20 times faster than for β-synuclein. This disparity between rates of isoaspartate was confirmed by exogenous methylation of synucleins by PIMT, protein resolution by one-dimensional denaturing gel electrophoresis, and visualisation of (3)H-methyl esters by autoradiography. Protein silver staining and autoradiography also revealed that α-synucleins accumulated stable oligomers that were resistant to denaturing conditions, and which also contained isoaspartate. Co-incubation of approximately equimolar β-synuclein with α-synuclein resulted in a significant reduction of isoaspartate formed in all α-synucleins after 20 days of ageing. Co-incubated α- and β-synucleins, or α, or β synucleins alone, were resolved by non-denaturing size exclusion chromatography and all formed oligomers of ∼57.5 kDa; consistent with tetramerization. Direct association of α-synuclein with β-synuclein in column fractions or from in vitro ageing co-incubations was

  17. Genetic Polymorphisms in DNA Repair Genes as Modulators of Hodgkin Disease Risk

    PubMed Central

    El-Zein, Randa; Monroy, Claudia M.; Etzel, Carol J.; Cortes, Andrea C.; Xing, Yun; Collier, Amanda L.; Strom, Sara S.

    2009-01-01

    BACKGROUND Although the pathogenesis of Hodgkin disease (HD) remains unknown, the results of epidemiologic studies suggest that heritable factors are important in terms of susceptibility. Polymorphisms in DNA repair genes may contribute to individual susceptibility for development of different cancers. However, to the authors’ knowledge, few studies to date have investigated the role of such polymorphisms as risk factors for development of HD. METHODS The authors evaluated the relation between polymorphisms in 3 nucleotide excision repair pathway genes (XPD [Lys751Gln], XPC [Lys939Gln], and XPG [Asp1104His]), the base excision repair XRCC1 (Arg399Gln), and double-strand break repair XRCC3 (Thr241Met) in a population of 200 HD cases and 220 matched controls. Variants were investigated independently and in combination; odd ratios (OR) were calculated. RESULTS A positive association was found for XRCC1 gene polymorphism Arg399Gln (OR, 1.77; 95% confidence interval [95% CI], 1.16−2.71) and risk of HD. The combined analysis demonstrated that XRCC1/XRCC3 and XRCC1/XPC polymorphisms were associated with a significant increase in HD risk. XRCC1 Arg/Arg and XRCC3 Thr/Met genotypes combined were associated with an OR of 2.38 (95% CI, 1.24−4.55). The XRCC1 Arg/Gln and XRCC3 Thr/Thr, Thr/Met, and Met/Met genotypes had ORs of 1.88 (95% CI, 1.02−4.10), 1.97 (95% CI, 1.05−3.73), and 4.13 (95% CI, 1.50−11.33), respectively. XRCC1 Gln/Gln and XRCC3 Thr/Thr variant led to a significant increase in risk, with ORs of 3.00 (95% CI, 1.15−7.80). Similarly, XRCC1 Arg/Gln together with XPC Lys/Lys was found to significantly increase the risk of HD (OR, 2.14; 95% CI, 1.09−4.23). CONCLUSIONS These data suggest that genetic polymorphisms in DNA repair genes may modify the risk of HD, especially when interactions between the pathways are considered. PMID:19280628

  18. Human Envelope Following Responses to Amplitude Modulation: Effects of Aging and Modulation Depth.

    PubMed

    Dimitrijevic, Andrew; Alsamri, Jamal; John, M Sasha; Purcell, David; George, Sahara; Zeng, Fan-Gang

    2016-01-01

    To record envelope following responses (EFRs) to monaural amplitude-modulated broadband noise carriers in which amplitude modulation (AM) depth was slowly changed over time and to compare these objective electrophysiological measures to subjective behavioral thresholds in young normal hearing and older subjects. three groups of subjects included a young normal-hearing group (YNH 18 to 28 years; pure-tone average = 5 dB HL), a first older group ("O1"; 41 to 62 years; pure-tone average = 19 dB HL), and a second older group ("O2"; 67 to 82 years; pure-tone average = 35 dB HL). Electrophysiology: In condition 1, the AM depth (41 Hz) of a white noise carrier, was continuously varied from 2% to 100% (5%/s). EFRs were analyzed as a function of the AM depth. In condition 2, auditory steady-state responses were recorded to fixed AM depths (100%, 75%, 50%, and 25%) at a rate of 41 Hz. Psychophysics: A 3 AFC (alternative forced choice) procedure was used to track the AM depth needed to detect AM at 41 Hz (AM detection). The minimum AM depth capable of eliciting a statistically detectable EFR was defined as the physiological AM detection threshold. Across all ages, the fixed AM depth auditory steady-state response and swept AM EFR yielded similar response amplitudes. Statistically significant correlations (r = 0.48) were observed between behavioral and physiological AM detection thresholds. Older subjects had slightly higher (not significant) behavioral AM detection thresholds than younger subjects. AM detection thresholds did not correlate with age. All groups showed a sigmoidal EFR amplitude versus AM depth function but the shape of the function differed across groups. The O2 group reached EFR amplitude plateau levels at lower modulation depths than the normal-hearing group and had a narrower neural dynamic range. In the young normal-hearing group, the EFR phase did not differ with AM depth, whereas in the older group, EFR phase showed a consistent decrease with increasing

  19. Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging.

    PubMed

    Martín-Guerrero, Idoia; de Prado, Elena; Lopez-Lopez, Elixabet; Ardanaz, Maite; Vitoria, Juan Carlos; Parada, Luis A; García-Orad, Cristina; García-Orad, Africa

    2014-01-01

    Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis. Indeed, several of the so-called tumor specific translocations have been detected in peripheral blood of healthy individuals, finding a higher frequency of some of them with aging. The inappropriate repair of DNA double strand breaks by the nonhomologous end joining (NHEJ) pathway is one of the reasons for a translocation to occur. Moreover, fidelity of this pathway has been shown to decline with age. Although the mechanism underlying this inefficacy is unknown, other repair pathways are inactivated by methylation with aging. In this study, we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age. To this aim, we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes. We found higher frequency of BCL2-JH and BCR-ABL (major) translocations with aging. In addition, we detected that two NHEJ genes (LIG4 and XRCC6) presented age-dependent promoter methylation changes. However, we did not observe a correlation between the increase of translocations and methylation, indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging.

  20. Nutrition and the Older Adult. Module A-9. Block A. Basic Knowledge of the Aging Process.

    ERIC Educational Resources Information Center

    Harvey, Dexter; Cap, Orest

    This instructional module on nutrition and the older adult is one in a block of 10 modules designed to provide the human services worker who works with older adults with basic information regarding the aging process. An introduction provides an overview of the module content. A listing of general objectives follows. Five sections present…

  1. Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells.

    PubMed

    Poletto, Mattia; Yang, Di; Fletcher, Sally C; Vendrell, Iolanda; Fischer, Roman; Legrand, Arnaud J; Dianov, Grigory L

    2017-09-29

    Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  2. Microsatellites in the Eukaryotic DNA Mismatch Repair Genes as Modulators of Evolutionary Mutation Rate

    NASA Technical Reports Server (NTRS)

    Chang, Dong Kyung; Metzgar, David; Wills, Christopher; Boland, C. Richard

    2003-01-01

    All "minor" components of the human DNA mismatch repair (MMR) system-MSH3, MSH6, PMS2, and the recently discovered MLH3-contain mononucleotide microsatellites in their coding sequences. This intriguing finding contrasts with the situation found in the major components of the DNA MMR system-MSH2 and MLH1-and, in fact, most human genes. Although eukaryotic genomes are rich in microsatellites, non-triplet microsatellites are rare in coding regions. The recurring presence of exonal mononucleotide repeat sequences within a single family of human genes would therefore be considered exceptional.

  3. Dynamic range in BOLD modulation: lifespan aging trajectories and association with performance.

    PubMed

    Kennedy, Kristen M; Boylan, Maria A; Rieck, Jenny R; Foster, Chris M; Rodrigue, Karen M

    2017-09-05

    Alteration of dynamic range of modulation to cognitive difficulty has been proposed as a salient predictor of cognitive aging. Here, we examine in 171 adults (aged 20-94 years) the effects of age on dynamic modulation of blood oxygenation-level dependent activation to difficulty in parametrically increasing working memory (WM) load (0-, 2-, 3-, and 4-back conditions). First, we examined parametric increases and decreases in activation to increasing WM load (positive modulation effect and negative modulation effect). Second, we examined the effect of age on modulation to difficulty (WM load) to identify regions that differed with age as difficulty increased (age-related positive and negative modulation effects). Weakened modulation to difficulty with age was found in both the positive modulation (middle frontal, superior/inferior parietal) and negative modulation effect (deactivated) regions (insula, cingulate, medial superior frontal, fusiform, and parahippocampal gyri, hippocampus, and lateral occipital cortex). Age-related alterations to positive modulation emerged later in the lifespan than negative modulation. Furthermore, these effects were significantly coupled in that greater upmodulation was associated with lesser downmodulation. Importantly, greater fronto-parietal upmodulation to difficulty and greater downmodulation of deactivated regions were associated with better task accuracy and upmodulation with better WM span measured outside the scanner. These findings suggest that greater dynamic range of modulation of activation to cognitive challenge is in service of current task performance, as well as generalizing to cognitive ability beyond the scanner task, lending support to its utility as a marker of successful cognitive aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Endothelial Aging Associated with Oxidative Stress Can Be Modulated by a Healthy Mediterranean Diet

    PubMed Central

    Marín, Carmen; Yubero-Serrano, Elena M; López-Miranda, José; Pérez-Jiménez, Francisco

    2013-01-01

    Aging is a condition which favors the development of atherosclerosis, which has been associated with a breakdown in repair processes that occurs in response to cell damage. The dysregulation of the biological systems associated with aging are produced partly through damage which accumulates over time. One major source of this injury is oxidative stress, which can impair biological structures and the mechanisms by which they are repaired. These mechanisms are based on the pathogenesis of endothelial dysfunction, which in turn is associated with cardiovascular disease, carcinogenesis and aging. The dependent dysfunction of aging has been correlated with a reduction in the number and/or functional activity of endothelial progenitor cells, which could hinder the repair and regeneration of the endothelium. In addition, aging, inflammation and oxidative stress are endogenous factors that cause telomere shortening, which is dependent on oxidative cell damage. Moreover, telomere length correlates with lifestyle and the consumption of a healthy diet. Thus, diseases associated with aging and age may be caused by the long-term effects of oxidative damage, which are modified by genetic and environmental factors. Considering that diet is a very important source of antioxidants, in this review we will analyze the relationship between oxidative stress, aging, and the mechanisms which may be involved in a higher survival rate and a lower incidence of the diseases associated with aging in populations which follow a healthy diet. PMID:23615475

  5. Studies in flexor tendon reconstruction: biomolecular modulation of tendon repair and tissue engineering.

    PubMed

    Chang, James

    2012-03-01

    The Andrew J. Weiland Medal is presented each year by the American Society for Surgery of the Hand and the American Foundation for Surgery of the Hand for a body of work related to hand surgery research. This essay, awarded the Weiland Medal in 2011, focuses on the clinical need for flexor tendon reconstruction and on investigations into flexor tendon biology. Reconstruction of the upper extremity is limited by 2 major problems after injury or degeneration of the flexor tendons. First, adhesions formed after flexor tendon repair can cause decreased postoperative range of motion and hand function. Second, tendon losses can result from trauma and degenerative diseases, necessitating additional tendon graft material. Tendon adhesions are even more prevalent after tendon grafting; therefore these 2 problems are interrelated and lead to considerable disability. The total costs in terms of disability and inability to return to work are enormous. In this essay, published work from the past 12 years in our basic science laboratory is summarized and presented with the common theme of using molecular techniques to understand the cellular process of flexor tendon wound healing and to create substances and materials to improve tendon repair and regeneration. These are efforts to address 2 interrelated and clinically relevant problems that all hand surgeons face in their practice. Copyright © 2012 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  6. Effect of aging conditions on the repair bond strength of a microhybrid and a nanohybrid resin composite.

    PubMed

    Ozcan, Mutlu; Cura, Cenk; Brendeke, Johannes

    2010-12-01

    this study evaluated the effect of different aging methods on the repair bond strength and failure types of a microhybrid and a nanohybrid composite. disk-shaped microhybrid (Quadrant Anterior Shine-QA) and nanohybrid (Tetric EvoCeram-TE) resin composite specimens (N = 192, n = 12/per group) were photopolymerized and randomly assigned to one of the three aging conditions: (1) immersion in deionized water (37°C, 2 months), (2) thermocycling (5000 times, 5 to 55 °C), (3) immersion in citric acid (pH: 3.0; 1 week). The control group was stored dry for 24 h at 37°C. After aging procedures, the specimens were silica coated (30 microm SiO2) (CoJet-Sand) using an intraoral air abrasion device, silanized (ESPESil) and an intermediate adhesive resin was applied (Visio-Bond, 3M ESPE). Resin composites, once of the same kind as the substrate (QA-QA, TE-TE) and once other than the substrate material (QA-TE, TE-QA) were adhered onto the conditioned substrates. Shear force was applied to the adhesive interface in a universal testing machine (cross-head speed: 1 mm/min). a significant influence of the aging method was observed (p < 0.05) but the composite type did not affect the repair bond strength (p = 0.755) (2-way ANOVA, Tukey's test). Interaction terms were significant (p < 0.05). Thermocycling showed lower results (10 ± 2.6 to 14.4 ± 4.4 MPa) than those of other aging methods (12.7 ± 5.2 to 28 ± 5.3 MPa). Using the substrate and the adherend interchangeably (QA-TE, TE-QA) did not show significant differences in the control group, but the results were significant after aging (p = 0.007) (2-way ANOVA, Tukey's test). Interaction terms were not significant (p = 0.124). The incidence of score A (cohesive failures in the substrate) was not significant between the composite combinations in the control groups (exclusively 100%) and water-storage aged groups (92% to 100%) (p > 0.05) (chi-square). Citric acid aging yielded significantly less incidence of score A (8

  7. Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer's disease.

    PubMed

    Gredilla, Ricardo; Weissman, Lior; Yang, Jenq-Lin; Bohr, Vilhelm A; Stevnsner, Tinna

    2012-04-01

    Brain aging is associated with synaptic decline and synaptic function is highly dependent on mitochondria. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of several neurodegenerative diseases. Here we have investigated the repair of oxidative base damage, in synaptosomes of mouse brain during normal aging and in an AD model. During normal aging, a reduction in the base excision repair (BER) capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of presymptomatic and symptomatic AD mice harboring mutated amyolid precursor protein (APP), Tau, and presinilin-1 (PS1) (3xTgAD). Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Nutrition as a Modulator of the Aging Process.

    ERIC Educational Resources Information Center

    Masoro, Edward J.

    1984-01-01

    Reviews research on the relationship of nutrition to the aging process. Extension of life-span, retardation of age-related physiological deterioration, retardation of age-related disease processes, and the four major hypotheses dominating thought about the mechanisms by which food restriction slows the aging process are discussed. (JN)

  9. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    ERIC Educational Resources Information Center

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  10. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    ERIC Educational Resources Information Center

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  11. DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair.

    PubMed

    Sibanda, Bancinyane L; Chirgadze, Dimitri Y; Ascher, David B; Blundell, Tom L

    2017-02-03

    DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a central component of nonhomologous end joining (NHEJ), repairing DNA double-strand breaks that would otherwise lead to apoptosis or cancer. We have solved its structure in complex with the C-terminal peptide of Ku80 at 4.3 angstrom resolution using x-ray crystallography. We show that the 4128-amino acid structure comprises three large structural units: the N-terminal unit, the Circular Cradle, and the Head. Conformational differences between the two molecules in the asymmetric unit are correlated with changes in accessibility of the kinase active site, which are consistent with an allosteric mechanism to bring about kinase activation. The location of KU80ct194 in the vicinity of the breast cancer 1 (BRCA1) binding site suggests competition with BRCA1, leading to pathway selection between NHEJ and homologous recombination.

  12. Three-Year Outcomes With the Multilayer Flow Modulator for Repair of Thoracoabdominal Aneurysms: A Follow-up Report From the STRATO Trial.

    PubMed

    Vaislic, Claude D; Fabiani, Jean Noël; Chocron, Sidney; Robin, Jacques; Costache, Victor S; Villemot, Jean-Pierre; Alsac, Jean Marc; Leprince, Pascal N; Unterseeh, Thierry; Portocarrero, Eric; Glock, Yves; Rousseau, Hervé

    2016-10-01

    To evaluate midterm outcomes of endovascular repair of types II and III thoracoabdominal aortic aneurysms (TAAA) using the Multilayer Flow Modulator (MFM) in patients unsuitable for open surgery or fenestrated stent-grafts. In the prospective, multicenter, nonrandomized STRATO trial (EudraCT registration: 2009-013678-42; ClinicalTrials.gov identifier NCT01756911), 23 patients (mean age 75.8 years; 19 men) with Crawford type II and III TAAA (mean diameter 6.5 cm) were implanted between April 2010 and February 2011. Outcomes included all-cause mortality and stable aneurysm thrombosis with associated branch vessel patency. Through 36 months, there were 7 deaths (none confirmed as aneurysm-related), and no cases of spinal cord injury, device migration or fracture, or respiratory, renal, or peripheral complications. Three patients were lost to follow-up and 2 devices were explanted. The device was patent in the 11 remaining patients at 3 years. Stable aneurysm thrombosis was achieved for 15 of 20 patients at 12 months, 12 of 13 at 24 months, and 10 of 11 at 36 months. The rate of branch patency was 96% at 12 months (primary patency), 100% at 24 months, and 97% at 36 months. Nine patients suffered from endoleaks (attachment site or device overlap); 9 patients underwent 11 reinterventions (3 surgical). Maximum aneurysm diameter was stable for 18 of 20 patients at 12 months, 11 of 13 at 24 months, and 9 of 11 at 36 months. For 10 patients with computed tomography at 36 months, the mean ratio of aneurysm flow volume to total volume had decreased by 83%; the mean ratio of thrombus volume to total volume increased by 159%. Through 3 years, endovascular repair with the MFM appears to be safe and effective while successfully maintaining branch vessel patency. © The Author(s) 2016.

  13. The role of the MORF/MRG family of genes in cell growth, differentiation, DNA repair, and thereby aging.

    PubMed

    Pena, Andreana N; Pereira-Smith, Olivia M

    2007-04-01

    The discovery that replicative cellular senescence is a dominant phenotype over immortality led to the discovery that there are at least four unique genetic subgroups of immortal cell lines that use distinct mechanistic pathways to evade cell cycle exit. Study of one of these genetic complementation groups demonstrated that one gene, MORF4, possessed the ability to induce senescence in group B cell lines. The MRG family of genes, of which MORF4 is a member, has since proven important for cellular aging, proliferation, positive and negative transcriptional regulation, and DNA damage repair. MRG15, the evolutionary ancestor of the family, is highly conserved in yeast, C. elegans, drosophila, plants, and mammals and has been implicated in chromatin remodeling in these species. Our proteomics studies have found that MRG15 is unique among mammalian genes in that it associates with both histone deacetylases and histone acetyl transferase complexes, and thus potentially plays a role in both transcriptional silencing and activation. Its knockout in mice is embryonic lethal, resulting in improper organogenesis, as well as cell proliferation and DNA damage repair defects. Future study of these genes will help clarify the role of chromatin remodeling in aging, cellular proliferation, and DNA damage repair.

  14. Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis.

    PubMed

    Chen, Mei; Rajapakse, Dinusha; Fraczek, Monika; Luo, Chang; Forrester, John V; Xu, Heping

    2016-06-01

    Retinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age-related retinal degenerative disorders particularly age-related macular degeneration. During aging RPE cells decline in number, suggesting an age-dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose-dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted 'postmitotic' status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long-standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age-related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  15. Myocyte repolarization modulates myocardial function in aging dogs.

    PubMed

    Sorrentino, Andrea; Signore, Sergio; Qanud, Khaled; Borghetti, Giulia; Meo, Marianna; Cannata, Antonio; Zhou, Yu; Wybieralska, Ewa; Luciani, Marco; Kannappan, Ramaswamy; Zhang, Eric; Matsuda, Alex; Webster, Andrew; Cimini, Maria; Kertowidjojo, Elizabeth; D'Alessandro, David A; Wunimenghe, Oriyanhan; Michler, Robert E; Royer, Christopher; Goichberg, Polina; Leri, Annarosa; Barrett, Edward G; Anversa, Piero; Hintze, Thomas H; Rota, Marcello

    2016-04-01

    Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions.

  16. Myocyte repolarization modulates myocardial function in aging dogs

    PubMed Central

    Sorrentino, Andrea; Signore, Sergio; Borghetti, Giulia; Meo, Marianna; Cannata, Antonio; Zhou, Yu; Wybieralska, Ewa; Luciani, Marco; Kannappan, Ramaswamy; Zhang, Eric; Matsuda, Alex; Webster, Andrew; Cimini, Maria; Kertowidjojo, Elizabeth; D'Alessandro, David A.; Wunimenghe, Oriyanhan; Michler, Robert E.; Royer, Christopher; Goichberg, Polina; Leri, Annarosa; Barrett, Edward G.; Anversa, Piero; Hintze, Thomas H.

    2016-01-01

    Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions. PMID:26801307

  17. Immune Modulation of Cardiac Repair and Regeneration: The Art of Mending Broken Hearts

    PubMed Central

    Zlatanova, Ivana; Pinto, Cristina; Silvestre, Jean-Sébastien

    2016-01-01

    The accumulation of immune cells is among the earliest responses that manifest in the cardiac tissue after injury. Both innate and adaptive immunity coordinate distinct and mutually non-exclusive events governing cardiac repair, including elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, and formation of a fibrotic scar. The present review summarizes the mounting evidence suggesting that the inflammatory response also guides the regenerative process following cardiac damage. In particular, recent literature has reinforced the central role of monocytes/macrophages in poising the refreshment of cardiomyocytes in myocardial infarction- or apical resection-induced cardiac insult. Macrophages dictate cardiac myocyte renewal through stimulation of preexisting cardiomyocyte proliferation and/or neovascularization. Nevertheless, substantial efforts are required to identify the nature of these macrophage-derived factors as well as the molecular mechanisms engendered by the distinct subsets of macrophages pertaining in the cardiac tissue. Among the growing inflammatory intermediaries that have been recognized as essential player in heart regeneration, we will focus on the role of interleukin (IL)-6 and IL-13. Finally, it is likely that within the mayhem of the injured cardiac tissue, additional types of inflammatory cells, such as neutrophils, will enter the dance to ignite and refresh the broken heart. However, the protective and detrimental inflammatory pathways have been mainly deciphered in animal models. Future research should be focused on understanding the cellular effectors and molecular signals regulating inflammation in human heart to pave the way for the development of factual therapies targeting the inflammatory compartment in cardiac diseases. PMID:27790620

  18. Nutritional modulation of age-related macular degeneration

    USDA-ARS?s Scientific Manuscript database

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. It affects 30-50 million individuals and clinical hallmarks of AMD are observed in at least one third of persons over the age of 75 in industrialized countries (Gehrs et al., 2006). Costs associated wi...

  19. Host age modulates within-host parasite competition

    PubMed Central

    Izhar, Rony; Routtu, Jarkko; Ben-Ami, Frida

    2015-01-01

    In many host populations, one of the most striking differences among hosts is their age. While parasite prevalence differences in relation to host age are well known, little is known on how host age impacts ecological and evolutionary dynamics of diseases. Using two clones of the water flea Daphnia magna and two clones of its bacterial parasite Pasteuria ramosa, we examined how host age at exposure influences within-host parasite competition and virulence. We found that multiply-exposed hosts were more susceptible to infection and suffered higher mortality than singly-exposed hosts. Hosts oldest at exposure were least often infected and vice versa. Furthermore, we found that in young multiply-exposed hosts competition was weak, allowing coexistence and transmission of both parasite clones, whereas in older multiply-exposed hosts competitive exclusion was observed. Thus, age-dependent parasite exposure and host demography (age structure) could together play an important role in mediating parasite evolution. At the individual level, our results demonstrate a previously unnoticed interaction of the host's immune system with host age, suggesting that the specificity of immune function changes as hosts mature. Therefore, evolutionary models of parasite virulence might benefit from incorporating age-dependent epidemiological parameters. PMID:25994010

  20. Age and Phonetic Influences on Velar Flutter as a Component of Nasal Turbulence in Children With Repaired Cleft Palate.

    PubMed

    Zajac, David J; Preisser, John

    2016-11-01

      The purpose of this study was to determine the influence of age and selected phonetic factors on velar flutter as a component of nasal turbulence in children with repaired cleft palate.   A total of 30 children with repaired cleft palate with or without cleft lip ranging in age from 4 to 13 years (mean, 8.6 years; standard deviation, 2.4 years) who exhibited nasal turbulence characterized by velar flutter participated in the study.   The headset of a nasometer was used to record the children producing multiple repetitions of consonant-vowel (CV) syllables that contrasted the stops /p/ and /t/ with the fricatives /f/ and /s/ and the high-front vowel /i/ with the low mid-central vowel /Λ/. All targeted consonants were coded relative to the presence of flutter using both perceptual and spectral criteria. Percentages of syllables coded for flutter were calculated as a function of consonant and vowel types. Intra-and interjudge reliability of coding was high.   Percentages of syllables with velar flutter ranged from a high of 100% to a low of 4% among the participants. A Spearman rank-order correlation between age and percentage of syllables with flutter was nonsignificant. Mantel-Haenszel tests for repeated measures indicated that flutter occurred more often during production of syllables containing /i/ (62%) when compared with /Λ/ (50%) (P = .029).   Velar flutter as a component of nasal turbulence varies widely among children with repaired cleft palate. CV syllables with high vowels appear to trigger velar flutter more often than syllables with low vowels.

  1. Effect of surface treatments on the tensile bond strength of repaired water-aged anterior restorative micro-fine hybrid resin composite.

    PubMed

    Fawzy, Amr S; El-Askary, Farid S; Amer, Mohamed A

    2008-12-01

    The purpose of this study was to characterize changes in surface topography associated with different surface treatments and their effect on tensile bond strength (TBS) of repaired water-aged anterior restorative micro-fine hybrid resin composite. The TBS of repaired resin-based composite slabs either non-treated or exposed to different mechanical and/or chemical surface treatment procedures were measured. The cohesive tensile strength of non-repaired intact slabs was used as a control group. The topographical effects of acid etching, grinding, and grinding followed by acid etching were characterized by AFM and SEM. All repaired groups showed significantly lower TBS than the control group. The TBS of repaired groups was ranged from 15% to 59% of the cohesive tensile strength of the control group (18.8+/-4.5MPa). The surface roughness of the non-treated aged specimens was significantly higher than other treated specimens. Specimens treated by acid etching showed significant increase in surface area compared to the non-treated and treated specimens. Aging process resulted in the formation of degradable surface layer which adversely affects the repair bond strength. The use of silane primer prior to the application of the adhesive after mechanical grinding, with or without the use of 37% phosphoric acid etching; improves the repair bond strength.

  2. Drugs that modulate aging: the promising yet difficult path ahead.

    PubMed

    Kennedy, Brian K; Pennypacker, Juniper K

    2014-05-01

    Once a backwater in medical sciences, aging research has emerged and now threatens to take the forefront. This dramatic change of stature is driven from 3 major events. First and foremost, the world is rapidly getting old. Never before have we lived in a demographic environment like today, and the trends will continue such that 20% percent of the global population of 9 billion will be over the age of 60 by 2050. Given current trends of sharply increasing chronic disease incidence, economic disaster from the impending silver tsunami may be ahead. A second major driver on the rise is the dramatic progress that aging research has made using invertebrate models such as worms, flies, and yeast. Genetic approaches using these organisms have led to hundreds of aging genes and, perhaps surprisingly, strong evidence of evolutionary conservation among longevity pathways between disparate species, including mammals. Current studies suggest that this conservation may extend to humans. Finally, small molecules such as rapamycin and resveratrol have been identified that slow aging in model organisms, although only rapamycin to date impacts longevity in mice. The potential now exists to delay human aging, whether it is through known classes of small molecules or a plethora of emerging ones. But how can a drug that slows aging become approved and make it to market when aging is not defined as a disease. Here, we discuss the strategies to translate discoveries from aging research into drugs. Will aging research lead to novel therapies toward chronic disease, prevention of disease or be targeted directly at extending lifespan?

  3. Drugs That Modulate Aging: The Promising yet Difficult Path Ahead

    PubMed Central

    Kennedy, Brian K.; Pennypacker, Juniper K.

    2014-01-01

    Once a backwater in medical sciences, aging research has emerged and now threatens to take the forefront. This dramatic change of stature is driven from three major events. First and foremost, the world is rapidly getting old. Never before have we lived in a demographic environment like today and the trends will continue such that 20% percent of the global population of 9 billion will be over the age of 60 by 2050. Given current trends of sharply increasing chronic disease incidence, economic disaster from the impending silver tsunami may be ahead. A second major driver on the rise is the dramatic progress that aging research has made using invertebrate models such as worms, flies and yeast. Genetic approaches using these organisms have led to hundreds of aging genes and, perhaps surprisingly, strong evidence of evolutionary conservation among longevity pathways between disparate species, including mammals. Current studies suggest that this conservation may extend to humans. Finally, small molecules such as rapamycin and resveratrol have been identified that slow aging in model organisms, although only rapamycin to date impacts longevity in mice. The potential now exists to delay human aging, whether it is through known classes of small molecules or a plethora of emerging ones. But how can a drug that slows aging become approved and make it to market when aging is not defined as a disease. Here, we discuss the strategies to translate discoveries from aging research into drugs. Will aging research lead to novel therapies toward chronic disease, prevention of disease or be targeted directly at extending lifespan? PMID:24316383

  4. New Technologies for Repairing Aging Cables in Nuclear Power Plants: M3LW-14OR0404015 Cable Rejuvenation Report

    SciTech Connect

    Simmons, Kevin L.; Fifield, Leonard S.; Westman, Matthew P.; Roberts, John A.

    2014-09-08

    The goal of this project is to conceptually demonstrate techniques to repair cables that have degraded through subjection to long-term thermal and radiation exposure in nuclear power plants. In fiscal year 2014 (FY14) we focused on commercially available ethylene-propylene rubber (EPR) as the relevant test material, isolated a high surface area form of the EPR material to facilitate chemical treatment screening and charaterization, and measured chemical changes in the material due to aging and treatment using Fourier Transfrom Infrared (FTIR) spectroscopy.

  5. WE-EF-BRA-08: Cell Survival in Modulated Radiation Fields and Altered DNA-Repair at Field Edges

    SciTech Connect

    Bartzsch, S; Oelfke, U; Eismann, S

    2015-06-15

    Purpose: Tissue damage prognoses in radiotherapy are based on clonogenic assays that provide dose dependent cell survival rates. However, recent work has shown that apart from dose, systemic reactions and cell-cell communication crucially influence the radiation response. These effects are probably a key in understanding treatment approaches such as microbeam radiation therapy (MRT). In this study we tried to quantify the effects on a cellular level in spatially modulated radiation fields. Methods: Pancreas carcinoma cells were cultured, plated and irradiated by spatially modulated radiation fields with an X-ray tube and at a synchrotron. During and after treatment cells were able to communicate via the intercellular medium. Afterwards we stained for DNA and DNA damage and imaged with a fluorescence microscope. Results: Intriguingly we found that DNA damage does not strictly increase with dose. Two cell entities appear that have either a high or a low amount of DNA lesions, indicating that DNA damage is also a cell stress reaction. Close to radiation boundaries damage-levels became alike; they were higher than expected at low and lower than expected at high doses. Neighbouring cells reacted similarly. 6 hours after exposure around 40% of the cells resembled in their reactions neighbouring cells more than randomly chosen cells that received the same dose. We also observed that close to radiation boundaries the radiation induced cell-cycle arrest disappeared and the size of DNA repair-centres increased. Conclusion: Cell communication plays an important role in the radiation response of tissues and may be both, protective and destructive. These effects may not only have the potential to affect conventional radiotherapy but may also be exploited to spare organs at risk by intelligently designing irradiation geometries. To that end intensive work is required to shed light on the still obscure processes in cell-signalling and radiation biology.

  6. [The assessment of modulated radiofrequence electromagnetic radiation on cognitive function in rats of different ages].

    PubMed

    Priakhin, E A; Triapitsyna, G A; Andreev, S S; Kolomiets, I A; Polevik, N D; Akleev, A V

    2007-01-01

    The modulated radiofrequence electromagnetic radiation influence on cognitive function of male uninbred Wister rat exposed at the age of sexual maturation (2 months) and at the age of morphofunctional maturity (3.5 months) was examined. Animals were subjected to pulse electromagnetic radiation (925 MHz) modulated as a GSM standard with the power density 1.2 mW/cm2 for 10 minutes every day for 12 days. At day 8 of exposure the cognitive function were examined with the Morris water maze. In the result of investigation it was determines that modulated radiofrequence electromagnetic radiation at the sexual maturation age did not affect the spatial learning and improve the visual orientation performance. Modulated radiofrequence electromagnetic exposure of animals at the sex maturity age did not affect the visual performance and improve the spatial performance of male rats.

  7. Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer’s disease

    PubMed Central

    Gredilla, Ricardo; Weissman, Lior; Yang, Jenq-Lin; Bohr, Vilhelm A.; Stevnsner, Tinna

    2010-01-01

    Brain aging is associated with synaptic decline and cognitive impairment. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). In mitochondria, base excision repair (BER) is the main DNA repair pathway for base modifications such as deamination and oxidation, and constitutes an important mechanism to avoid accumulation of mtDNA mutations. Synaptic function is highly dependent on mitochondria, and in the current study we have investigated BER in synaptosomes of mouse brain during normal aging and in an AD model. Synaptosomes are isolated synapses in membranous structures produced by subcellular fractionation of brain tissue. They include the whole presynaptic terminal as well as portions of the postsynaptic terminal. Synaptosomes contain the molecular machinery necessary for uptake, storage, and release of neurotransmitters, including synaptic vesicles and mitochondria. BER activities were measured in synaptosomal fractions from young and old mice and from pre-symptomatic and symptomatic AD mice harboring mutated APP, Tau and PS1 (3xTgAD). During normal aging, a reduction in the BER capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of pre-symptomatic and symptomatic AD mice. Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed. PMID:20708822

  8. Biochemical Genetic Pathways that Modulate Aging in Multiple Species

    PubMed Central

    Bitto, Alessandro; Wang, Adrienne M.; Bennett, Christopher F.; Kaeberlein, Matt

    2016-01-01

    The mechanisms underlying biological aging have been extensively studied in the past 20 years with the avail of mainly four model organisms: the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the domestic mouse Mus musculus. Extensive research in these four model organisms has identified a few conserved genetic pathways that affect longevity as well as metabolism and development. Here, we review how the mechanistic target of rapamycin (mTOR), sirtuins, adenosine monophosphate-activated protein kinase (AMPK), growth hormone/insulin-like growth factor 1 (IGF-1), and mitochondrial stress-signaling pathways influence aging and life span in the aforementioned models and their possible implications for delaying aging in humans. We also draw some connections between these biochemical pathways and comment on what new developments aging research will likely bring in the near future. PMID:26525455

  9. Immediate electrical stimulation enhances regeneration and reinnervation and modulates spinal plastic changes after sciatic nerve injury and repair.

    PubMed

    Vivó, Meritxell; Puigdemasa, Antoni; Casals, Laura; Asensio, Elena; Udina, Esther; Navarro, Xavier

    2008-05-01

    We have studied whether electrical stimulation immediately after nerve injury may enhance axonal regeneration and modulate plastic changes at the spinal cord level underlying the appearance of hyperreflexia. Two groups of adult rats were subjected to sciatic nerve section followed by suture repair. One group (ES) received electrical stimulation (3 V, 0.1 ms at 20 Hz) for 1 h after injury. A second group served as control (C). Nerve conduction, H reflex, motor evoked potentials, and algesimetry tests were performed at 1, 3, 5, 7 and 9 weeks after surgery, to assess muscle reinnervation and changes in excitability of spinal cord circuitry. The electrophysiological results showed higher levels of reinnervation, and histological results a significantly higher number of regenerated myelinated fibers in the distal tibial nerve in group ES in comparison with group C. The monosynaptic H reflex was facilitated in the injured limb, to a higher degree in group C than in group ES. The amplitudes of motor evoked potentials were similar in both groups, although the MEP/M ratio was increased in group C compared to group ES, indicating mild central motor hyperexcitability. Immunohistochemical labeling of sensory afferents in the spinal cord dorsal horn showed prevention of the reduction in expression of substance P at one month postlesion in group ES. In conclusion, brief electrical stimulation applied after sciatic nerve injury promotes axonal regeneration over a long distance and reduces facilitation of spinal motor responses.

  10. The mismatch repair system modulates curcumin sensitivity through induction of DNA strand breaks and activation of G2-M checkpoint.

    PubMed

    Jiang, Zhihua; Jin, ShunQian; Yalowich, Jack C; Brown, Kevin D; Rajasekaran, Baskaran

    2010-03-01

    The highly conserved mismatch (MMR) repair system corrects postreplicative errors and modulates cellular responses to genotoxic agents. Here, we show that the MMR system strongly influences cellular sensitivity to curcumin. Compared with MMR-proficient cells, isogenically matched MMR-deficient cells displayed enhanced sensitivity to curcumin. Similarly, cells suppressed for MLH1 or MSH2 expression by RNA interference displayed increased curcumin sensitivity. Curcumin treatment generated comparable levels of reactive oxygen species and the mutagenic adduct 8-oxo-guanine in MMR-proficient and MMR-deficient cells; however, accumulation of gammaH2AX foci, a marker for DNA double-strand breaks (DSB), occurred only in MMR-positive cells in response to curcumin treatment. Additionally, MMR-positive cells showed activation of Chk1 and induction of G(2)-M cell cycle checkpoint following curcumin treatment and inhibition of Chk1 by UCN-01 abrogated Chk1 activation and heightened apoptosis in MMR-proficient cells. These results indicate that curcumin triggers the accumulation of DNA DSB and induction of a checkpoint response through a MMR-dependent mechanism. Conversely, in MMR-compromised cells, curcumin-induced DSB is significantly blunted, and as a result, cells fail to undergo cell cycle arrest, enter mitosis, and die through mitotic catastrophe. The results have potential therapeutic value, especially in the treatment of tumors with compromised MMR function.

  11. Aging modulates cuticular hydrocarbons and sexual attractiveness in Drosophila melanogaster

    PubMed Central

    Kuo, Tsung-Han; Yew, Joanne Y.; Fedina, Tatyana Y.; Dreisewerd, Klaus; Dierick, Herman A.; Pletcher, Scott D.

    2012-01-01

    SUMMARY Attractiveness is a major component of sexual selection that is dependent on sexual characteristics, such as pheromone production, which often reflect an individual’s fitness and reproductive potential. Aging is a process that results in a steady decline in survival and reproductive output, yet little is known about its effect on specific aspects of attractiveness. In this report we asked how aging impacts pheromone production and sexual attractiveness in Drosophila melanogaster. Evidence suggests that key pheromones in Drosophila are produced as cuticular hydrocarbons (CHC), whose functions in attracting mates and influencing behavior have been widely studied. We employed gas chromatography/mass spectrometry and laser desorption/ionization mass spectrometry to show that the composition of D. melanogaster CHC is significantly affected by aging in both sexes and that these changes are robust to different genetic backgrounds. Aging affected the relative levels of many individual CHC, and it shifted overall hydrocarbon profiles to favor compounds with longer chain lengths. We also show that the observed aging-related changes in CHC profiles are responsible for a significant reduction in sexual attractiveness. These studies illuminate causal links among pheromones, aging and attractiveness and suggest that CHC production may be an honest indicator of animal health and fertility. PMID:22323204

  12. Serotonin modulation of cerebral glucose metabolism: sex and age effects.

    PubMed

    Munro, Cynthia A; Workman, Clifford I; Kramer, Elisse; Hermann, Carol; Ma, Yilong; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David; Smith, Gwenn S

    2012-11-01

    The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20-79 years) underwent two resting positron emission tomography studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([(18)F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response. Copyright © 2012 Wiley Periodicals, Inc.

  13. SEROTONIN MODULATION OF CEREBRAL GLUCOSE METABOLISM: SEX AND AGE EFFECTS

    PubMed Central

    Munro, Cynthia A.; Workman, Clifford; Kramer, Elisse; Hermann, Carol; Ma, Yilong; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David; Smith, Gwenn S.

    2012-01-01

    The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20–79 years) underwent two resting positron emission tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([18F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response. PMID:22836227

  14. Nutrition modulation of human aging: The calorie restriction paradigm.

    PubMed

    Das, Sai Krupa; Balasubramanian, Priya; Weerasekara, Yasoma K

    2017-11-05

    Globally, the aging population is growing rapidly, creating an urgent need to attenuate age-related health conditions, including metabolic disease and disability. A promising strategy for healthy aging based on consistently positive results from studies with a variety of species, including non-human primates (NHP), is calorie restriction (CR), or the restriction of energy intake while maintaining intake of essential nutrients. The burgeoning evidence for this approach in humans is reviewed and the major study to date to address this question, CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy), is described. CALERIE findings indicate the feasibility of CR in non-obese humans, confirm observations in NHP, and are consistent with improvements in disease risk reduction and potential anti-aging effects. Finally, the mechanisms of CR in humans are reviewed which sums up the fact that evolutionarily conserved mechanisms mediate the anti-aging effects of CR. Overall, the prospect for further research in both NHP and humans is highly encouraging. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. The Histone-Deacetylase-Inhibitor Suberoylanilide Hydroxamic Acid Promotes Dental Pulp Repair Mechanisms Through Modulation of Matrix Metalloproteinase-13 Activity.

    PubMed

    Duncan, Henry F; Smith, Anthony J; Fleming, Garry J P; Partridge, Nicola C; Shimizu, Emi; Moran, Gary P; Cooper, Paul R

    2016-04-01

    Direct application of histone-deacetylase-inhibitors (HDACis) to dental pulp cells (DPCs) induces chromatin changes, promoting gene expression and cellular-reparative events. We have previously demonstrated that HDACis (valproic acid, trichostatin A) increase mineralization in dental papillae-derived cell-lines and primary DPCs by stimulation of dentinogenic gene expression. Here, we investigated novel genes regulated by the HDACi, suberoylanilide hydroxamic acid (SAHA), to identify new pathways contributing to DPC differentiation. SAHA significantly compromised DPC viability only at relatively high concentrations (5 μM); while low concentrations (1 μM) SAHA did not increase apoptosis. HDACi-exposure for 24 h induced mineralization-per-cell dose-dependently after 2 weeks; however, constant 14d SAHA-exposure inhibited mineralization. Microarray analysis (24 h and 14 days) of SAHA exposed cultures highlighted that 764 transcripts showed a significant >2.0-fold change at 24 h, which reduced to 36 genes at 14 days. 59% of genes were down-regulated at 24 h and 36% at 14 days, respectively. Pathway analysis indicated SAHA increased expression of members of the matrix metalloproteinase (MMP) family. Furthermore, SAHA-supplementation increased MMP-13 protein expression (7 d, 14 days) and enzyme activity (48 h, 14 days). Selective MMP-13-inhibition (MMP-13i) dose-dependently accelerated mineralization in both SAHA-treated and non-treated cultures. MMP-13i-supplementation promoted expression of several mineralization-associated markers, however, HDACi-induced cell migration and wound healing were impaired. Data demonstrate that short-term low-dose SAHA-exposure promotes mineralization in DPCs by modulating gene pathways and tissue proteases. MMP-13i further increased mineralization-associated events, but decreased HDACi cell migration indicating a specific role for MMP-13 in pulpal repair processes. Pharmacological inhibition of HDAC and MMP may

  16. Age Modulates Attitudes to Whole Body Donation among Medical Students

    ERIC Educational Resources Information Center

    Perry, Gary F.; Ettarh, Raj R.

    2009-01-01

    Managing a whole body donor program is necessary for facilitating a traditional dissection-based anatomy curriculum in medicine and health sciences. Factors which influence body donations to medical science can therefore affect dissection-based anatomy teaching. In order to determine whether age influences the attitudes of medical students to…

  17. Restoration of regenerative osteoblastogenesis in aged mice: Modulation of TNF

    USDA-ARS?s Scientific Manuscript database

    Skeletal changes accompanying aging are associated with both increased risk of fractures and impaired fracture healing, which, in turn, is due to compromised bone regeneration potential. These changes are associated with increased serum levels of selected proinflammatory cytokines, e.g., tumor necro...

  18. Age Modulates Attitudes to Whole Body Donation among Medical Students

    ERIC Educational Resources Information Center

    Perry, Gary F.; Ettarh, Raj R.

    2009-01-01

    Managing a whole body donor program is necessary for facilitating a traditional dissection-based anatomy curriculum in medicine and health sciences. Factors which influence body donations to medical science can therefore affect dissection-based anatomy teaching. In order to determine whether age influences the attitudes of medical students to…

  19. Meta-analyses identify 13 novel loci associated with age at menopause and highlights DNA repair and immune pathways

    PubMed Central

    Stolk, Lisette; Perry, John RB; Chasman, Daniel I; He, Chunyan; Mangino, Massimo; Sulem, Patrick; Barbalic, Maja; Broer, Linda; Byrne, Enda M; Ernst, Florian; Esko, Tõnu; Franceschini, Nora; Gudbjartsson, Daniel F; Hottenga, Jouke-Jan; Kraft, Peter; McArdle, Patick F; Porcu, Eleonora; Shin, So-Youn; Smith, Albert V; van Wingerden, Sophie; Zhai, Guangju; Zhuang, Wei V; Albrecht, Eva; Alizadeh, Behrooz Z; Aspelund, Thor; Bandinelli, Stefania; Lauc, Lovorka Barac; Beckmann, Jacques S; Boban, Mladen; Boerwinkle, Eric; Broekmans, Frank J; Burri, Andrea; Campbell, Harry; Chanock, Stephen J; Chen, Constance; Cornelis, Marilyn C; Corre, Tanguy; Coviello, Andrea D; d’Adamo, Pio; Davies, Gail; de Faire, Ulf; de Geus, Eco JC; Deary, Ian J; Dedoussis, George VZ; Deloukas, Panagiotis; Ebrahim, Shah; Eiriksdottir, Gudny; Emilsson, Valur; Eriksson, Johan G; Fauser, Bart CJM; Ferreli, Liana; Ferrucci, Luigi; Fischer, Krista; Folsom, Aaron R; Garcia, Melissa E; Gasparini, Paolo; Gieger, Christian; Glazer, Nicole; Grobbee, Diederick E; Hall, Per; Haller, Toomas; Hankinson, Susan E; Hass, Merli; Hayward, Caroline; Heath, Andrew C; Hofman, Albert; Ingelsson, Erik; Janssens, A Cecile JW; Johnson, Andrew D; Karasik, David; Kardia, Sharon LR; Keyzer, Jules; Kiel, Douglas P; Kolcic, Ivana; Kutalik, Zoltán; Lahti, Jari; Lai, Sandra; Laisk, Triin; Laven, Joop SE; Lawlor, Debbie A; Liu, Jianjun; Lopez, Lorna M; Louwers, Yvonne V; Magnusson, Patrik KE; Marongiu, Mara; Martin, Nicholas G; Klaric, Irena Martinovic; Masciullo, Corrado; McKnight, Barbara; Medland, Sarah E; Melzer, David; Mooser, Vincent; Navarro, Pau; Newman, Anne B; Nyholt, Dale R; Onland-Moret, N. Charlotte; Palotie, Aarno; Paré, Guillaume; Parker, Alex N; Pedersen, Nancy L; Peeters, Petra HM; Pistis, Giorgio; Plump, Andrew S; Polasek, Ozren; Pop, Victor JM; Psaty, Bruce M; Räikkönen, Katri; Rehnberg, Emil; Rotter, Jerome I; Rudan, Igor; Sala, Cinzia; Salumets, Andres; Scuteri, Angelo; Singleton, Andrew; Smith, Jennifer A; Snieder, Harold; Soranzo, Nicole; Stacey, Simon N; Starr, John M; Stathopoulou, Maria G; Stirrups, Kathleen; Stolk, Ronald P; Styrkarsdottir, Unnur; Sun, Yan V; Tenesa, Albert; Thorand, Barbara; Toniolo, Daniela; Tryggvadottir, Laufey; Tsui, Kim; Ulivi, Sheila; van Dam, Rob M; van der Schouw, Yvonne T; van Gils, Carla H; van Nierop, Peter; Vink, Jacqueline M; Visscher, Peter M; Voorhuis, Marlies; Waeber, Gérard; Wallaschofski, Henri; Wichmann, H Erich; Widen, Elisabeth; Gent, Colette JM Wijnands-van; Willemsen, Gonneke; Wilson, James F; Wolffenbuttel, Bruce HR; Wright, Alan F; Yerges-Armstrong, Laura M; Zemunik, Tatijana; Zgaga, Lina; Zillikens, M. Carola; Zygmunt, Marek; Arnold, Alice M; Boomsma, Dorret I; Buring, Julie E.; Crisponi, Laura; Demerath, Ellen W; Gudnason, Vilmundur; Harris, Tamara B; Hu, Frank B; Hunter, David J; Launer, Lenore J; Metspalu, Andres; Montgomery, Grant W; Oostra, Ben A; Ridker, Paul M; Sanna, Serena; Schlessinger, David; Spector, Tim D; Stefansson, Kari; Streeten, Elizabeth A; Thorsteinsdottir, Unnur; Uda, Manuela; Uitterlinden, André G; van Duijn, Cornelia M; Völzke, Henry; Murray, Anna; Murabito, Joanne M; Visser, Jenny A; Lunetta, Kathryn L

    2011-01-01

    To identify novel loci for age at natural menopause, we performed a meta-analysis of 22 genome-wide association studies in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 new age at natural menopause loci (P < 5 × 10−8). The new loci included genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG, PRIM1) and immune function (IL11, NLRP11, BAT2). Gene-set enrichment pathway analyses using the full GWAS dataset identified exodeoxyribonuclease, NFκB signalling and mitochondrial dysfunction as biological processes related to timing of menopause. PMID:22267201

  20. Restoration of Regenerative Osteoblastogenesis in Aged Mice: Modulation of TNF

    PubMed Central

    Wahl, Elizabeth C; Aronson, James; Liu, Lichu; Fowlkes, John L; Thrailkill, Kathryn M; Bunn, Robert C; Skinner, Robert A; Miller, Mike J; Cockrell, Gael E; Clark, Lindsey M; Ou, Yang; Isales, Carlos M; Badger, Thomas M; Ronis, Martin J; Sims, John; Lumpkin, Charles K

    2010-01-01

    Skeletal changes accompanying aging are associated with both increased risk of fractures and impaired fracture healing, which, in turn, is due to compromised bone regeneration potential. These changes are associated with increased serum levels of selected proinflammatory cytokines, e.g., tumor necrosis factor α (TNF-α). We have used a unique model of bone regeneration to demonstrate (1) that aged-related deficits in direct bone formation can be restored to young mice by treatment with TNF blockers and (2) that the cyclin-dependent kinase inhibitor p21 is a candidate for mediation of the osteoinhibitory effects of TNF. It has been hypothesized recently that TNF antagonists may represent novel anabolic agents, and we believe that the data presented here represent a successful test of this hypothesis. © 2010 American Society for Bone and Mineral Research PMID:19580462

  1. Top-down modulation of visual and auditory cortical processing in aging.

    PubMed

    Guerreiro, Maria J S; Eck, Judith; Moerel, Michelle; Evers, Elisabeth A T; Van Gerven, Pascal W M

    2015-02-01

    Age-related cognitive decline has been accounted for by an age-related deficit in top-down attentional modulation of sensory cortical processing. In light of recent behavioral findings showing that age-related differences in selective attention are modality dependent, our goal was to investigate the role of sensory modality in age-related differences in top-down modulation of sensory cortical processing. This question was addressed by testing younger and older individuals in several memory tasks while undergoing fMRI. Throughout these tasks, perceptual features were kept constant while attentional instructions were varied, allowing us to devise all combinations of relevant and irrelevant, visual and auditory information. We found no top-down modulation of auditory sensory cortical processing in either age group. In contrast, we found top-down modulation of visual cortical processing in both age groups, and this effect did not differ between age groups. That is, older adults enhanced cortical processing of relevant visual information and suppressed cortical processing of visual distractors during auditory attention to the same extent as younger adults. The present results indicate that older adults are capable of suppressing irrelevant visual information in the context of cross-modal auditory attention, and thereby challenge the view that age-related attentional and cognitive decline is due to a general deficits in the ability to suppress irrelevant information. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. The Effect of Physiological Stimuli on Sarcopenia; Impact of Notch and Wnt Signaling on Impaired Aged Skeletal Muscle Repair

    PubMed Central

    Arthur, Susan Tsivitse; Cooley, Ian D.

    2012-01-01

    The age-related loss of skeletal muscle mass and function that is associated with sarcopenia can result in ultimate consequences such as decreased quality of life. The causes of sarcopenia are multifactorial and include environmental and biological factors. The purpose of this review is to synthesize what the literature reveals in regards to the cellular regulation of sarcopenia, including impaired muscle regenerative capacity in the aged, and to discuss if physiological stimuli have the potential to slow the loss of myogenic potential that is associated with sarcopenia. In addition, this review article will discuss the effect of aging on Notch and Wnt signaling, and whether physiological stimuli have the ability to restore Notch and Wnt signaling resulting in rejuvenated aged muscle repair. The intention of this summary is to bring awareness to the benefits of consistent physiological stimulus (exercise) to combating sarcopenia as well as proclaiming the usefulness of contraction-induced injury models to studying the effects of local and systemic influences on aged myogenic capability. PMID:22701343

  3. The effect of physiological stimuli on sarcopenia; impact of Notch and Wnt signaling on impaired aged skeletal muscle repair.

    PubMed

    Arthur, Susan Tsivitse; Cooley, Ian D

    2012-01-01

    The age-related loss of skeletal muscle mass and function that is associated with sarcopenia can result in ultimate consequences such as decreased quality of life. The causes of sarcopenia are multifactorial and include environmental and biological factors. The purpose of this review is to synthesize what the literature reveals in regards to the cellular regulation of sarcopenia, including impaired muscle regenerative capacity in the aged, and to discuss if physiological stimuli have the potential to slow the loss of myogenic potential that is associated with sarcopenia. In addition, this review article will discuss the effect of aging on Notch and Wnt signaling, and whether physiological stimuli have the ability to restore Notch and Wnt signaling resulting in rejuvenated aged muscle repair. The intention of this summary is to bring awareness to the benefits of consistent physiological stimulus (exercise) to combating sarcopenia as well as proclaiming the usefulness of contraction-induced injury models to studying the effects of local and systemic influences on aged myogenic capability.

  4. Aging and sequential modulations of poorer strategy effects: An EEG study in arithmetic problem solving.

    PubMed

    Hinault, Thomas; Lemaire, Patrick; Phillips, Natalie

    2016-01-01

    This study investigated age-related differences in electrophysiological signatures of sequential modulations of poorer strategy effects. Sequential modulations of poorer strategy effects refer to decreased poorer strategy effects (i.e., poorer performance when the cued strategy is not the best) on current problem following poorer strategy problems compared to after better strategy problems. Analyses on electrophysiological (EEG) data revealed important age-related changes in time, frequency, and coherence of brain activities underlying sequential modulations of poorer strategy effects. More specifically, sequential modulations of poorer strategy effects were associated with earlier and later time windows (i.e., between 200- and 550 ms and between 850- and 1250 ms). Event-related potentials (ERPs) also revealed an earlier onset in older adults, together with more anterior and less lateralized activations. Furthermore, sequential modulations of poorer strategy effects were associated with theta and alpha frequencies in young adults while these modulations were found in delta frequency and theta inter-hemispheric coherence in older adults, consistent with qualitatively distinct patterns of brain activity. These findings have important implications to further our understanding of age-related differences and similarities in sequential modulations of cognitive control processes during arithmetic strategy execution. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. MOF and H4 K16 Acetylation Play Important Roles in DNA Damage Repair by Modulating Recruitment of DNA Damage Repair Protein Mdc1 ▿

    PubMed Central

    Li, Xiangzhi; Corsa, Callie Ann Sprunger; Pan, Patricia W.; Wu, Lipeng; Ferguson, David; Yu, Xiaochun; Min, Jinrong; Dou, Yali

    2010-01-01

    MOF (MYST1) is the major enzyme to catalyze acetylation of histone H4 lysine 16 (K16) and is highly conserved through evolution. Using a conditional knockout mouse model and the derived mouse embryonic fibroblast cell lines, we showed that loss of Mof led to a global reduction of H4 K16 acetylation, severe G2/M cell cycle arrest, massive chromosome aberration, and defects in ionizing radiation-induced DNA damage repair. We further showed that although early DNA damage sensing and signaling by ATM were normal in Mof-null cells, the recruitment of repair mediator protein Mdc1 and its downstream signaling proteins 53bp1 and Brca1 to DNA damage foci was completely abolished. Mechanistic studies suggested that Mof-mediated H4 K16 acetylation and an intact acidic pocket on H2A.X were essential for the recruitment of Mdc1. Removal of Mof and its associated proteins phenocopied a charge-neutralizing mutant of H2A.X. Given the well-characterized H4-H2A trans interactions in regulating higher-order chromatin structure, our study revealed a novel chromatin-based mechanism that regulates the DNA damage repair process. PMID:20837706

  6. MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1.

    PubMed

    Li, Xiangzhi; Corsa, Callie Ann Sprunger; Pan, Patricia W; Wu, Lipeng; Ferguson, David; Yu, Xiaochun; Min, Jinrong; Dou, Yali

    2010-11-01

    MOF (MYST1) is the major enzyme to catalyze acetylation of histone H4 lysine 16 (K16) and is highly conserved through evolution. Using a conditional knockout mouse model and the derived mouse embryonic fibroblast cell lines, we showed that loss of Mof led to a global reduction of H4 K16 acetylation, severe G(2)/M cell cycle arrest, massive chromosome aberration, and defects in ionizing radiation-induced DNA damage repair. We further showed that although early DNA damage sensing and signaling by ATM were normal in Mof-null cells, the recruitment of repair mediator protein Mdc1 and its downstream signaling proteins 53bp1 and Brca1 to DNA damage foci was completely abolished. Mechanistic studies suggested that Mof-mediated H4 K16 acetylation and an intact acidic pocket on H2A.X were essential for the recruitment of Mdc1. Removal of Mof and its associated proteins phenocopied a charge-neutralizing mutant of H2A.X. Given the well-characterized H4-H2A trans interactions in regulating higher-order chromatin structure, our study revealed a novel chromatin-based mechanism that regulates the DNA damage repair process.

  7. Development of an aerosol microphysical module: Aerosol Two-dimensional bin module for foRmation and Aging Simulation (ATRAS)

    NASA Astrophysics Data System (ADS)

    Matsui, H.; Koike, M.; Kondo, Y.; Fast, J. D.; Takigawa, M.

    2014-09-01

    Number concentrations, size distributions, and mixing states of aerosols are essential parameters for accurate estimations of aerosol direct and indirect effects. In this study, we develop an aerosol module, designated the Aerosol Two-dimensional bin module for foRmation and Aging Simulation (ATRAS), that can explicitly represent these parameters by considering new particle formation (NPF), black carbon (BC) aging, and secondary organic aerosol (SOA) processes. A two-dimensional bin representation is used for particles with dry diameters from 40 nm to 10 μm to resolve both aerosol sizes (12 bins) and BC mixing states (10 bins) for a total of 120 bins. The particles with diameters between 1 and 40 nm are resolved using additional eight size bins to calculate NPF. The ATRAS module is implemented in the WRF-Chem model and applied to examine the sensitivity of simulated mass, number, size distributions, and optical and radiative parameters of aerosols to NPF, BC aging, and SOA processes over East Asia during the spring of 2009. The BC absorption enhancement by coating materials is about 50% over East Asia during the spring, and the contribution of SOA processes to the absorption enhancement is estimated to be 10-20% over northern East Asia and 20-35% over southern East Asia. A clear north-south contrast is also found between the impacts of NPF and SOA processes on cloud condensation nuclei (CCN) concentrations: NPF increases CCN concentrations at higher supersaturations (smaller particles) over northern East Asia, whereas SOA increases CCN concentrations at lower supersaturations (larger particles) over southern East Asia. The application of ATRAS in East Asia also shows that the impact of each process on each optical and radiative parameter depends strongly on the process and the parameter in question. The module can be used in the future as a benchmark model to evaluate the accuracy of simpler aerosol models and examine interactions between NPF, BC aging, and SOA

  8. Development of an aerosol microphysical module: Aerosol Two-dimensional bin module for foRmation and Aging Simulation (ATRAS)

    NASA Astrophysics Data System (ADS)

    Matsui, H.; Koike, M.; Kondo, Y.; Fast, J. D.; Takigawa, M.

    2014-04-01

    Number concentrations, size distributions, and mixing states of aerosols are essential parameters for accurate estimation of aerosol direct and indirect effects. In this study, we develop an aerosol module, designated Aerosol Two-dimensional bin module for foRmation and Aging Simulation (ATRAS), that can represent these parameters explicitly by considering new particle formation (NPF), black carbon (BC) aging, and secondary organic aerosol (SOA) processes. A two-dimensional bin representation is used for particles with dry diameters from 40 nm to 10 μm to resolve both aerosol size (12 bins) and BC mixing state (10 bins) for a total of 120 bins. The particles with diameters from 1 to 40 nm are resolved using an additional 8 size bins to calculate NPF. The ATRAS module is implemented in the WRF-chem model and applied to examine the sensitivity of simulated mass, number, size distributions, and optical and radiative parameters of aerosols to NPF, BC aging and SOA processes over East Asia during the spring of 2009. BC absorption enhancement by coating materials is about 50% over East Asia during the spring, and the contribution of SOA processes to the absorption enhancement is estimated to be 10-20% over northern East Asia and 20-35% over southern East Asia. A clear north-south contrast is also found between the impacts of NPF and SOA processes on cloud condensation nuclei (CCN) concentrations: NPF increases CCN concentrations at higher supersaturations (smaller particles) over northern East Asia, whereas SOA increases CCN concentrations at lower supersaturations (larger particles) over southern East Asia. Application of ATRAS to East Asia also shows that the impact of each process on each optical and radiative parameter depends strongly on the process and the parameter in question. The module can be used in the future as a benchmark model to evaluate the accuracy of simpler aerosol models and examine interactions between NPF, BC aging, and SOA processes under

  9. Development of an aerosol microphysical module: Aerosol Two-dimensional bin module for foRmation and Aging Simulation (ATRAS)

    SciTech Connect

    Matsui, H.; Koike, Makoto; Kondo, Yutaka; Fast, Jerome D.; Takigawa, M.

    2014-09-30

    Number concentrations, size distributions, and mixing states of aerosols are essential parameters for accurate estimation of aerosol direct and indirect effects. In this study, we developed an aerosol module, designated Aerosol Two-dimensional bin module for foRmation and Aging Simulation (ATRAS), that can represent these parameters explicitly by considering new particle formation (NPF), black carbon (BC) aging, and secondary organic aerosol (SOA) processes. A two-dimensional bin representation is used for particles with dry diameters from 40 nm to 10 µm to resolve both aerosol size (12 bins) and BC mixing state (10 bins) for a total of 120 bins. The particles with diameters from 1 to 40 nm are resolved using an additional 8 size bins to calculate NPF. The ATRAS module was implemented in the WRF-chem model and applied to examine the sensitivity of simulated mass, number, size distributions, and optical and radiative parameters of aerosols to NPF, BC aging and SOA processes over East Asia during the spring of 2009. BC absorption enhancement by coating materials was about 50% over East Asia during the spring, and the contribution of SOA processes to the absorption enhancement was estimated to be 10 – 20% over northern East Asia and 20 – 35% over southern East Asia. A clear north-south contrast was also found between the impacts of NPF and SOA processes on cloud condensation nuclei (CCN) concentrations: NPF increased CCN concentrations at higher supersaturations (smaller particles) over northern East Asia, whereas SOA increased CCN concentrations at lower supersaturations (larger particles) over southern East Asia. Application of ATRAS to East Asia also showed that the impact of each process on each optical and radiative parameter depended strongly on the process and the parameter in question. The module can be used in the future as a benchmark model to evaluate the accuracy of simpler aerosol models and examine interactions between NPF, BC aging, and SOA

  10. Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma.

    PubMed

    Pal, Ipsita; Dey, Kaushik Kumar; Chaurasia, Madhuri; Parida, Sheetal; Das, Subhayan; Rajesh, Y; Sharma, Kulbhushan; Chowdhury, Tamohan; Mandal, Mahitosh

    2016-05-01

    Amplification of PI3K-Akt pathway promotes radioresistance in various cancers including colorectal carcinoma. Local recurrence in colon cancer causes poor prognosis affecting overall survival of cancer-affected patient population. To avoid local recurrence, pre-operative or post-operative additional radiotherapy is given. However, main concern regarding radiotherapy is to increase the radiosensitivity of malignant cell without hampering the activities of normal cells. In this context, addition of two or more than two chemotherapeutic drugs as a radiosensitizer is a common practice in radiation biology. BI-69A11 earlier showed potential apoptosis-inducing effect in melanoma and colon carcinoma. Celecoxib showed anti-cancer effects in both COX-2 dependent and independent pathways and used to act as a radiosensitizing enhancer. Here, we suggest that the combination of BI-69A11 and celecoxib inhibits the phosphorylation of ataxia telangiectasia mutated (ATM) kinase and DNA-PK responsible for ionizing radiation (IR)-induced double-strand break (DSB) repair. Moreover, the combinatorial effect of BI-69A11 and celecoxib attenuates the IR-induced G2/M cell cycle arrest. Furthermore, this combination also impairs IR-induced activation of Akt and downstream targets of ATM. This might lead to induced activation of apoptotic pathway after triple therapy treatment modulating pro-apoptotic and anti-apoptotic proteins. This activation of apoptotic pathway also showed the interdependence of PUMA and BAD in triple combination-treated colon cancer cells in a p53 independent manner. This study reveals the therapeutic potential of the triple combination therapy in prevention of radioresistance. Besides, it also demonstrates the cytotoxic effects of triple combination therapy in colon cancer. This study shows utility and potential implication on safety of the patients undergoing radiation therapy.

  11. Anoxygenic photosynthesis modulated Proterozoic oxygen and sustained Earth's middle age

    PubMed Central

    Johnston, D. T.; Wolfe-Simon, F.; Pearson, A.; Knoll, A. H.

    2009-01-01

    Molecular oxygen (O2) began to accumulate in the atmosphere and surface ocean ca. 2,400 million years ago (Ma), but the persistent oxygenation of water masses throughout the oceans developed much later, perhaps beginning as recently as 580–550 Ma. For much of the intervening interval, moderately oxic surface waters lay above an oxygen minimum zone (OMZ) that tended toward euxinia (anoxic and sulfidic). Here we illustrate how contributions to primary production by anoxygenic photoautotrophs (including physiologically versatile cyanobacteria) influenced biogeochemical cycling during Earth's middle age, helping to perpetuate our planet's intermediate redox state by tempering O2 production. Specifically, the ability to generate organic matter (OM) using sulfide as an electron donor enabled a positive biogeochemical feedback that sustained euxinia in the OMZ. On a geologic time scale, pyrite precipitation and burial governed a second feedback that moderated sulfide availability and water column oxygenation. Thus, we argue that the proportional contribution of anoxygenic photosynthesis to overall primary production would have influenced oceanic redox and the Proterozoic O2 budget. Later Neoproterozoic collapse of widespread euxinia and a concomitant return to ferruginous (anoxic and Fe2+ rich) subsurface waters set in motion Earth's transition from its prokaryote-dominated middle age, removing a physiological barrier to eukaryotic diversification (sulfide) and establishing, for the first time in Earth's history, complete dominance of oxygenic photosynthesis in the oceans. This paved the way for the further oxygenation of the oceans and atmosphere and, ultimately, the evolution of complex multicellular organisms. PMID:19805080

  12. Anoxygenic photosynthesis modulated Proterozoic oxygen and sustained Earth's middle age.

    PubMed

    Johnston, D T; Wolfe-Simon, F; Pearson, A; Knoll, A H

    2009-10-06

    Molecular oxygen (O(2)) began to accumulate in the atmosphere and surface ocean ca. 2,400 million years ago (Ma), but the persistent oxygenation of water masses throughout the oceans developed much later, perhaps beginning as recently as 580-550 Ma. For much of the intervening interval, moderately oxic surface waters lay above an oxygen minimum zone (OMZ) that tended toward euxinia (anoxic and sulfidic). Here we illustrate how contributions to primary production by anoxygenic photoautotrophs (including physiologically versatile cyanobacteria) influenced biogeochemical cycling during Earth's middle age, helping to perpetuate our planet's intermediate redox state by tempering O(2) production. Specifically, the ability to generate organic matter (OM) using sulfide as an electron donor enabled a positive biogeochemical feedback that sustained euxinia in the OMZ. On a geologic time scale, pyrite precipitation and burial governed a second feedback that moderated sulfide availability and water column oxygenation. Thus, we argue that the proportional contribution of anoxygenic photosynthesis to overall primary production would have influenced oceanic redox and the Proterozoic O(2) budget. Later Neoproterozoic collapse of widespread euxinia and a concomitant return to ferruginous (anoxic and Fe(2+) rich) subsurface waters set in motion Earth's transition from its prokaryote-dominated middle age, removing a physiological barrier to eukaryotic diversification (sulfide) and establishing, for the first time in Earth's history, complete dominance of oxygenic photosynthesis in the oceans. This paved the way for the further oxygenation of the oceans and atmosphere and, ultimately, the evolution of complex multicellular organisms.

  13. Cell cycle age dependence for radiation-induced G/sub 2/ arrest: evidence for time-dependent repair

    SciTech Connect

    Rowley, R.

    1985-09-01

    Exponentially growing eucaryotic cells, irradiated in interphase, are delayed in progression to mitosis chiefly by arrest in G/sub 2/. The sensitivity of Chinese hamster ovary cells to G/sub 2/ arrest induction by X rays increases through the cell cycle, up to the X-ray transition point (TP) in G/sub 2/. This age response can be explained by cell cycle age-dependent changes in susceptibility of the target(s) for G/sub 2/ arrest and/or by changes in capability for postirradiation recovery from G/sub 2/ arrest damage. Discrimination between sensitivity changes and repair phenomena is possible only if the level of G/sub 2/ arrest-causing damage sustained by a cell at the time of irradiation and the level ultimately expressed as arrest can be determined. The ability of caffeine to ameliorate radiation-induced G/sub 2/ arrest, while inhibiting repair of G/sub 2/ arrest-causing damage makes such an analysis possible. In the presence of caffeine, progression of irradiated cells was relatively unperturbed, but on caffeine removal, G/sub 2/ arrest was expressed. The duration of G/sub 2/ arrest was independent of the length of the prior caffeine exposure. This finding indicates that the target for G/sub 2/ arrest induction is present throughout the cell cycle and that the level of G/sub 2/ arrest damage incurred is initially constant for all cell cycle phases. The data are consistent with the existence of a time-dependent recovery mechanism to explain the age dependence for radiation induction of G/sub 2/ arrest.

  14. Gene expression and DNA repair in progeroid syndromes and human aging.

    PubMed

    Kyng, Kasper J; Bohr, Vilhelm A

    2005-11-01

    Human progeroid syndromes are caused by mutations in single genes accelerating some but not all features of normal aging. Most progeroid disorders are linked to defects in genome maintenance, and while it remains unknown if similar processes underlie normal and premature aging, they provide useful models for the study of aging. Altered transcription is speculated to play a causative role in aging, and is involved in the pathology of most if not all progeroid syndromes. Previous studies demonstrate that there is a similar pattern of gene expression changes in primary cells from old and Werner syndrome compared to young suggesting a presence of common cellular aging mechanisms in old and progeria. Here we review the role of transcription in progeroid syndromes and discuss the implications of similar transcription aberrations in normal and premature aging.

  15. Protein repair L-isoaspartyl methyltransferase in plants. Phylogenetic distribution and the accumulation of substrate proteins in aged barley seeds.

    PubMed Central

    Mudgett, M B; Lowenson, J D; Clarke, S

    1997-01-01

    Protein L-isoaspartate (D-aspartate) O-methyltransferases (MTs; EC 2.1.1.77) can initiate the conversion of detrimental L-isoaspartyl residues in spontaneously damaged proteins to normal L-aspartyl residues. We detected this enzyme in 45 species from 23 families representing most of the divisions of the plant kingdom. MT activity is often localized in seeds, suggesting that it has a role in their maturation, quiescence, and germination. The relationship among MT activity, the accumulation of abnormal protein L-isoaspartyl residues, and seed viability was explored in barley (Hordeum vulgare cultivar Himalaya) seeds, which contain high levels of MT. Natural aging of barley seeds for 17 years resulted in a significant reduction in MT activity and in seed viability, coupled with increased levels of "unrepaired" L-isoaspartyl residues. In seeds heated to accelerate aging, we found no reduction of MT activity, but we did observe decreased seed viability and the accumulation of isoaspartyl residues. Among populations of accelerated aged seed, those possessing the highest levels of L-isoaspartyl-containing proteins had the lowest germination percentages. These results suggest that the MT present in seeds cannot efficiently repair all spontaneously damaged proteins containing altered aspartyl residues, and their accumulation during aging may contribute to the loss of seed viability. PMID:9414558

  16. Age-related reduction of BOLD modulation to cognitive difficulty predicts poorer task accuracy and poorer fluid reasoning ability.

    PubMed

    Rieck, Jenny R; Rodrigue, Karen M; Boylan, Maria A; Kennedy, Kristen M

    2017-02-15

    Aging is associated with reduced resources needed to perform difficult cognitive tasks, but the neural underpinnings are not well understood, especially as there is scant evidence linking functional brain differences to aging cognition. Therefore, the current study examined modulation of fMRI activation from easier to harder spatial distance judgments across a large lifespan sample (N=161; ages 20-94) to identify when in the lifespan modulation to difficulty begins to show deficits and if age-related modulation predicts cognition. Analyses revealed two sets of regions in which modulation increased with difficulty due to either more activation (positive modulation) or more deactivation (negative modulation) to difficulty. These two networks evidenced differential aging trajectories: a right-lateralized fronto-parietal network that decreased in modulation to difficulty between middle- and older-age, and a network of regions in ventromedial prefrontal cortex, posterior cingulate, left angular and middle frontal gyri that showed decreased modulation at the transition from younger to middle-age. Critically, older adults who maintained negative modulation to difficulty showed higher task accuracy. Further, individuals who showed greater coupling between positive and negative modulation performed better on a fluid reasoning task. Age-related preservation of coupled modulation in both cognitive control regions and regions typically associated with default network may be a salient marker of how the brain adapts to maintain cognitive function as we age. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Anger management: age differences in emotional modulation of visual processing.

    PubMed

    Mienaltowski, Andrew; Corballis, Paul M; Blanchard-Fields, Fredda; Parks, Nathan A; Hilimire, Matthew R

    2011-03-01

    Although positive and negative images enhance the visual processing of young adults, recent work suggests that a life-span shift in emotion processing goals may lead older adults to avoid negative images. To examine this tendency for older adults to regulate their intake of negative emotional information, the current study investigated age-related differences in the perceptual boost received by probes appearing over facial expressions of emotion. Visually-evoked event-related potentials were recorded from the scalp over cortical regions associated with visual processing as a probe appeared over facial expressions depicting anger, sadness, happiness, or no emotion. The activity of the visual system in response to each probe was operationalized in terms of the P1 component of the event-related potentials evoked by the probe. For young adults, the visual system was more active (i.e., greater P1 amplitude) when the probes appeared over any of the emotional facial expressions. However, for older adults, the visual system displayed reduced activity when the probe appeared over angry facial expressions.

  18. Impact of age-associated cyclopurine lesions on DNA repair helicases.

    PubMed

    Khan, Irfan; Suhasini, Avvaru N; Banerjee, Taraswi; Sommers, Joshua A; Kaplan, Daniel L; Kuper, Jochen; Kisker, Caroline; Brosh, Robert M

    2014-01-01

    8,5' cyclopurine deoxynucleosides (cPu) are locally distorting DNA base lesions corrected by nucleotide excision repair (NER) and proposed to play a role in neurodegeneration prevalent in genetically defined Xeroderma pigmentosum (XP) patients. In the current study, purified recombinant helicases from different classifications based on sequence homology were examined for their ability to unwind partial duplex DNA substrates harboring a single site-specific cPu adduct. Superfamily (SF) 2 RecQ helicases (RECQ1, BLM, WRN, RecQ) were inhibited by cPu in the helicase translocating strand, whereas helicases from SF1 (UvrD) and SF4 (DnaB) tolerated cPu in either strand. SF2 Fe-S helicases (FANCJ, DDX11 (ChlR1), DinG, XPD) displayed marked differences in their ability to unwind the cPu DNA substrates. Archaeal Thermoplasma acidophilum XPD (taXPD), homologue to the human XPD helicase involved in NER DNA damage verification, was impeded by cPu in the non-translocating strand, while FANCJ was uniquely inhibited by the cPu in the translocating strand. Sequestration experiments demonstrated that FANCJ became trapped by the translocating strand cPu whereas RECQ1 was not, suggesting the two SF2 helicases interact with the cPu lesion by distinct mechanisms despite strand-specific inhibition for both. Using a protein trap to simulate single-turnover conditions, the rate of FANCJ or RECQ1 helicase activity was reduced 10-fold and 4.5-fold, respectively, by cPu in the translocating strand. In contrast, single-turnover rates of DNA unwinding by DDX11 and UvrD helicases were only modestly affected by the cPu lesion in the translocating strand. The marked difference in effect of the translocating strand cPu on rate of DNA unwinding between DDX11 and FANCJ helicase suggests the two Fe-S cluster helicases unwind damaged DNA by distinct mechanisms. The apparent complexity of helicase encounters with an unusual form of oxidative damage is likely to have important consequences in the

  19. Spirit of aging rising: cross-cutting thematic modules to enrich foundation graduate social work courses.

    PubMed

    Saltz Corley, Connie; Davis, Pamela; Jackson, LaTina; Bach, Marlena Stuart

    2007-01-01

    To enrich an urban generalist MSW program serving a diverse aging community, an innovative approach was initiated. A team of students, faculty and a field instructor collaborated in creating and evaluating 3 sets of cross-cutting thematic modules. An overview of the thematic modules (addressing elder abuse, family caregiving, and mental health), integrated across multiple curriculum areas (Human Behavior and the Social Environment, Macro/Policy, Practice and Research), is presented along with results of a faculty focus group evaluating the process of coordinating module content for one full week of class per foundation area (one topic per quarter).

  20. Age at hysterectomy as a predictor for subsequent pelvic organ prolapse repair.

    PubMed

    Lykke, Rune; Blaakær, Jan; Ottesen, Bent; Gimbel, Helga

    2016-05-01

    The aim of this study was to investigate the association between patient age at the time of hysterectomy and subsequent pelvic organ prolapse (POP) surgery. We gathered data on all benign hysterectomies and POP surgeries performed in Denmark on Danish women from 1977 to 2009 from the Danish National Patient Registry. The cohort consisted of 154,882 hysterectomized women, who were followed up for up to 32 years. Survival analysis for each age group at hysterectomy was performed using Kaplan-Meier product limit methods. For all hysterectomized women, we found that low age at hysterectomy yielded a lower risk of subsequent POP surgery than did hysterectomy at an older age. This difference diminished after stratification by indication; all non-POP hysterectomies had a low cumulative incidence at 8-11 % at the end of the follow-up period. For all women hysterectomized, the predominant compartment for POP surgery was the posterior. Women hysterectomized when aged over 66 years had a higher proportion of POP surgery in the apical compartment than in the other age groups (p = 0.000). Our findings indicate that age at hysterectomy only marginally influences the risk of subsequent POP surgery for women hysterectomized for indications other than POP. If POP is the indication for hysterectomy, the risk of undergoing subsequent POP surgery increases substantially.

  1. Age-dependent modulation of the somatosensory network upon eye closure.

    PubMed

    Brodoehl, Stefan; Klingner, Carsten; Witte, Otto W

    2016-02-01

    Eye closure even in complete darkness can improve somatosensory perception by switching the brain to a uni-sensory processing mode. This causes an increased information flow between the thalamus and the somatosensory cortex while decreasing modulation by the visual cortex. Previous work suggests that these modulations are age-dependent and that the benefit in somatosensory performance due to eye closing diminishes with age. The cause of this age-dependency and to what extent somatosensory processing is involved remains unclear. Therefore, we intended to characterize the underlying age-dependent modifications in the interaction and connectivity of different sensory networks caused by eye closure. We performed functional MR-imaging with tactile stimulation of the right hand under the conditions of opened and closed eyes in healthy young and elderly participants. Conditional Granger causality analysis was performed to assess the somatosensory and visual networks, including the thalamus. Independent of age, eye closure improved the information transfer from the thalamus to and within the somatosensory cortex. However, beyond that, we found an age-dependent recruitment strategy. Whereas young participants were characterized by an optimized information flow within the relays of the somatosensory network, elderly participants revealed a stronger modulatory influence of the visual network upon the somatosensory cortex. Our results demonstrate that the modulation of the somatosensory and visual networks by eye closure diminishes with age and that the dominance of the visual system is more pronounced in the aging brain.

  2. Meningocele repair

    MedlinePlus

    ... Myelodysplasia repair; Spinal dysraphism repair; Meningomyelocele repair; Neural tube defect repair; Spina bifida repair ... If your child has hydrocephalus, a shunt (plastic tube) will be put in the child's brain to ...

  3. Identification of small juvenile stem cells in aged bone marrow and their therapeutic potential for repair of the ischemic heart.

    PubMed

    Igura, Koichi; Okada, Motoi; Kim, Ha Won; Ashraf, Muhammad

    2013-11-01

    Stem cell-mediated cardiac regeneration is impaired with age. In this study, we identified a novel subpopulation of small juvenile stem cells (SJSCs) isolated from aged bone marrow-derived stem cells (BMSCs) with high proliferation and differentiation potential. SJSCs expressed mesenchymal stem cell markers, CD29(+)/CD44(+)/CD59(+)/CD90(+), but were negative for CD45(-)/CD117(-) as examined by flow cytometry analysis. SJSCs showed higher proliferation, colony formation, and differentiation abilities compared with BMSCs. We also observed that SJSCs significantly expressed cardiac lineage markers (Gata-4 and myocyte-specific enhancer factor 2C) and pluripotency markers (octamer-binding transcription factor 4, sex-determining region Y box 2, stage-specific embryonic antigen 1, and Nanog) as well as antiaging factors such as telomerase reverse transcriptase and sirtuin 1. Interestingly, SJSCs either from young or aged animals showed significantly longer telomere length as well as lower senescence-associated β-galactosidase expression, suggesting that SJSCs possess antiaging properties, whereas aged BMSCs have limited potential for proliferation and differentiation. Furthermore, transplantation of aged SJSCs into the infarcted rat heart significantly reduced the infarction size and improved left ventricular function, whereas transplantation of aged BMSCs was less effective. Moreover, neovascularization as well as cardiomyogenic differentiation in the peri-infarcted area were significantly increased in the SJSC-transplanted group compared with the BMSC-transplated group, as evaluated by immunohistochemical analysis. Taken together, these findings demonstrate that SJSCs possess characteristics of antiaging, pluripotency, and high proliferation and differentiation rates, and, therefore, these cells offer great therapeutic potential for repair of the injured myocardium.

  4. Neuromechanical Modulation of the Achilles Tendon During Bilateral Hopping in Patients with Unilateral Achilles Tendon Rupture, Over 1 Year After Surgical Repair.

    PubMed

    Oda, Hiroyuki; Sano, Kanae; Kunimasa, Yoko; Komi, Paavo V; Ishikawa, Masaki

    2017-06-01

    Patients who have had an Achilles tendon (AT) rupture repaired are potentially at higher risk for re-rupture than those without previous rupture. Little attention has been given to the neuromechanical modulation of muscle-tendon interaction and muscle activation profiles during human dynamic movements after AT rupture repair. The purpose of this study was to examine muscle-tendon behavior and muscle activation during bilateral hopping. We enrolled nine subjects who had undergone surgical repair of unilateral AT rupture within the past 1-2 years. Subjects performed bilateral hopping while we took ultrasound, kinematic, and electromyogram recordings and measurements. AT behaviors were also recorded. We then compared responses between values obtained from the ruptured AT leg (LEGATR) and non-ruptured AT leg (LEGNOR). During hopping, the AT stretching amplitudes were greater in the LEGATR than in the LEGNOR, although the peak AT force and stiffness were smaller in the LEGATR than in the LEGNOR. The AT negative mechanical work did not show any significant differences between both legs. However, positive works were significantly lower in the LEGATR than in the LEGNOR. Electromyogram patterns in both soleus and tibialis anterior muscles clearly differed after ground contact for the LEGATR and the LEGNOR. These results suggest that the repaired ruptured AT can be compliant and have insufficient Young's modulus, which can influence mechanical responses in muscle activities. The modulation of agonist-antagonist muscle activities corresponding to the different levels of stiffness between the LEGATR and the LEGNOR may not be fully functioning during the pre-activation phase.

  5. Application of rapid artificial cardiac pacing in thoracic endovascular aortic repair in aged patients

    PubMed Central

    Chen, Jun; Huang, Wenhui; Luo, Songyuan; Yang, Dahao; Xu, Zhengrong; Luo, Jianfang

    2014-01-01

    Objective To compare the safety, efficacy, and impact on stent graft positioning between rapid artificial cardiac pacing (RACP), induced hypotension and sodium nitroprusside (SNP) induced hypotension during thoracic endovascular aortic repair (TEVAR) for Stanford B aortic dissection. Methods One hundred and sixty-eight patients, who were diagnosed with Stanford B aortic dissection and who underwent selective TEVAR in Guangdong General Hospital and the People’s Hospital of Baoan District, Shenzhen, People’s Republic of China, were enrolled in this study. Patients were randomly divided into a RACP group (n=77) and a SNP group (n=91). During localization and deployment of the stent graft, hypotension was induced by RACP or intravenous SNP, according to randomization. Hemodynamics, landing precision (deviation from planned placement site), duration of procedure, renal function, neurocognitive function, and incidence of endoleaks and paraplegia/hemiplegia were compared. Except for methods of inducing hypotension, TEVAR was performed according to the same protocol in each group. Results RACP was successfully performed in all patients assigned to the RACP group. Compared with the SNP group, blood pressure was significantly lower (43±5 versus 81±6 mmHg, P=0.003) and the restoration time of blood pressure and the operation duration were significantly shorter (7±2 versus 451±87 seconds, P<0.001; 87±15 versus 106±18 minutes, P<0.001, respectively) in the RACP group. Stent graft localization/deployment was more precise in the RACP group (2±1 versus 5±2 mm, P<0.001). Compared to baseline, there was no significant change after TEVAR in either group in regard to renal function, neurocognitive function, and incidence of endoleaks and paraplegia/hemiplegia. Conclusion RACP can be safely applied to patients undergoing TEVAR for Stanford B dissection. RACP can shorten the operation duration and facilitate precise graft localization/deployment. PMID:24403824

  6. Application of rapid artificial cardiac pacing in thoracic endovascular aortic repair in aged patients.

    PubMed

    Chen, Jun; Huang, Wenhui; Luo, Songyuan; Yang, Dahao; Xu, Zhengrong; Luo, Jianfang

    2014-01-01

    To compare the safety, efficacy, and impact on stent graft positioning between rapid artificial cardiac pacing (RACP), induced hypotension and sodium nitroprusside (SNP) induced hypotension during thoracic endovascular aortic repair (TEVAR) for Stanford B aortic dissection. One hundred and sixty-eight patients, who were diagnosed with Stanford B aortic dissection and who underwent selective TEVAR in Guangdong General Hospital and the People's Hospital of Baoan District, Shenzhen, People's Republic of China, were enrolled in this study. Patients were randomly divided into a RACP group (n=77) and a SNP group (n=91). During localization and deployment of the stent graft, hypotension was induced by RACP or intravenous SNP, according to randomization. Hemodynamics, landing precision (deviation from planned placement site), duration of procedure, renal function, neurocognitive function, and incidence of endoleaks and paraplegia/hemiplegia were compared. Except for methods of inducing hypotension, TEVAR was performed according to the same protocol in each group. RACP was successfully performed in all patients assigned to the RACP group. Compared with the SNP group, blood pressure was significantly lower (43±5 versus 81±6 mmHg, P=0.003) and the restoration time of blood pressure and the operation duration were significantly shorter (7±2 versus 451±87 seconds, P<0.001; 87±15 versus 106±18 minutes, P<0.001, respectively) in the RACP group. Stent graft localization/deployment was more precise in the RACP group (2±1 versus 5±2 mm, P<0.001). Compared to baseline, there was no significant change after TEVAR in either group in regard to renal function, neurocognitive function, and incidence of endoleaks and paraplegia/hemiplegia. RACP can be safely applied to patients undergoing TEVAR for Stanford B dissection. RACP can shorten the operation duration and facilitate precise graft localization/deployment.

  7. CtIP-BRCA1 modulates the choice of DNA double-strand break repair pathway throughout the cell cycle

    PubMed Central

    Yun, Maximina H.; Hiom, Kevin

    2009-01-01

    The repair of DNA double-strand breaks (DSB) is tightly regulated during the cell cycle. In G1 phase, the absence of a sister chromatid means that repair of DSB occurs through non-homologous end-joining (NHEJ) or microhomology-mediated end-joining (MMEJ)1. These pathways often involve loss of DNA sequences at the break site and are therefore error-prone. In late S and G2 phases, even though DNA end-joining pathways remain functional2, there is an increase in repair of DSB by homologous recombination (HR), which is mostly error-free3,4. Consequently, the relative contribution of these different pathways to DSB repair in the cell cycle has a profound influence on the maintenance of genetic integrity. How then are DSB directed for repair by different, potentially competing, repair pathways? Here we identify a role for CtIP in this process in DT40. We establish that CtIP is not only required for repair of DSB by HR in S/G2 phase, but also for MMEJ in G1. The function of CtIP in HR, but not MMEJ, is dependent on the phosphorylation of serine residue 327 and recruitment of BRCA1. Cells expressing CtIP protein that cannot be phosphorylated at serine 327 are specifically defective in HR and exhibit decreased level of single-stranded DNA (ssDNA) after DNA damage, while MMEJ remains unaffected. Our data support a model in which phosphorylation of serine 327 of CtIP as cells enter S-phase and the recruitment of BRCA1 functions as a molecular switch to shift the balance of DSB repair from error-prone DNA end-joining to error-free homologous recombination (Supplementary Fig. 1). PMID:19357644

  8. Subchondral chitosan/blood implant-guided bone plate resorption and woven bone repair is coupled to hyaline cartilage regeneration from microdrill holes in aged rabbit knees.

    PubMed

    Guzmán-Morales, J; Lafantaisie-Favreau, C-H; Chen, G; Hoemann, C D

    2014-02-01

    Little is known of how to routinely elicit hyaline cartilage repair tissue in middle-aged patients. We tested the hypothesis that in skeletally aged rabbit knees, microdrill holes can be stimulated to remodel the bone plate and induce a more integrated, voluminous and hyaline cartilage repair tissue when treated by subchondral chitosan/blood implants. New Zealand White rabbits (13 or 32 months old, N = 7) received two 1.5 mm diameter, 2 mm depth drill holes in each knee, either left to bleed as surgical controls or press-fit with a 10 kDa (distal hole: 10K) or 40 kDa (proximal hole: 40K) chitosan/blood implant with fluorescent chitosan tracer. Post-operative knee effusion was documented. Repair tissues at day 0 (N = 1) and day 70 post-surgery (N = 6) were analyzed by micro-computed tomography, and by histological scoring and histomorphometry (SafO, Col-2, and Col-1) at day 70. All chitosan implants were completely cleared after 70 days, without increasing transient post-operative knee effusion compared to controls. Proximal control holes had worse osteochondral repair than distal holes. Both implant formulations induced bone remodeling and improved lateral integration of the bone plate at the hole edge. The 40K implant inhibited further bone repair inside 50% of the proximal holes, while the 10K implant specifically induced a "wound bloom" reaction, characterized by decreased bone plate density in a limited zone beyond the initial hole edge, and increased woven bone (WB) plate repair inside the initial hole (P = 0.016), which was accompanied by a more voluminous and hyaline cartilage repair (P < 0.05 vs control defects). In a challenging aged rabbit model, bone marrow-derived hyaline cartilage repair can be promoted by treating acute drill holes with a biodegradable subchondral implant that elicits bone plate resorption followed by anabolic WB repair within a 70-day repair period. Copyright © 2013 Osteoarthritis Research Society International. Published by

  9. Aging increases cytochrome P450 4A modulation of alpha1-adrenergic vasoconstriction in mesenteric arteries.

    PubMed

    Berezan, Dellice J; Dunn, Kathryn M J; Falck, John R; Davidge, Sandra T

    2008-03-01

    Aging is associated with peripheral vascular dysfunction. In vascular smooth muscle, cytochrome P450 4A (CYP4A) enzymes form the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE acts as an intracellular messenger to modulate vasoconstriction induced by various agonists, including the alpha1-adrenergic agonist phenylephrine (PE) and endothelin-1 (ET-1). Eicosanoids produced by CYP4A contribute to the elevated vascular tone in hypertension, but the effects of advanced age on CYP4A modulation of vasoconstriction are unknown. Mesenteric arteries were isolated from young (3 to 4 months) and aged (17 to 18 months) Sprague-Dawley rats. Vasoconstriction was induced with PE or ET-1 in the absence or presence of the CYP4A inhibitor DDMS and/or the ETA inhibitor BQ123. CYP4A inhibition with DDMS significantly reduced PE sensitivity in aged rats, but it had no effect in young. Furthermore, in aged rats only, ETA inhibition reduced PE sensitivity while combined inhibition of CYP4A and ETA had no additional effect, suggesting that the pathways work in concert in aging. Exogenous ET-1 constriction was not altered by DDMS in young or aged rats. Overall, our data indicate that aging increases the contribution of CYP4A to alpha1-adrenergic vasoconstriction in systemic arteries. Understanding aging-related changes in vascular function is important for development of novel targets for the prevention of cardiovascular disease.

  10. Successful surgical repair of pentalogy of cantrell at 14 months of age.

    PubMed

    Akhtar, Khurram; Sultan, Mehboob; Ahmed, Waqar; Ullah, Maad; Sadiq, Nadeem

    2014-05-01

    Pentalogy of Cantrell with ectopia cordis is a rare congenital anomaly, first described in 1958 by Cantrell, has a reported incidence of around 5-10 cases per one million live births with wide variety of clinical presentations. We are reporting a child with ectopia cordis along with cleft lower sternum, upper abdominal wall defect, ectopic umbilicus and diaphragmatic defect. Echocardiography in first month of life revealed a restrictive perimembranous ventricular septal defect and a small patent Foramen Ovale, both closed spontaneously in infancy. CT angiography at 10 months of age revealed a defect in the thoracic and abdominal walls along with herniation of left ventricular apex into epigastrium. The two ventriculi formed a tail that looked like a crocodile. This patient underwent surgical correction at our institution at 14 months of age and recovered well with no residual issue.

  11. Using individual differences to assess modulation-processing mechanisms and age effects.

    PubMed

    Paraouty, Nihaad; Lorenzi, Christian

    2017-02-01

    This study used a correlational approach to clarify the mechanisms involved in modulation coding. Amplitude-modulation (AM) and frequency-modulation (FM) detection thresholds (AMDTs and FMDTs, respectively) were assessed for 70 normal-hearing listeners. In order to increase between-listeners variability in peripheral coding, participants with a wide range of age (20-70 years) were included. AMDTs and FMDTs were measured at a 5-Hz rate, using a 500-Hz sinusoidal carrier. FMDTs were also measured in the presence of an interfering AM to discourage the use of temporal-envelope cues. The results showed that AMDTs were significantly correlated with FMDTs, but not with FMDTs measured with interfering AM. FMDTs with and without interfering AM were significantly correlated with each other. This pattern of correlation proved to be robust, providing additional evidence that for low carrier frequencies, (i) low-rate AM and FM detection is based on a common code using temporal-envelope cues and (ii) low-rate FM detection is based on an additional code using cues distinct from temporal-envelope. The analyses also showed that age was correlated with FMDTs only. However, no significant difference was found when comparing the various correlations with age. Hence, the effects of age on modulation sensitivity remain unclear. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. EVALUATION OF THE RESULTS FROM ARTHROSCOPIC REPAIR ON ROTATOR CUFF INJURIES AMONG PATIENTS UNDER 50 YEARS OF AGE

    PubMed Central

    Miyazaki, Alberto Naoki; Fregoneze, Marcelo; Santos, Pedro Doneux; da Silva, Luciana Andrade; do Val Sella, Guilherme; Santos, Ruy Mesquita Maranhão; de Souza, Adriano; Checchia, Sérgio Luiz

    2015-01-01

    Objective: To assess the results from arthroscopic surgical treatment of rotator cuff injuries among patients under 50 years of age. Methods: Sixty-three patients with rotator cuff injuries who underwent arthroscopic surgical treatment performed by the Shoulder and Elbow Group of the Department of Orthopedics and Traumatology, in the Fernandinho Simonsen wing of Santa Casa Medical School, São Paulo, between August 1998 and December 2007, were reassessed. The study included all patients with rotator cuff injuries who were under 50 years of age and had been followed up postoperatively for at least 24 months. Results: According to the UCLA evaluation criteria, 59 patients (92%) showed excellent and good results; five (8%) showed fair results; and none showed poor results. The postoperative evaluation showed that the mean range of motion was 145° for elevation, 47° for lateral rotation and T10 for medial rotation. Unsatisfactory results were associated with prolonged duration of the injury, with a statistically significant relationship. Conclusion: Arthroscopic repair of rotator cuff injuries in young patients produces excellent or good results for most patients. PMID:27047819

  13. Modulation of xylosyltransferase I expression provides a mechanism regulating glycosaminoglycan chain synthesis during cartilage destruction and repair.

    PubMed

    Venkatesan, Narayanan; Barré, Lydia; Magdalou, Jacques; Mainard, Didier; Netter, Patrick; Fournel-Gigleux, Sylvie; Ouzzine, Mohamed

    2009-03-01

    Osteoarthritis and rheumatoid arthritis are characterized by loss of proteoglycans (PGs) and their glycosaminoglycan (GAG) chains that are essential for cartilage function. Here, we investigated the role of glycosyltransferases (GTs) responsible for PG-GAG chain assembly during joint cartilage destruction and repair processes. At various times after antigen-induced arthritis (AIA) and papain-induced cartilage repair in rats, PG synthesis and deposition, expression of GTs, and GAG chain composition were analyzed. Our data showed that expression of the GT xylosyltransferase I (XT-I) gene initiating PG-GAG chain synthesis was significantly reduced in AIA rat cartilage and was associated with a decrease in PG synthesis. Interestingly, interleukin-1beta, the main proinflammatory cytokine incriminated in joint diseases, down-regulated the XT-I gene expression with a concomitant decrease in PG synthesis in rat cartilage explants ex vivo. However, cartilage from papain-injected rat knees showed up-regulation of XT-I gene expression and increased PG synthesis at early stages of cartilage repair, a process associated with up-regulation of TGF-beta1 gene expression and mediated by p38 mitogen-activated protein kinase activation. Consistently, silencing of XT-I expression by intraarticular injection of XT-I shRNA in rat knees prevented cartilage repair by decreasing PG synthesis and content. These findings show that GTs play a key role in the loss of PG-GAGs in joint diseases and identify novel targets for stimulating cartilage repair.

  14. Mitochondrial autophagy involving renal injury and aging is modulated by caloric intake in aged rat kidneys.

    PubMed

    Cui, Jing; Shi, Suozhu; Sun, Xuefeng; Cai, Guangyan; Cui, Shaoyuan; Hong, Quan; Chen, Xiangmei; Bai, Xue-Yuan

    2013-01-01

    A high-calorie (HC) diet induces renal injury and promotes aging, and calorie restriction (CR) may ameliorate these responses. However, the effects of long-term HC and CR on renal damage and aging have been not fully determined. Autophagy plays a crucial role in removing protein aggregates and damaged organelles to maintain intracellular homeostasis and function. The role of autophagy in HC-induced renal damage is unknown. We evaluated the expression of LC3/Atg8 as a marker of the autophagosome; p62/SQSTM1; polyubiquitin aggregates as markers of autophagy flux; Ambra1, PINK1, Parkin and Bnip3 as markers of mitophagy; 8-hydroxydeoxyguanosine (8-OHdG) as a marker of DNA oxidative damage; and p16 as a marker of organ aging by western blot and immunohistochemical staining in the kidneys of 24-month-old Fischer 344 rats. We also observed mitochondrial structure and autolysosomes by transmission electron microscopy. Expression of the autophagosome formation marker LC3/Atg8 and markers of mitochondrial autophagy (mitophagy) were markedly decreased in the kidneys of the HC group, and markedly increased in CR kidneys. p62/SQSTM1 and polyubiquitin aggregates increased in HC kidneys, and decreased in CR kidneys. Transmission electron microscopy demonstrated that HC kidneys showed severe abnormal mitochondrial morphology with fewer autolysosomes, while CR kidneys exhibited normal mitochondrial morphology with numerous autolysosomes. The level of 8-hydroxydeoxyguanosine was increased in HC kidneys and decreased in CR kidneys. Markers of aging, such as p16 and senescence-associated-galactosidase, were increased significantly in the HC group and decreased significantly in the CR group. The study firstly suggests that HC diet inhibits renal autophagy and aggravates renal oxidative damage and aging, while CR enhances renal autophagy and ameliorates oxidative damage and aging in the kidneys.

  15. Modulation of DNA polymerase beta-dependent base excision repair in cultured human cells after low dose exposure to arsenite

    SciTech Connect

    Sykora, Peter; Snow, Elizabeth T.

    2008-05-01

    Base excision repair (BER) is crucial for development and for the repair of endogenous DNA damage. However, unlike nucleotide excision repair, the regulation of BER is not well understood. Arsenic, a well-established human carcinogen, is known to produce oxidative DNA damage, which is repaired primarily by BER, whilst high doses of arsenic can also inhibit DNA repair. However, the mechanism of repair inhibition by arsenic and the steps inhibited are not well defined. To address this question we have investigated the regulation of DNA polymerase {beta} (Pol {beta}) and AP endonuclease (APE1), in response to low, physiologically relevant doses of arsenic. GM847 lung fibroblasts and HaCaT keratinocytes were exposed to sodium arsenite, As(III), and mRNA, protein levels and BER activity were assessed. Both Pol {beta} and APE1 mRNA exhibited significant dose-dependant down regulation at doses of As(III) above 1 {mu}M. However, at lower doses Pol {beta} mRNA and protein levels, and consequently, BER activity were significantly increased. In contrast, APE1 protein levels were only marginally increased by low doses of As(III) and there was no correlation between APE1 and overall BER activity. Enzyme supplementation of nuclear extracts confirmed that Pol {beta} was rate limiting. These changes in BER correlated with overall protection against sunlight UV-induced toxicity at low doses of As(III) and produced synergistic toxicity at high doses. The results provide evidence that changes in BER due to low doses of arsenic could contribute to a non-linear, threshold dose response for arsenic carcinogenesis.

  16. ATM-mediated phosphorylation of the chromatin remodeling enzyme BRG1 modulates DNA double-strand break repair.

    PubMed

    Kwon, S-J; Park, J-H; Park, E-J; Lee, S-A; Lee, H-S; Kang, S W; Kwon, J

    2015-01-15

    ATP-dependent chromatin remodeling complexes such as SWI/SNF (SWItch/Sucrose NonFermentable) have been implicated in DNA double-strand break (DSB) repair and damage responses. However, the regulatory mechanisms that control the function of chromatin remodelers in DNA damage response are largely unknown. Here, we show that ataxia telangiectasia mutated (ATM) mediates the phosphorylation of BRG1, the catalytic ATPase of the SWI/SNF complex that contributes to DSB repair by binding γ-H2AX-containing nucleosomes via interaction with acetylated histone H3 and stimulating γ-H2AX formation, at Ser-721 in response to DNA damage. ATM-mediated phosphorylation of BRG1 occurs rapidly and transiently after DNA damage. Phosphorylated BRG1 binds γ-H2AX-containing nucleosomes to form the repair foci. The Ser-721 phosphorylation of BRG1 is critical for binding γ-H2AX-containing nucleosomes and stimulating γ-H2AX formation and DSB repair. BRG1 binds to acetylated H3 peptides much better after phosphorylation at Ser-721 by DNA damage. However, the phosphorylation of Ser-721 does not significantly affect the ATPase and transcriptional activities of BRG1. These results, establishing BRG1 as a novel and functional ATM substrate, suggest that the ATM-mediated phosphorylation of BRG1 facilitates DSB repair by stimulating the association of this remodeler with γ-H2AX nucleosomes via enhancing the affinity to acetylated H3. Our work also suggests that the mechanism of BRG1 stimulation of DNA repair is independent of the remodeler's enzymatic or transcriptional activities.

  17. Phenolic composition and antioxidant activity in sparkling wines: modulation by the ageing on lees.

    PubMed

    Stefenon, C A; Bonesi, C De M; Marzarotto, V; Barnabé, D; Spinelli, F R; Webber, V; Vanderlinde, R

    2014-02-15

    Sparkling wines (SW) have a special biological ageing on lees that is performed using two distinct methods: in the bottle (Champenoise) or in isobaric tanks (Charmat method). The objective of this study was to compare the levels of phenolic compounds, β-Glucosidase and antioxidant activity during the ageing on lees, in samples of SW produced at industrial scale by both methods. The β-Glucosidase activity has been constant over time, showing a close relationship with all the polyphenols studied (resveratrol, piceid, tyrosol, gallic, caffeic and ferulic acids), which were affected by the sur lie time. With these cross-reactions, the biological properties of the SW were also modulated. The results showed that the long period of ageing decreased the antioxidant potential in all samples. This work demonstrates that the sur lie is more important than the production method itself, due to its ability to modulate the necessary changes to achieve the specific objective.

  18. Aging and List-Wide Modulations of Strategy Execution:A Study in Arithmetic.

    PubMed

    Hinault, Thomas; Lemaire, Patrick

    2017-01-01

    Background/Study Context: This study aimed at further our understanding of the cognitive processes involved during strategy execution, and how the processes involved change with age. More specifically, the main goal was to investigate whether poorer-strategy effects (i.e., poorer performance when a cued strategy is not the best) and sequential modulations of poorer-strategy effects (i.e., decreased poorer-strategy effects on current problems following poorer-strategy problems compared with after better-strategy problems) are influenced by proportions of poorer-strategy problems. We used a computational estimation task (i.e., providing approximate products to two-digit multiplication problems such as 38 × 74) with problems sets including 75%, 50%, or 25% of poorer-strategy problems (i.e., participants have to estimate products with another strategy than the better strategy). The remaining problems were cued with the better strategy. Age-related differences were also investigated. We found that proportions of poorer-strategy problems influenced sequential modulations of poorer-strategy effects. Indeed, sequential modulations of poorer-strategy effects were larger when proportions of poorer-strategy problems were equal than unequal. Moreover, proportion effects were different for young and older adults, as older adults benefited more from low proportions of poorer-strategy problems compared with young adults. These findings have important implications regarding cognitive control mechanisms underlying both list-wide and trial-to-trial modulations of strategy execution, and how these processes change during aging.

  19. High throughput screening technology and the small molecules modulating aging related signals.

    PubMed

    Mo, Chunfen; Zhang, Wei; Liu, Luhong; Wang, Ling; Xiao, Hengyi

    2012-03-01

    Aging and its related diseases are severe issues in modern society. Many efforts have been made to understand the mechanisms of aging and to find the ways to prevent age-related diseases. Identifying the compounds targeting aging-related signals is a challenging work because there are so many proteins and signals involved. Recently, alone with the progresses in high throughput screening (HTS) technology, increasing numbers of small molecules targeting aging-related pathologic processes have been identified. In this review, we introduce the basic workflow, classification and assay strategies of HTS technology, and sort out known small molecules identified via HTS technology by their roles in aging related diseases, such as neural degenerative diseases, diabetes and tumors. Given the fact that application of HTS on aging research is still at an early stage, we also summarize the cellular mechanisms about aging process, paralleled with the compounds which can modulate the functions of proteins important for aging signals. Finally, we briefly discuss some advanced HTS technologies for their potent applications on the discovery of anti-aging compounds. The main purpose of this review is to provide updated and useful information to those who are interested in pharmacology and HTS technology, but not familiar with aging biology, or vice versa.

  20. Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing.

    PubMed

    Gruber, Jan; Fong, Sheng; Chen, Ce-Belle; Yoong, Sialee; Pastorin, Giorgia; Schaffer, Sebastian; Cheah, Irwin; Halliwell, Barry

    2013-01-01

    Populations in many nations today are rapidly ageing. This unprecedented demographic change represents one of the main challenges of our time. A defining property of the ageing process is a marked increase in the risk of mortality and morbidity with age. The incidence of cancer, cardiovascular and neurodegenerative diseases increases non-linearly, sometimes exponentially with age. One of the most important tasks in biogerontology is to develop interventions leading to an increase in healthy lifespan (health span), and a better understanding of basic mechanisms underlying the ageing process itself may lead to interventions able to delay or prevent many or even all age-dependent conditions. One of the putative basic mechanisms of ageing is age-dependent mitochondrial deterioration, closely associated with damage mediated by reactive oxygen species (ROS). Given the central role that mitochondria and mitochondrial dysfunction play not only in ageing but also in apoptosis, cancer, neurodegeneration and other age-related diseases there is great interest in approaches to protect mitochondria from ROS-mediated damage. In this review, we explore strategies of targeting mitochondria to reduce mitochondrial oxidative damage with the aim of preventing or delaying age-dependent decline in mitochondrial function and some of the resulting pathologies. We discuss mitochondria-targeted and -localized antioxidants (e.g.: MitoQ, SkQ, ergothioneine), mitochondrial metabolic modulators (e.g. dichloroacetic acid), and uncouplers (e.g.: uncoupling proteins, dinitrophenol) as well as some alternative future approaches for targeting compounds to the mitochondria, including advances from nanotechnology.

  1. Modulation of RhoA GTPase Activity Sensitizes Human Cervix Carcinoma Cells to γ-Radiation by Attenuating DNA Repair Pathways.

    PubMed

    Osaki, Juliana H; Espinha, Gisele; Magalhaes, Yuli T; Forti, Fabio L

    2016-01-01

    Radiotherapy with γ-radiation is widely used in cancer treatment to induce DNA damage reducing cell proliferation and to kill tumor cells. Although RhoA GTPase overexpression/hyperactivation is observed in many malignancies, the effect of RhoA activity modulation on cancer radiosensitivity has not been previously investigated. Here, we generated stable HeLa cell clones expressing either the dominant negative RhoA-N19 or the constitutively active RhoA-V14 and compared the responses of these cell lines with those of parental HeLa cells, after treatment with low doses of γ-radiation. HeLa-RhoA-N19 and HeLa-RhoA-V14 clones displayed reduced proliferation and survival compared to parental cells after radiation and became arrested at cell cycle stages correlated with increased cellular senescence and apoptosis. Also, Chk1/Chk2 and histone H2A phosphorylation data, as well as comet assays, suggest that the levels of DNA damage and DNA repair activation and efficiency in HeLa cell lines are correlated with active RhoA. In agreement with these results, RhoA inhibition by C3 toxin expression drastically affected homologous recombination (HR) and nonhomologous end joining (NHEJ). These data suggest that modulation of RhoA GTPase activity impairs DNA damage repair, increasing HeLa cell radiosensitivity.

  2. Modulation of RhoA GTPase Activity Sensitizes Human Cervix Carcinoma Cells to γ-Radiation by Attenuating DNA Repair Pathways

    PubMed Central

    Osaki, Juliana H.; Espinha, Gisele; Magalhaes, Yuli T.; Forti, Fabio L.

    2016-01-01

    Radiotherapy with γ-radiation is widely used in cancer treatment to induce DNA damage reducing cell proliferation and to kill tumor cells. Although RhoA GTPase overexpression/hyperactivation is observed in many malignancies, the effect of RhoA activity modulation on cancer radiosensitivity has not been previously investigated. Here, we generated stable HeLa cell clones expressing either the dominant negative RhoA-N19 or the constitutively active RhoA-V14 and compared the responses of these cell lines with those of parental HeLa cells, after treatment with low doses of γ-radiation. HeLa-RhoA-N19 and HeLa-RhoA-V14 clones displayed reduced proliferation and survival compared to parental cells after radiation and became arrested at cell cycle stages correlated with increased cellular senescence and apoptosis. Also, Chk1/Chk2 and histone H2A phosphorylation data, as well as comet assays, suggest that the levels of DNA damage and DNA repair activation and efficiency in HeLa cell lines are correlated with active RhoA. In agreement with these results, RhoA inhibition by C3 toxin expression drastically affected homologous recombination (HR) and nonhomologous end joining (NHEJ). These data suggest that modulation of RhoA GTPase activity impairs DNA damage repair, increasing HeLa cell radiosensitivity. PMID:26649141

  3. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

    PubMed

    Deniz, Miriam; Kaufmann, Julia; Stahl, Andreea; Gundelach, Theresa; Janni, Wolfgang; Hoffmann, Isabell; Keimling, Marlen; Hampp, Stephanie; Ihle, Michaela; Wiesmüller, Lisa

    2016-11-01

    Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer-predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error-prone DNA double-strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelial-mesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence-based test system, we analyzed the error-prone DSB repair pathway microhomology-mediated end joining in these tumor-derived cell types and peripheral blood lymphocytes. In parallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP-ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology-mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high-risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair-dysfunctional tumors.-Deniz, M., Kaufmann, J., Stahl, A., Gundelach, T., Janni, W., Hoffmann, I., Keimling, M., Hampp, S., Ihle, M., Wiesmüller, L. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

  4. Delayed grip relaxation and altered modulation of intracortical inhibition with aging

    PubMed Central

    Motawar, Binal; Stinear, James W.; Lauer, Abigail W.; Ramakrishnan, V. Viswanathan; Seo, Na Jin

    2015-01-01

    Grip relaxation is a voluntary action that requires an increase in short-interval intracortical inhibition (SICI) in healthy young adults, rather than a simple termination of excitatory drive. The way aging affects this voluntary inhibitory action and timing of grip relaxation is currently unknown. The objective of this study was to examine aging-related delays in grip relaxation and SICI modulation for the flexor digitorum superficialis (FDS) muscle during grip relaxation. The main finding was that young adults increased SICI to relax their grips, whereas older adults did not increase SICI with a prolonged grip relaxation time (p<0.05 for both SICI modulation and grip relaxation time). A secondary experiment showed that both young and older adults did not change H reflex excitability during grip relaxation. Our data suggest that grip relaxation is mediated by increased cortical inhibitory output in young adults, and aging-related impairment in increasing cortical inhibitory output may hamper timely cessation of muscle activity. Our data also suggest a lesser role of the spinal circuits in grip muscle relaxation. This knowledge may contribute to understanding of aging-related movement deterioration and development of interventions for improving modulation of SICI to improve muscle relaxation and movement coordination. PMID:26686531

  5. Age at First Episode Modulates Diagnosis-Related Structural Brain Abnormalities in Psychosis.

    PubMed

    Pina-Camacho, Laura; Del Rey-Mejías, Ángel; Janssen, Joost; Bioque, Miquel; González-Pinto, Ana; Arango, Celso; Lobo, Antonio; Sarró, Salvador; Desco, Manuel; Sanjuan, Julio; Lacalle-Aurioles, Maria; Cuesta, Manuel J; Saiz-Ruiz, Jerónimo; Bernardo, Miguel; Parellada, Mara

    2016-03-01

    Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12-35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15-20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18-20 y). The AFP group also had age-constant (12-35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  6. Age at First Episode Modulates Diagnosis-Related Structural Brain Abnormalities in Psychosis

    PubMed Central

    Pina-Camacho, Laura; Del Rey-Mejías, Ángel; Janssen, Joost; Bioque, Miquel; González-Pinto, Ana; Arango, Celso; Lobo, Antonio; Sarró, Salvador; Desco, Manuel; Sanjuan, Julio; Lacalle-Aurioles, Maria; Cuesta, Manuel J.; Saiz-Ruiz, Jerónimo; Bernardo, Miguel; Parellada, Mara

    2016-01-01

    Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12–35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15–20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18–20 y). The AFP group also had age-constant (12–35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis. PMID:26371339

  7. Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging.

    PubMed

    Neuner, Sarah M; Garfinkel, Benjamin P; Wilmott, Lynda A; Ignatowska-Jankowska, Bogna M; Citri, Ami; Orly, Joseph; Lu, Lu; Overall, Rupert W; Mulligan, Megan K; Kempermann, Gerd; Williams, Robert W; O'Connell, Kristen M S; Kaczorowski, Catherine C

    2016-10-01

    An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  8. From DNA repair to proteome protection: new molecular insights for preventing non-melanoma skin cancers and skin aging.

    PubMed

    Emanuele, Enzo; Spencer, James M; Braun, Martin

    2014-03-01

    Non-melanoma skin cancers (NMSC) are the most common human neoplasms and continue to represent an important public health issue with greater than one million cases diagnosed each year. The primary factor contributing to the molecular pathogenesis of NMSC is unprotected skin exposure to ultraviolet (UV) radiation, ie, UVA (wavelength: 315-400 nm) and UVB rays (wavelength: 280-315 nm) with additional albeit less damaging factors of infrared radiation (wavelength: ~750 nm-1 mm) and environmental pollutants. Skin carcinogenesis by DNA damage is the current predominant paradigm of UV toxicity, which may be caused by direct damaging effects of energy deposited by photons or indirect oxidative action of short-lived reactive oxygen species (ROS) formed from water that reacts with biomacromolecules. UV rays are capable to induce direct both DNA damages, mainly consisting in the formation of helix-distorting photoproducts such as cyclobutane pyrimidine dimers (CPDs), as well as oxidative damage to DNA bases, including the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8OHdG). Growing evidence also suggests that the efficiency of DNA repair after exposure to UV radiation is crucially dependent on the levels of oxidative protein damage, including but not limited to DNA repair proteins. Besides DNA lesions, UV-induced oxidative stress can indeed result in carbonylation of proteins, a major form of irreversible protein damage that inactivates their biological function. Interestingly, microorganisms characterized by extreme resistance to UV rays have an intrinsic capacity to protect their proteome, rather than genome, from radiation-induced damage, suggesting that protein carbonylation (PC) may serve as a reliable and innovative biomarker of UV photodamage. This review discusses the main DNA and protein markers of UV-induced damage (eg, CPDs, 8OHdG, and PC) and their relationship and importance to the current understanding of skin carcinogenesis. The identification of key DNA

  9. Anhydrobiosis vs. aging: comparative genomics of protein repair L-isoaspartyl methyltransferases in the sleeping chironomid. .

    NASA Astrophysics Data System (ADS)

    Gusev, Oleg; Kikawada, Takahiro; Shagimardanova, Elena; Suetsugu, Yoshitaka; Ayupov, Rustam

    Origin of anhydrobiosis in the larvae of the sleeping chironomid Polypedilum vanderplanki represents unique example of set of evolutionary events in a single species, resulted in acquiring new ability allowing survival in extremely changeable environment. Complex comparative analysis of the genome of P. vanderplanki resulted in discovery of a set of features, including existence of the set of unique clusters of genes contributing in desiccation resistance. Surprisingly, in several cases, the genes mainly contributing to the formation of the molecular shield in the larvae are sleeping chironomid-specific and have no homology with genes from other insects, including P. nubifer - a chironomid from the same genus. Protein L-isoaspartyl methyltransferase (PIMT) acts on proteins that have been non-enzymatically damaged due to age, and partially restores aspartic residues, extending life of the polypeptides. PIMT a highly conserved enzyme present in nearly all eukaryotes, and microorganisms mostly in a single copy (or in a few isoforms in certain plants and some bacteria). While conducting a comparative analysis of the genomes of two chironomid midge species different in their ability to stand complete water loss, we have noticed that structure and number of PIMT-coding genes in the desiccation resistant (anhydrobiotic) midge (Polypedilum vanderplanki, Pv) is different from those of the common desiccation-sensitive midge (Polypedilum nubifer, Pn) and the rest of insects. Both species have a clear orthologous PIMT shared by all insects. At the same time, in contrast to Pn which has only one PIMT gene (PnPimt-1), the Pv genome contains 12 additional genes paralogous to Pimt1 (PvPimt-2-12) presumably coding functional PIMT proteins, which are arranged in a single cluster. Remarkably, PvPimt-1 location in the Pv is different from the rest of Pimt-like genes. PvPimt-1 gene is ubiquitously expressed during the life cycle, but expression of the PvPimt2-12 is limited to the eggs

  10. Failure to Modulate Attentional Control in Advanced Aging Linked to White Matter Pathology

    PubMed Central

    Van Dijk, Koene R. A.; Shire, Emily H.; Sperling, Reisa A.; Johnson, Keith A.; Buckner, Randy L.

    2012-01-01

    Advanced aging is associated with reduced attentional control and less flexible information processing. Here, the origins of these cognitive effects were explored using a functional magnetic resonance imaging task that systematically varied demands to shift attention and inhibit irrelevant information across task blocks. Prefrontal and parietal regions previously implicated in attentional control were recruited by the task and most so for the most demanding task configurations. A subset of older individuals did not modulate activity in frontal and parietal regions in response to changing task requirements. Older adults who did not dynamically modulate activity underperformed their peers and scored more poorly on neuropsychological measures of executive function and speed of processing. Examining 2 markers of preclinical pathology in older adults revealed that white matter hyperintensities (WMHs), but not high amyloid burden, were associated with failure to modulate activity in response to changing task demands. In contrast, high amyloid burden was associated with alterations in default network activity. These results suggest failure to modulate frontal and parietal activity reflects a disruptive process in advanced aging associated with specific neuropathologic processes. PMID:21765181

  11. The microRNA miR-34 modulates aging and neurodegeneration in Drosophila

    PubMed Central

    Liu, Nan; Landreh, Michael; Cao, Kajia; Abe, Masashi; Hendriks, Gert-Jan; Kennerdell, Jason; Zhu, Yongqing; Wang, Li-San; Bonini, Nancy M

    2012-01-01

    Human neurodegenerative diseases possess the temporal hallmark of afflicting the elderly population. Hence, aging is among the most significant factors to impinge on disease onset and progression1, yet little is known of molecular pathways that connect these processes. Central to understanding this connection is to unmask the nature of pathways that functionally integrate aging, chronic maintenance of the brain and modulation of neurodegenerative disease. microRNAs (miRNA) are emerging as critical players in gene regulation during development, yet their role in adult-onset, age-associated processes are only beginning to be revealed. Here we report that the conserved miRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, presenting such a molecular link between aging and neurodegeneration. Fly miR-34 expression is adult-onset, brain-enriched and age-modulated. Whereas miR-34 loss triggers a gene profile of accelerated brain aging, late-onset brain degeneration and a catastrophic decline in survival, miR-34 upregulation extends median lifespan and mitigates neurodegeneration induced by human pathogenic polyglutamine (polyQ) disease protein. Some of the age-associated effects of miR-34 require adult-onset translational repression of Eip74EF, an essential ETS domain transcription factor involved in steroid hormone pathways. These studies indicate that miRNA-dependent pathways may impact adult-onset, age-associated events by silencing developmental genes that later have a deleterious influence on adult life cycle and disease, and highlight fly miR-34 as a key miRNA with a role in this process PMID:22343898

  12. Involving Older People in the Design, Development, and Delivery of an Innovative Module on Aging for Undergraduate Students

    ERIC Educational Resources Information Center

    Tullo, Ellen; Greaves, Laura; Wakeling, Luisa

    2016-01-01

    As the number of older people in society increases, gaining an awareness of the needs of an aging population is important for university students from all academic backgrounds. Using a multidisciplinary approach to aging, we developed a new teaching module (NU-AGE [Newcastle University Aging Generations Education]) aimed at students enrolled in…

  13. Involving Older People in the Design, Development, and Delivery of an Innovative Module on Aging for Undergraduate Students

    ERIC Educational Resources Information Center

    Tullo, Ellen; Greaves, Laura; Wakeling, Luisa

    2016-01-01

    As the number of older people in society increases, gaining an awareness of the needs of an aging population is important for university students from all academic backgrounds. Using a multidisciplinary approach to aging, we developed a new teaching module (NU-AGE [Newcastle University Aging Generations Education]) aimed at students enrolled in…

  14. Age-equivalent top-down modulation during cross-modal selective attention.

    PubMed

    Guerreiro, Maria J S; Anguera, Joaquin A; Mishra, Jyoti; Van Gerven, Pascal W M; Gazzaley, Adam

    2014-12-01

    Selective attention involves top-down modulation of sensory cortical areas, such that responses to relevant information are enhanced whereas responses to irrelevant information are suppressed. Suppression of irrelevant information, unlike enhancement of relevant information, has been shown to be deficient in aging. Although these attentional mechanisms have been well characterized within the visual modality, little is known about these mechanisms when attention is selectively allocated across sensory modalities. The present EEG study addressed this issue by testing younger and older participants in three different tasks: Participants attended to the visual modality and ignored the auditory modality, attended to the auditory modality and ignored the visual modality, or passively perceived information presented through either modality. We found overall modulation of visual and auditory processing during cross-modal selective attention in both age groups. Top-down modulation of visual processing was observed as a trend toward enhancement of visual information in the setting of auditory distraction, but no significant suppression of visual distraction when auditory information was relevant. Top-down modulation of auditory processing, on the other hand, was observed as suppression of auditory distraction when visual stimuli were relevant, but no significant enhancement of auditory information in the setting of visual distraction. In addition, greater visual enhancement was associated with better recognition of relevant visual information, and greater auditory distractor suppression was associated with a better ability to ignore auditory distraction. There were no age differences in these effects, suggesting that when relevant and irrelevant information are presented through different sensory modalities, selective attention remains intact in older age.

  15. Inter-individual variation in nucleotide excision repair pathway is modulated by non-synonymous polymorphisms in ERCC4 and MBD4 genes.

    PubMed

    Allione, Alessandra; Guarrera, Simonetta; Russo, Alessia; Ricceri, Fulvio; Purohit, Rituraj; Pagnani, Andrea; Rosa, Fabio; Polidoro, Silvia; Voglino, Floriana; Matullo, Giuseppe

    2013-01-01

    Inter-individual differences in DNA repair capacity (DRC) may lead to genome instability and, consequently, modulate individual cancer risk. Among the different DNA repair pathways, nucleotide excision repair (NER) is one of the most versatile, as it can eliminate a wide range of helix-distorting DNA lesions caused by ultraviolet light irradiation and chemical mutagens. We performed a genotype-phenotype correlation study in 122 healthy subjects in order to assess if any associations exist between phenotypic profiles of NER and DNA repair gene single nucleotide polymorphisms (SNPs). Individuals were genotyped for 768 SNPs with a custom Illumina Golden Gate Assay, and peripheral blood mononuclear cells (PBMCs) of the same subjects were tested for a NER comet assay to measure DRC after challenging cells by benzo(a)pyrene diolepoxide (BPDE). We observed a large inter-individual variability of NER capacity, with women showing a statistically significant lower DRC (mean ± SD: 6.68 ± 4.76; p = 0.004) than men (mean ± SD: 8.89 ± 5.20). Moreover, DRC was significantly lower in individuals carrying a variant allele for the ERCC4 rs1800124 non-synonymous SNP (nsSNP) (p = 0.006) and significantly higher in subjects with the variant allele of MBD4 rs2005618 SNP (p = 0.008), in linkage disequilibrium (r(2) = 0.908) with rs10342 nsSNP. Traditional in silico docking approaches on protein-DNA and protein-protein interaction showed that Gly875 variant in ERCC4 (rs1800124) decreases the DNA-protein interaction and that Ser273 and Thr273 variants in MBD4 (rs10342) indicate complete loss of protein-DNA interactions. Our results showed that NER inter-individual capacity can be modulated by cross-talk activity involving nsSNPs in ERCC4 and MBD4 genes, and they suggested to better investigate SNP effect on cancer risk and response to chemo- and radiotherapies.

  16. Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging

    PubMed Central

    Wang, Rui-Hong; Zhao, Tingrui; Cui, Kairong; Hu, Gangqing; Chen, Qiang; Chen, Weiping; Wang, Xin-Wei; Soto-Gutierrez, Alejandro; Zhao, Keji; Deng, Chu-Xia

    2016-01-01

    Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance. PMID:27346580

  17. Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging.

    PubMed

    Wang, Rui-Hong; Zhao, Tingrui; Cui, Kairong; Hu, Gangqing; Chen, Qiang; Chen, Weiping; Wang, Xin-Wei; Soto-Gutierrez, Alejandro; Zhao, Keji; Deng, Chu-Xia

    2016-06-27

    Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.

  18. Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age.

    PubMed

    de Boer, Lieke; Axelsson, Jan; Riklund, Katrine; Nyberg, Lars; Dayan, Peter; Bäckman, Lars; Guitart-Masip, Marc

    2017-09-05

    Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability.

  19. Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits.

    PubMed

    Ichikawa, Yasuhiro; Zemljic-Harpf, Alice E; Zhang, Zheng; McKirnan, M Dan; Manso, Ana Maria; Ross, Robert S; Hammond, H Kirk; Patel, Hemal H; Roth, David M

    2017-01-01

    Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes. Caveolin-3 (Cav-3), integrins and related membrane repair proteins can function as cardioprotective proteins. Expression of these proteins in anthracycline-induced heart failure has not been evaluated. We tested the hypothesis that daunorubicin alters cardioprotective protein expression in the heart. Rabbits were administered daunorubicin (3 mg/kg, IV) weekly, for three weeks or nine weeks. Nine weeks but not three weeks of daunorubicin resulted in progressive reduced left ventricular function. Cav-3 expression in the heart was unchanged at three weeks of daunorubicin and increased in nine week treated rabbits when compared to control hearts. Electron microscopy showed caveolae in the heart were increased and mitochondrial number and size were decreased after nine weeks of daunorubicin. Activated beta-1 (β1) integrin and the membrane repair protein MG53 were increased after nine weeks of daunorubicin vs. controls with no change at the three week time point. The results suggest a potential pathophysiological role for Cav3, integrins and membrane repair in daunorubicin-induced heart failure.

  20. Major Appliance Repair. Teacher Edition.

    ERIC Educational Resources Information Center

    Smreker, Eugene; Calvert, King

    This module is a comprehensive text on basic appliance repair, designed to prepare students for entry-level jobs in this growing field. Ensuring a firm grounding in electrical knowledge, the module contains 13 instructional units that cover the following topics: (1) major appliance repair orientation; (2) safety and first aid; (3) fundamentals of…

  1. A Computational Model of Inferior Colliculus Responses to Amplitude Modulated Sounds in Young and Aged Rats

    PubMed Central

    Rabang, Cal F.; Parthasarathy, Aravindakshan; Venkataraman, Yamini; Fisher, Zachery L.; Gardner, Stephanie M.; Bartlett, Edward L.

    2012-01-01

    The inferior colliculus (IC) receives ascending excitatory and inhibitory inputs from multiple sources, but how these auditory inputs converge to generate IC spike patterns is poorly understood. Simulating patterns of in vivo spike train data from cellular and synaptic models creates a powerful framework to identify factors that contribute to changes in IC responses, such as those resulting in age-related loss of temporal processing. A conductance-based single neuron IC model was constructed, and its responses were compared to those observed during in vivo IC recordings in rats. IC spike patterns were evoked using amplitude-modulated tone or noise carriers at 20–40 dB above threshold and were classified as low-pass, band-pass, band-reject, all-pass, or complex based on their rate modulation transfer function tuning shape. Their temporal modulation transfer functions were also measured. These spike patterns provided experimental measures of rate, vector strength, and firing pattern for comparison with model outputs. Patterns of excitatory and inhibitory synaptic convergence to IC neurons were based on anatomical studies and generalized input tuning for modulation frequency. Responses of modeled ascending inputs were derived from experimental data from previous studies. Adapting and sustained IC intrinsic models were created, with adaptation created via calcium-activated potassium currents. Short-term synaptic plasticity was incorporated into the model in the form of synaptic depression, which was shown to have a substantial effect on the magnitude and time course of the IC response. The most commonly observed IC response sub-types were recreated and enabled dissociation of inherited response properties from those that were generated in IC. Furthermore, the model was used to make predictions about the consequences of reduction in inhibition for age-related loss of temporal processing due to a reduction in GABA seen anatomically with age. PMID:23129994

  2. Is rotator cuff repair appropriate in patients older than 60 years of age? prospective, randomised trial in 103 patients with a mean four-year follow-up.

    PubMed

    Jacquot, A; Dezaly, C; Goetzmann, T; Roche, O; Sirveaux, F; Molé, D

    2014-10-01

    The objective of this randomised trial was to compare surgical rotator cuff repair to simple decompression by acromioplasty and biceps tenotomy in patients older than 60 years of age with a mean follow-up of 4 years. Tendon repair produces better functional outcomes than simple decompression and prevents progression towards cuff tear arthropathy in the longer term. Of 130 initially included patients older than 60 years of age and having rotator cuff tears deemed amenable to surgical repair, 103 (79%) were evaluated after a mean of 4 years. These patients had been randomly allocated to acromioplasty and tenotomy (AT group, n=49) or to acromioplasty, tenotomy, and tendon suture (CR group, n=54). The tear was distal in 41 patients, intermediate in 40, and retracted in 22. At last follow-up, the evaluation included the clinical Constant's Score, radiographs and, in the CR group, ultrasonography. The complication rate was 4%. The mean Constant Score was 44 preoperatively; values after 4 years were 76 overall (P=0.01), 78 in the CR group, and 73 in the AT group (P=0.01). The tendon-healing rate as assessed using ultrasonography was 63%. The Constant Score was significantly better when tendon healing was achieved (82/73, P<0.001). In the AT group, the acromio-humeral distance was significantly shorter (6.9 mm/7.8mm, P=0.03) and eccentric humeral head position was more common (44%/26%, P=0.01). Arthroscopic rotator cuff repair provides better functional outcomes than does simple decompression in patients older than 60 years and prevents cuff tear arthropathy with eccentric humeral head position in the medium term. Tendon healing is the main determinant of outcomes after rotator cuff repair. II, randomised trial. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. Emotion processing in the aging brain is modulated by semantic elaboration.

    PubMed

    Ritchey, Maureen; Bessette-Symons, Brandy; Hayes, Scott M; Cabeza, Roberto

    2011-03-01

    The neural correlates of emotion processing have been shown to vary with age: older adults (OAs) exhibit increased frontal activations and, under some circumstances, decreased amygdala activations relative to young adults (YAs) during emotion processing. Some of these differences are additionally modulated by valence, with age-related biases toward positive versus negative stimuli, and are thought to depend on OAs' capacity for controlled elaboration. However, the role of semantic elaboration in mediating valence effects in the aging brain has not yet been explicitly tested. In the present study, YAs and OAs were scanned while they viewed negative, neutral, and positive pictures during either a deep, elaborative task or a shallow, perceptual task. fMRI results reveal that emotion-related activity in the amygdala is preserved in aging and insensitive to elaboration demands. This study provides novel evidence that differences in valence processing are modulated by elaboration: relative to YAs, OAs show enhanced activity in the medial prefrontal cortex (PFC) and ventrolateral PFC in response to positive versus negative stimuli, but only during elaborative processing. These positive valence effects are predicted by individual differences in executive function in OAs for the deep but not shallow task. Finally, psychophysiological interaction analyses reveal age effects on valence-dependent functional connectivity between medial PFC and ventral striatum, as well as age and task effects on medial PFC-retrosplenial cortex interactions. Altogether, these findings provide support for the hypothesis that valence shifts in the aging brain are mediated by controlled processes such as semantic elaboration, self-referential processing, and emotion regulation.

  4. Age and Social Context Modulate the Effect of Anxiety on Risk-taking in Pediatric Samples

    PubMed Central

    Rosen, Dana; Patel, Nilam; Pavletic, Nevia; Grillon, Christian; Pine, Daniel S.

    2016-01-01

    Although risk-taking has been studied from a developmental perspective, no study has examined how anxiety, age, risk-valence and social context interact to modulate decision-making in youths. This study probes this question using a risk-taking task, the Stunt Task, in clinically anxious children (n=17, 10 F, age=8.3–12.1 years), healthy children (n=13, 4 F, age=9.3–12.2 years), clinically anxious adolescents (n=18, 6 F, age=12.3–17.7 years), and healthy adolescents (n =14, 10 F, age=12.5–17.3 years). Social context was manipulated: in one condition, participants were led to believe that a group of peers were observing and judging their performance (peer-judge), while, in the other condition, they were led to believe that peers were not observing them (control). Only anxious children showed an influence of social context on their risk-taking behavior. Specifically, anxious children bet significantly less and had slower reaction times (RT) during the peer-judge than control condition. However, across social conditions, risk-valence modulated RT differently in function of age and diagnosis. Anxious children were slower on the positive-valence risky trial, whereas anxious adolescents were slower on the negative-valence risky trials relative to their respective healthy peers. In conclusion, clinically anxious children were the only group that was sensitive (risk-averse) to the effect of a negative peer-judge context. The negative peer-judge context did not affect risky decision-making in adolescents, whether they were anxious or healthy. Future work using a stronger aversive social context might be more effective at influencing risky behavior in this age group. PMID:26659306

  5. Modulation of Mcl-1 expression reduces age-related cochlear degeneration.

    PubMed

    Yang, Wei Ping; Xu, Yang; Guo, Wei Wei; Liu, Hui Zhan; Hu, Bo Hua

    2013-11-01

    Mcl-1 is an anti-apoptotic member of the Bcl-2 family that modulates apoptosis-related signaling pathways and promotes cell survival. We have previously demonstrated a reduction of Mcl-1 expression in aging cochleae. To investigate whether restoring Mcl-1 expression would reduce aging-related cochlear degeneration, we developed a rat model of Mcl-1 overexpression. A plasmid encoding human Mcl-1/enhanced green fluorescent protein was applied to the round window of the cochlea. This in vivo treatment transfected both the sensory and supporting cells of the cochlear sensory epithelium and enhanced Mcl-1 expression at both the mRNA and the protein level. The upregulation of Mcl-1 expression reduced the progression of age-related cochlear dysfunction and sensory cell death. Furthermore, the transfection of Mcl-1 exerted its protective effect by suppressing cochlear apoptosis at the mitochondrial level. This study demonstrates that the genetic modulation of Mcl-1 expression reduces the progression of age-related cochlear degeneration.

  6. Porcine Dermis Patch Augmentation of Supraspinatus Tendon Repairs: A Pilot Study Assessing Tendon Integrity and Shoulder Function 2 Years After Arthroscopic Repair in Patients Aged 60 Years or Older.

    PubMed

    Flury, Matthias; Rickenbacher, Dominik; Jung, Christian; Schneider, Marco M; Endell, David; Audigé, Laurent

    2017-08-16

    To investigate the 2-year postoperative clinical and subjective outcomes after arthroscopic rotator cuff repair (ARCR) with xenologous porcine dermal patch augmentation compared with ARCR alone. Patients aged 60 years or older with a complete supraspinatus (SSP) tendon tear underwent primary ARCR with a transosseous-equivalent technique. By use of a matched-pair comparative trial design, a consecutive series of 20 patients receiving additional xenologous porcine dermal patch augmentation (patch group) was matched by tear location with 20 patients who received ARCR only (control group). Prior conservative treatment failed in all patients. Patients with concomitant pathologies precluding accurate repair assessment, partial or open reconstruction, or a latissimus dorsi and/or pectoralis major muscle transfer were excluded. Patients reported daily pain levels for 10 days after surgery. Clinical parameters and various patient-reported outcome scores were documented preoperatively and at 3, 6, and 24 months after surgery. Repair integrity was determined by magnetic resonance imaging or ultrasound at 24 months. Adverse events were recorded. Group outcome differences were analyzed with t tests, Fisher exact tests, and mixed models. Patients in both groups were aged 67 years on average (range, 60-74 years), and 70% of patients were men. Patients in the patch group had slightly more SSP fatty infiltration preoperatively. Patch surgical procedures were on average 22 minutes longer than control interventions (P = .003). At 24 months, 4 patients and 9 patients were diagnosed with a recurrent SSP tendon defect in the control group (n = 20) and patch group (n = 19), respectively (relative risk, 2.4; P = .096). Of 11 defects (85%) identified as medial cuff failure, 8 occurred in the patch group. Pain rated by all patients decreased from postoperative day 1 to day 10 without any significant group difference (P = .348). No significant group differences were noted for

  7. Aging Selectively Modulates Vitamin C Transporter Expression Patterns in the Kidney.

    PubMed

    Forman, Katherine; Martínez, Fernando; Cifuentes, Manuel; Bertinat, Romina; Salazar, Katterine; Nualart, Francisco

    2016-07-27

    In the kidney, vitamin C is reabsorbed from the glomerular ultrafiltrate by sodium-vitamin C cotransporter isoform 1 (SVCT1) located in the brush border membrane of the proximal tubules. Although we know that vitamin C levels decrease with age, the adaptive physiological mechanisms used by the kidney for vitamin C reabsorption during aging remain unknown. In this study, we used an animal model of accelerated senescence (SAMP8 mice) to define the morphological alterations and aging-induced changes in the expression of vitamin C transporters in renal tissue. Aging induced significant morphological changes, such as periglomerular lymphocytic infiltrate and glomerular congestion, in the kidneys of SAMP8 mice, although no increase in collagen deposits was observed using 2-photon microscopy analysis and second harmonic generation. The most characteristic histological alteration was the dilation of intracellular spaces in the basolateral region of proximal tubule epithelial cells. Furthermore, a combination of laser microdissection, qRT-PCR and immunohistochemical analyses allowed us to determine that SVCT1 expression specifically increased in the proximal tubules from the outer strip of the outer medulla (segment S3) and cortex (segment S2) during aging and that these tubules also express GLUT1. We conclude that aging modulates vitamin C transporter expression and that renal over-expression of SVCT1 enhances vitamin C reabsorption in aged animals that may synthesize less vitamin C. This article is protected by copyright. All rights reserved.

  8. Aging effects in sequential modulations of poorer-strategy effects during execution of memory strategies.

    PubMed

    Hinault, Thomas; Lemaire, Patrick; Touron, Dayna

    2017-02-01

    In this study, we asked young adults and older adults to encode pairs of words. For each item, they were told which strategy to use, interactive imagery or rote repetition. Data revealed poorer-strategy effects in both young adults and older adults: Participants obtained better performance when executing better strategies (i.e., interactive-imagery strategy to encode pairs of concrete words; rote-repetition strategy on pairs of abstract words) than with poorer strategies (i.e., interactive-imagery strategy on pairs of abstract words; rote-repetition strategy on pairs of concrete words). Crucially, we showed that sequential modulations of poorer-strategy effects (i.e., poorer-strategy effects being larger when previous items were encoded with better relative to poorer strategies), previously demonstrated in arithmetic, generalise to memory strategies. We also found reduced sequential modulations of poorer-strategy effects in older adults relative to young adults. Finally, sequential modulations of poorer-strategy effects correlated with measures of cognitive control processes, suggesting that these processes underlie efficient trial-to-trial modulations during strategy execution. Differences in correlations with cognitive control processes were also found between older adults and young adults. These findings have important implications regarding mechanisms underlying memory strategy execution and age differences in memory performance.

  9. Age-related differences in sequential modulations of poorer-strategy effects.

    PubMed

    Lemaire, Patrick; Hinault, Thomas

    2014-01-01

    To determine how younger and older adults modulate execution of strategies across successive trials, we asked participants to accomplish a computational estimation task (i.e., provide approximate products to two-digit multiplication problems like 38 × 74). For each problem, they were cued to execute a better versus a poorer strategy. Their performance revealed sequential modulations of poorer-strategy effects (i.e., longer solution times and larger error rates when asked to execute a poorer than a better strategy). That is, poorer-strategy effects were smaller on current problems after using a poorer strategy on preceding problems than after using a better strategy. Moreover, sequential modulations of these poorer-strategy effects were smaller in older than in younger adults, especially older adults with low-cognitive control skills (as measured by conflict adaptation effects in the Simon task). Our findings suggest that these sequential modulations may result from executive control mechanisms, the efficiency of which is known to decrease in older adults. These findings have important implications regarding mechanisms underlying strategy execution and aging effects on strategic variations.

  10. Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair.

    PubMed

    Nguyen, Hal X; Hooshmand, Mitra J; Saiwai, Hirokazu; Maddox, Jake; Salehi, Arjang; Lakatos, Anita; Nishi, Rebecca A; Salazar, Desiree; Uchida, Nobuko; Anderson, Aileen J

    2017-09-20

    The interaction of transplanted stem cells with local cellular and molecular cues in the host CNS microenvironment may affect the potential for repair by therapeutic cell populations. In this regard, spinal cord injury (SCI), Alzheimer's disease, and other neurological injuries and diseases all exhibit dramatic and dynamic changes to the host microenvironment over time. Previously, we reported that delayed transplantation of human CNS-derived neural stem cells (hCNS-SCns) at 9 or 30 d post-SCI (dpi) resulted in extensive donor cell migration, predominantly neuronal and oligodendrocytic donor cell differentiation, and functional locomotor improvements. Here, we report that acute transplantation of hCNS-SCns at 0 dpi resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement in an all-female immunodeficient mouse model. Critically, specific immunodepletion of neutrophils (polymorphonuclear leukocytes) blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function. These data represent novel evidence that a host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population, and support targeting the inflammatory microenvironment in combination with cell transplantation after SCI.SIGNIFICANCE STATEMENT The interaction of transplanted cells with local cellular and molecular cues in the host microenvironment is a key variable that may shape the translation of neurotransplantation research to the clinical spinal cord injury (SCI) human population, and few studies have investigated these events. We show that the specific immunodepletion of polymorphonuclear leukocyte neutrophils using anti-Ly6G inhibits donor cell astrogliosis and rescues the capacity of a donor cell population to promote locomotor improvement after SCI. Critically, our data demonstrate novel evidence that a

  11. Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration

    PubMed Central

    Wang, Likui; Gao, Shijuan; Jiang, Wei; Luo, Cheng; Xu, Maonian; Bohlin, Lars; Rosendahl, Markus; Huang, Wenlin

    2014-01-01

    Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair. PMID:25226533

  12. G-Protein βγ Subunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

    PubMed Central

    White, Sarah M.; North, Lauren M.; Haines, Emily; Goldberg, Megan; Sullivan, Lydia M.; Pressly, Jeffrey D.; Weber, David S.

    2014-01-01

    Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G-protein βγ subunit (Gβγ) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gβγ activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P < 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P < 0.05) the number of proliferating cell nuclear antigen–positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P < 0.05) S-phase cell cycle entry compared with vehicle-treated cells as determined by 5′-bromo-2′-deoxyuridine incorporation. Taken together, these data suggest that Gβγ signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury. PMID:25028481

  13. The interplay among chromatin dynamics, cell cycle checkpoints and repair mechanisms modulates the cellular response to DNA damage.

    PubMed

    Lazzaro, Federico; Giannattasio, Michele; Muzi-Falconi, Marco; Plevani, Paolo

    2007-06-01

    Cells are continuously under the assault of endogenous and exogenous genotoxic stress that challenges the integrity of DNA. To cope with such a formidable task cells have evolved surveillance mechanisms, known as checkpoints, and a variety of DNA repair systems responding to different types of DNA lesions. These lesions occur in the context of the chromatin structure and, as expected for all DNA transactions, the cellular response to DNA damage is going to be influenced by the chromatin enviroment. In this review, we will discuss recent studies implicating chromatin remodelling factors and histone modifications in the response to DNA double-strand breaks (DSBs) and in checkpoint activation in response to UV lesions.

  14. Ageing diminishes the modulation of human brain responses to visual food cues by meal ingestion.

    PubMed

    Cheah, Y S; Lee, S; Ashoor, G; Nathan, Y; Reed, L J; Zelaya, F O; Brammer, M J; Amiel, S A

    2014-09-01

    Rates of obesity are greatest in middle age. Obesity is associated with altered activity of brain networks sensing food-related stimuli and internal signals of energy balance, which modulate eating behaviour. The impact of healthy mid-life ageing on these processes has not been characterised. We therefore aimed to investigate changes in brain responses to food cues, and the modulatory effect of meal ingestion on such evoked neural activity, from young adulthood to middle age. Twenty-four healthy, right-handed subjects, aged 19.5-52.6 years, were studied on separate days after an overnight fast, randomly receiving 50 ml water or 554 kcal mixed meal before functional brain magnetic resonance imaging while viewing visual food cues. Across the group, meal ingestion reduced food cue-evoked activity of amygdala, putamen, insula and thalamus, and increased activity in precuneus and bilateral parietal cortex. Corrected for body mass index, ageing was associated with decreasing food cue-evoked activation of right dorsolateral prefrontal cortex (DLPFC) and precuneus, and increasing activation of left ventrolateral prefrontal cortex (VLPFC), bilateral temporal lobe and posterior cingulate in the fasted state. Ageing was also positively associated with the difference in food cue-evoked activation between fed and fasted states in the right DLPFC, bilateral amygdala and striatum, and negatively associated with that of the left orbitofrontal cortex and VLPFC, superior frontal gyrus, left middle and temporal gyri, posterior cingulate and precuneus. There was an overall tendency towards decreasing modulatory effects of prior meal ingestion on food cue-evoked regional brain activity with increasing age. Healthy ageing to middle age is associated with diminishing sensitivity to meal ingestion of visual food cue-evoked activity in brain regions that represent the salience of food and direct food-associated behaviour. Reduced satiety sensing may have a role in the greater risk of

  15. Pacemaking the ice ages by frequency modulation of Earth's orbital eccentricity

    PubMed

    Rial

    1999-07-23

    Evidence from power spectra of deep-sea oxygen isotope time series suggests that the climate system of Earth responds nonlinearly to astronomical forcing by frequency modulating eccentricity-related variations in insolation. With the help of a simple model, it is shown that frequency modulation of the approximate 100,000-year eccentricity cycles by the 413,000-year component accounts for the variable duration of the ice ages, the multiple-peak character of the time series spectra, and the notorious absence of significant spectral amplitude at the 413,000-year period. The observed spectra are consistent with the classic Milankovitch theories of insolation, so that climate forcing by 100,000-year variations in orbital inclination that cause periodic dust accretion appear unnecessary.

  16. Modulation of DNA-Induced Damage and Repair Capacity in Humans after Dietary Intervention with Lutein-Enriched Fermented Milk

    PubMed Central

    Herrero-Barbudo, Carmen; Soldevilla, Beatriz; Pérez-Sacristán, Belén; Blanco-Navarro, Inmaculada; Herrera, Mercedes; Granado-Lorencio, Fernando; Domínguez, Gemma

    2013-01-01

    Dietary factors provide protection against several forms of DNA damage. Additionally, consumer demand for natural products favours the development of bioactive food ingredients with health benefits. Lutein is a promising biologically active component in the food industry. The EFSA Panel on Dietetic Products, Nutrition and Allergies considers that protection from oxidative damage may be a beneficial physiological effect but that a cause and effect relationship has not been established. Thus, our aim was to evaluate the safety and potential functional effect of a lutein-enriched milk product using the Comet Assay in order to analyze the baseline, the induced DNA-damage and the repair capacity in the lymphocytes of 10 healthy donors before and after the intake of the mentioned product. Our data suggest that the regular consumption of lutein-enriched fermented milk results in a significant increase in serum lutein levels and this change is associated with an improvement in the resistance of DNA to damage and the capacity of DNA repair in lymphocytes. Our results also support the lack of a genotoxic effect at the doses supplied as well as the absence of interactions and side effects on other nutritional and biochemicals markers. PMID:24040187

  17. Modulation of DNA-induced damage and repair capacity in humans after dietary intervention with lutein-enriched fermented milk.

    PubMed

    Herrero-Barbudo, Carmen; Soldevilla, Beatriz; Pérez-Sacristán, Belén; Blanco-Navarro, Inmaculada; Herrera, Mercedes; Granado-Lorencio, Fernando; Domínguez, Gemma

    2013-01-01

    Dietary factors provide protection against several forms of DNA damage. Additionally, consumer demand for natural products favours the development of bioactive food ingredients with health benefits. Lutein is a promising biologically active component in the food industry. The EFSA Panel on Dietetic Products, Nutrition and Allergies considers that protection from oxidative damage may be a beneficial physiological effect but that a cause and effect relationship has not been established. Thus, our aim was to evaluate the safety and potential functional effect of a lutein-enriched milk product using the Comet Assay in order to analyze the baseline, the induced DNA-damage and the repair capacity in the lymphocytes of 10 healthy donors before and after the intake of the mentioned product. Our data suggest that the regular consumption of lutein-enriched fermented milk results in a significant increase in serum lutein levels and this change is associated with an improvement in the resistance of DNA to damage and the capacity of DNA repair in lymphocytes. Our results also support the lack of a genotoxic effect at the doses supplied as well as the absence of interactions and side effects on other nutritional and biochemicals markers.

  18. Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues

    PubMed Central

    Honek, Jennifer; Seki, Takahiro; Iwamoto, Hideki; Fischer, Carina; Li, Jingrong; Lim, Sharon; Samani, Nilesh J.; Zang, Jingwu; Cao, Yihai

    2014-01-01

    Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs. PMID:25271320

  19. Face age and sex modulate the other-race effect in face recognition.

    PubMed

    Wallis, Jennifer; Lipp, Ottmar V; Vanman, Eric J

    2012-11-01

    Faces convey a variety of socially relevant cues that have been shown to affect recognition, such as age, sex, and race, but few studies have examined the interactive effect of these cues. White participants of two distinct age groups were presented with faces that differed in race, age, and sex in a face recognition paradigm. Replicating the other-race effect, young participants recognized young own-race faces better than young other-race faces. However, recognition performance did not differ across old faces of different races (Experiments 1, 2A). In addition, participants showed an other-age effect, recognizing White young faces better than White old faces. Sex affected recognition performance only when age was not varied (Experiment 2B). Overall, older participants showed a similar recognition pattern (Experiment 3) as young participants, displaying an other-race effect for young, but not old, faces. However, they recognized young and old White faces on a similar level. These findings indicate that face cues interact to affect recognition performance such that age and sex information reliably modulate the effect of race cues. These results extend accounts of face recognition that explain recognition biases (such as the other-race effect) as a function of dichotomous ingroup/outgroup categorization, in that outgroup characteristics are not simply additive but interactively determine recognition performance.

  20. Lifestyle Modulators of Neuroplasticity: How Physical Activity, Mental Engagement, and Diet Promote Cognitive Health during Aging.

    PubMed

    Phillips, Cristy

    2017-01-01

    The number of the elderly across the globe will approximate 2.1 billion by 2050. Juxtaposed against this burgeoning segment of the population is evidence that nonpathological aging is associated with an increased risk for cognitive decline in a variety of domains, changes that can cause mild disability even before the onset of dementia. Given that pharmacological treatments that mitigate dementia are still outstanding, alternative therapeutic options are being investigated increasingly. The results from translational studies have shown that modifiable lifestyle factors-including physical activity, cognitive engagement, and diet-are a key strategy for maintaining brain health during aging. Indeed, a multiplicity of studies has demonstrated relationships between lifestyle factors, brain structure and function, and cognitive function in aging adults. For example, physical activity and diet modulate common neuroplasticity substrates (neurotrophic signaling, neurogenesis, inflammation, stress response, and antioxidant defense) in the brain whereas cognitive engagement enhances brain and cognitive reserve. The aims of this review are to evaluate the relationship between modifiable lifestyle factors, neuroplasticity, and optimal brain health during aging; to identify putative mechanisms that contribute positive brain aging; and to highlight future directions for scientists and clinicians. Undoubtedly, the translation of cutting-edge knowledge derived from the field of cognitive neuroscience will advance our understanding and enhance clinical treatment interventions as we endeavor to promote brain health during aging.

  1. Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues.

    PubMed

    Honek, Jennifer; Seki, Takahiro; Iwamoto, Hideki; Fischer, Carina; Li, Jingrong; Lim, Sharon; Samani, Nilesh J; Zang, Jingwu; Cao, Yihai

    2014-10-14

    Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.

  2. Lifestyle Modulators of Neuroplasticity: How Physical Activity, Mental Engagement, and Diet Promote Cognitive Health during Aging

    PubMed Central

    2017-01-01

    The number of the elderly across the globe will approximate 2.1 billion by 2050. Juxtaposed against this burgeoning segment of the population is evidence that nonpathological aging is associated with an increased risk for cognitive decline in a variety of domains, changes that can cause mild disability even before the onset of dementia. Given that pharmacological treatments that mitigate dementia are still outstanding, alternative therapeutic options are being investigated increasingly. The results from translational studies have shown that modifiable lifestyle factors—including physical activity, cognitive engagement, and diet—are a key strategy for maintaining brain health during aging. Indeed, a multiplicity of studies has demonstrated relationships between lifestyle factors, brain structure and function, and cognitive function in aging adults. For example, physical activity and diet modulate common neuroplasticity substrates (neurotrophic signaling, neurogenesis, inflammation, stress response, and antioxidant defense) in the brain whereas cognitive engagement enhances brain and cognitive reserve. The aims of this review are to evaluate the relationship between modifiable lifestyle factors, neuroplasticity, and optimal brain health during aging; to identify putative mechanisms that contribute positive brain aging; and to highlight future directions for scientists and clinicians. Undoubtedly, the translation of cutting-edge knowledge derived from the field of cognitive neuroscience will advance our understanding and enhance clinical treatment interventions as we endeavor to promote brain health during aging. PMID:28695017

  3. Positive Lysosomal Modulation As a Unique Strategy to Treat Age-Related Protein Accumulation Diseases

    PubMed Central

    Wisniewski, Meagan L.; Butler, David

    2012-01-01

    Abstract Lysosomes are involved in degrading and recycling cellular ingredients, and their disruption with age may contribute to amyloidogenesis, paired helical filaments (PHFs), and α-synuclein and mutant huntingtin aggregation. Lysosomal cathepsins are upregulated by accumulating proteins and more so by the modulator Z-Phe-Ala-diazomethylketone (PADK). Such positive modulators of the lysosomal system have been studied in the well-characterized hippocampal slice model of protein accumulation that exhibits the pathogenic cascade of tau aggregation, tubulin breakdown, microtubule destabilization, transport failure, and synaptic decline. Active cathepsins were upregulated by PADK; Rab proteins were modified as well, indicating enhanced trafficking, whereas lysosome-associated membrane protein and proteasome markers were unchanged. Lysosomal modulation reduced the pre-existing PHF deposits, restored tubulin structure and transport, and recovered synaptic components. Further proof-of-principle studies used Alzheimer disease mouse models. It was recently reported that systemic PADK administration caused dramatic increases in cathepsin B protein and activity levels, whereas neprilysin, insulin-degrading enzyme, α-secretase, and β-secretase were unaffected by PADK. In the transgenic models, PADK treatment resulted in clearance of intracellular amyloid beta (Aβ) peptide and concomitant reduction of extracellular deposits. Production of the less pathogenic Aβ1–38 peptide corresponded with decreased levels of Aβ1–42, supporting the lysosome's antiamyloidogenic role through intracellular truncation. Amelioration of synaptic and behavioral deficits also indicates a neuroprotective function of the lysosomal system, identifying lysosomal modulation as an avenue for disease-modifying therapies. From the in vitro and in vivo findings, unique lysosomal modulators represent a minimally invasive, pharmacologically controlled strategy against protein accumulation disorders

  4. Genome-Environment Interactions That Modulate Aging: Powerful Targets for Drug Discovery

    PubMed Central

    Wuttke, Daniel; Wood, Shona H.; Plank, Michael; Vora, Chintan

    2012-01-01

    Aging is the major biomedical challenge of this century. The percentage of elderly people, and consequently the incidence of age-related diseases such as heart disease, cancer, and neurodegenerative diseases, is projected to increase considerably in the coming decades. Findings from model organisms have revealed that aging is a surprisingly plastic process that can be manipulated by both genetic and environmental factors. Here we review a broad range of findings in model organisms, from environmental to genetic manipulations of aging, with a focus on those with underlying gene-environment interactions with potential for drug discovery and development. One well-studied dietary manipulation of aging is caloric restriction, which consists of restricting the food intake of organisms without triggering malnutrition and has been shown to retard aging in model organisms. Caloric restriction is already being used as a paradigm for developing compounds that mimic its life-extension effects and might therefore have therapeutic value. The potential for further advances in this field is immense; hundreds of genes in several pathways have recently emerged as regulators of aging and caloric restriction in model organisms. Some of these genes, such as IGF1R and FOXO3, have also been associated with human longevity in genetic association studies. The parallel emergence of network approaches offers prospects to develop multitarget drugs and combinatorial therapies. Understanding how the environment modulates aging-related genes may lead to human applications and disease therapies through diet, lifestyle, or pharmacological interventions. Unlocking the capacity to manipulate human aging would result in unprecedented health benefits. PMID:22090473

  5. Gut Microbiota: A Modulator of Brain Plasticity and Cognitive Function in Ageing.

    PubMed

    Leung, Katherine; Thuret, Sandrine

    2015-09-29

    Gut microbiota have recently been a topic of great interest in the field of microbiology, particularly their role in normal physiology and its influence on human health in disease. A large body of research has supported the presence of a pathway of communication between the gut and the brain, modulated by gut microbiota, giving rise to the term "microbiota-gut-brain" axis. It is now thought that, through this pathway, microbiota can affect behaviour and modulate brain plasticity and cognitive function in ageing. This review summarizes the evidence supporting the existence of such a connection and possible mechanisms of action whereby microbiota can influence the function of the central nervous system. Since normalisation of gut flora has been shown to prevent changes in behaviour, we further postulate on possible therapeutic targets to intervene with cognitive decline in ageing. The research poses various limitations, for example uncertainty about how this data translates to broad human populations. Nonetheless, the microbiota-gut-brain axis is an exciting field worthy of further investigation, particularly with regards to its implications on the ageing population.

  6. The AMPA modulator S 18986 improves declarative and working memory performances in aged mice.

    PubMed

    Marighetto, Aline; Valerio, Stephane; Jaffard, Robert; Mormede, Cecile; Muñoz, Carmen; Bernard, Katy; Morain, Philippe

    2008-05-01

    The aim of this study was to further characterize the memory-enhancing profile of S 18986 a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. S 18986 was studied in two mouse models of age-related memory deficits, using radial maze paradigms involving long-term/declarative memory and short-term/working memory. Aged mice exhibited severe deficits when compared with their younger counterparts in the two behavioural tests. S 18986 at the dose of 0.1 mg/kg selectively improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on short-term retention of successive arm-visits in the short-term/working memory test. This study confirms the memory-enhancing properties of S 18986 and, in line with emerging data on multiple AMPA modulators, highlights the relevance of targeting AMPA receptors in the development of new memory enhancers.

  7. Adipogenic signaling in rat white adipose tissue: modulation by aging and calorie restriction.

    PubMed

    Zhu, Min; Lee, Garrick D; Ding, Liusong; Hu, Jingping; Qiu, Guang; de Cabo, Rafa; Bernier, Michel; Ingram, Donald K; Zou, Sige

    2007-08-01

    Alterations in adipogenesis could have significant impact on several aging processes. We previously reported that calorie restriction (CR) in rats significantly increases the level of circulating adiponectin, a distinctive marker of differentiated adipocytes, leading to a concerted modulation in the expression of key transcription target genes and, as a result, to increased fatty acid oxidation and reduced deleterious lipid accumulation in other tissues. These findings led us to investigate further the effects of aging on adipocytes and to determine how CR modulates adipogenic signaling in vivo. CR for 2 and 25 months, significantly increased the expression of PPARgamma, C/EBPbeta and Cdk-4, and partially attenuated age-related decline in C/EBPalpha expression relative to rats fed ad libitum (AL). As a result, adiponectin was upregulated at both mRNA and protein levels, resulting in activation of target genes involved in fatty acid oxidation and fatty acid synthesis, and greater responsiveness of adipose tissue to insulin. Moreover, CR significantly decreased the ratio of C/EBPbeta isoforms LAP/LIP, suggesting the suppression of gene transcription associated with terminal differentiation while facilitating preadipocytes proliferation. Morphometric analysis revealed a greater number of small adipocytes in CR relative to AL feeding. Immunostaining confirmed that small adipocytes were more strongly positive for adiponectin than the large ones. Overall these results suggest that CR increased the expression of adipogenic factors, and maintained the differentiated state of adipocytes, which is critically important for adiponectin biosynthesis and insulin sensitivity.

  8. User Preferences for Web-Based Module Design Layout and Design Impact on Information Recall Considering Age

    ERIC Educational Resources Information Center

    Pomales-García, Cristina; Rivera-Nivar, Mericia

    2015-01-01

    Research in design of Web-based modules should incorporate aging as an important factor given the diversity of the current workforce. This work aims to understand how Web-Based Learning modules can be designed to accommodate young (25-35 years) as well as older (55-65 years) users by: (1) identifying how information sources (instructor video,…

  9. User Preferences for Web-Based Module Design Layout and Design Impact on Information Recall Considering Age

    ERIC Educational Resources Information Center

    Pomales-García, Cristina; Rivera-Nivar, Mericia

    2015-01-01

    Research in design of Web-based modules should incorporate aging as an important factor given the diversity of the current workforce. This work aims to understand how Web-Based Learning modules can be designed to accommodate young (25-35 years) as well as older (55-65 years) users by: (1) identifying how information sources (instructor video,…

  10. Age differences in the emotional modulation of ERP old/new effects.

    PubMed

    Langeslag, Sandra J E; Van Strien, Jan W

    2008-11-01

    The emotional salience of stimuli influences ERP old/new effects, but despite proven age differences in emotional processing, the influence of emotion on old/new effects has previously been investigated in younger adults only. Therefore, we set out to examine age differences in the emotional modulation of old/new effects. To this end, the electroencephalogram of younger (17-27 years) and older (63-77 years) adults was recorded while they completed a continuous recognition test with unpleasant, neutral and pleasant pictures. Because recollection is typically enhanced by emotion, the parietal old/new effect was expected to be larger for emotional than neutral stimuli in the younger adults. Because recollection suffers from age-related decline, emotion enhancement of the parietal old/new effect was not expected in the older adults. The results showed that, in both age groups, recognition accuracy was not affected by emotion and that the response bias was more liberal for unpleasant pictures. The younger adults displayed an early, a parietal and a late frontal old/new effect, whereas the older adults showed an early, no parietal and an inverse left-lateralized late frontal old/new effect. Further, the emotional modulation of the old/new effects differed with age. Importantly, emotion enhanced the parietal and late frontal old/new effects in younger adults, and the early old/new effect in older adults. This suggests that whereas recollection and post-retrieval processes are augmented in emotional recognition memory in younger adults, familiarity is enhanced by emotional salience in older adults.

  11. Selective GABAA α5 Positive Allosteric Modulators Improve Cognitive Function in Aged Rats with Memory Impairment

    PubMed Central

    Koh, Ming Teng; Rosenzweig-Lipson, Sharon; Gallagher, Michela

    2012-01-01

    A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer’s disease. Compounds that act as positive allosteric modulators at GABAA α5 receptors might be useful in targeting this condition because GABAA α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABAA α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABAA α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. PMID:22732440

  12. β2-Adrenergic receptor ablation modulates hepatic lipid accumulation and glucose tolerance in aging mice.

    PubMed

    Shi, Yun; Shu, Zhen-Ju; Xue, Xiaoling; Yeh, Chih-Ko; Katz, Michael S; Kamat, Amrita

    2016-06-01

    Catecholamines acting through β-adrenergic receptors (β(1)-, β(2)-, β(3)-AR subtypes) modulate important biological responses in various tissues. Our previous studies suggest a role for increased hepatic β-AR-mediated signaling during aging as a mediator of hepatic steatosis, liver glucose output, and insulin resistance in rodents. In the current study, we have utilized β(2)-AR knockout (KO) and wildtype (WT) control mice to define further the role of β(2)-AR signaling during aging on lipid and glucose metabolism. Our results demonstrate for the first time that age-related increases in hepatic triglyceride accumulation and body weight are attenuated upon β(2)-AR ablation. Although no differences in plasma triglyceride, non-esterified fatty acids or insulin levels were detected between old WT and KO animals, an age-associated increase in hepatic expression of lipid homeostasis regulator Cidea was significantly reduced in old KO mice. Interestingly, we also observed a shift from reduced glucose tolerance in young adult KO animals to significantly improved glucose tolerance in old KO when compared to age-matched WT mice. These results provide evidence for an important role played by β(2)-ARs in the regulation of lipid and glucose metabolism during aging. The effect of β(2)-AR ablation on caloric intake during aging is currently not known and requires investigation. Future studies are also warranted to delineate the β(2)-AR-mediated mechanisms involved in the control of lipid and glucose homeostasis, especially in the context of a growing aging population. Published by Elsevier Inc.

  13. Conditioned pain modulation (CPM) in children and adolescents: Effects of sex and age

    PubMed Central

    Tsao, Jennie C. I.; Seidman, Laura C.; Evans, Subhadra; Lung, Kirsten C.; Zeltzer, Lonnie K.; Naliboff, Bruce D.

    2013-01-01

    Conditioned pain modulation (CPM) refers to the diminution of perceived pain intensity for a test stimulus following application of a conditioning stimulus to a remote area of the body, and is thought to reflect the descending inhibition of nociceptive signals. Studying CPM in children may inform interventions to enhance central pain inhibition within a developmental framework. We assessed CPM in 133 healthy children (mean age = 13 years; 52.6% girls) and tested the effects of sex and age. Participants were exposed to four trials of a pressure test stimulus before, during, and after the application of a cold water conditioning stimulus. CPM was documented by a reduction in pressure pain ratings during cold water administration. Older children (12–17 years) exhibited greater CPM than younger (8–11 years) children. No sex differences in CPM were found. Lower heart rate variability (HRV) at baseline and after pain induction was associated with less CPM controlling for child age. The findings of greater CPM in the older age cohort suggest a developmental improvement in central pain inhibitory mechanisms. The results highlight the need to examine developmental and contributory factors in central pain inhibitory mechanisms in children to guide effective, age appropriate, pain interventions. PMID:23541066

  14. Zeatin modulates flower bud development and tocopherol levels in Cistus albidus (L.) plants as they age.

    PubMed

    Hernández, I; Miret, J A; Van Der Kelen, K; Rombaut, D; Van Breusegem, F; Munné-Bosch, S

    2015-01-01

    In a previous study we showed that Cistus albidus (L.) experiences an age-dependent decay in flower vigour correlated with a decline in trans-zeatin (tZ) levels. In the present study we aimed to establish a causal relationship between these two phenomena. Exogenous tZ applied to plants grown under semi-controlled conditions did not rescue flower vigour; however, it accelerated flower development, but only in younger individuals. Older plants showed lower tocopherol levels in flower buds, which were restored by exogenous tZ, suggesting that a loss of antioxidant defences may underlie the age-dependent decay in flower vigour. We conclude that declining tZ levels may not be directly responsible for the age-associated loss of floral vigour; that tZ modulates the speed of flower development as plants age; and that flower buds alter their sensitivity to tZ as plants age. © 2014 German Botanical Society and The Royal Botanical Society of the Netherlands.

  15. Mitochondrial Dysfunction during Brain Aging: Role of Oxidative Stress and Modulation by Antioxidant Supplementation

    PubMed Central

    Chakrabarti, Sasanka; Munshi, Soumyabrata; Banerjee, Kalpita; Thakurta, Ishita Guha; Sinha, Maitrayee; Bagh, Maria Bindu

    2011-01-01

    Mitochondrial dysfunction and oxidative stress are two interdependent and reinforcing damage mechanisms that play a central role in brain aging. Oxidative stress initiated and propagated by active oxyradicals and various other free radicals in the presence of catalytic metal ions not only can damage the phospholipid, protein and DNA molecules within the cell but can also modulate cell signalling pathways and gene expression pattern and all these processes may be of critical importance in the aging of brain. The present article describes the mechanism of formation of reactive oxyradicals within mitochondria and then explains how these can initiate mitochondrial biogenesis program and activate various transcriptional factors in the cytosol to boost up the antioxidative capacity of the mitochondria and the cell. However, a high level of oxidative stress finally inflicts critical damage to the oxidative phosphorylation machinery and mitochondrial DNA (mtDNA). The latter part of the article is a catalogue showing the accumulating evidence in favour of oxidative inactivation of mitochondrial functions in aged brain and the detailed reports of various studies with antioxidant supplementation claiming variable success in preventing the age-related brain mitochondrial decay and cognitive decline. The antioxidant supplementation approach may be of potential help in the management of neurodegenerative diseases like Alzheimer’s disease. The newly developed mitochondria-targeted antioxidants have brought a new direction to experimental studies related to oxidative damage and they may provide potential drugs in near future for a variety of diseases or degenerative conditions including brain aging and neurodegenerative disorders. PMID:22396876

  16. Trait anxiety mimics age-related cardiovascular autonomic modulation in young adults.

    PubMed

    Sanchez-Gonzalez, M A; Guzik, P; May, R W; Koutnik, A P; Hughes, R; Muniz, S; Kabbaj, M; Fincham, F D

    2015-04-01

    Anxiety produces maladaptive cardiovascular changes and accelerates biological aging. We evaluated cardiovascular reactivity in young and middle-aged individuals with varying anxiety scores to test the hypothesis that anxiety mimics cardiovascular aging by influencing cardiovascular autonomic modulation. The State-Trait Anxiety Inventory was used to classify healthy young individuals (20-29 years) into high (YHA, n=22;10 men) and low (YLA, n=21;10 men) anxiety, and to identify middle-aged individuals (50-60 years) with low anxiety (MLA, n=22;11 men). Heart rate, blood pressure (BP) and their variability (HRV and BPV, respectively) and baroreflex function were analyzed from beat-to-beat finger BP and electrocardiogram recordings collected during 5-min baseline, 6-min speech task (ST) and 3-min post ST recovery. Analyses of covariance showed significant differences (P<0.05) at baseline for HRV, BPV and barorelfex, and low-frequency power of systolic BP variability (LFSBP) was lower, whereas baroreflex and high frequency (HF) normalized units were higher in the YLA compared with YHA and MLA groups. Compared with YLA, YHA and MLA displayed attenuated vagal withdraw response (HF) to ST. BP and LFSBP responses to ST in YHA and MLA were higher compared with the YLA group. These findings suggest that anxiety could be linked to cardiovascular aging as it attenuates cardiac reactivity and exaggerates vascular responses to stress.

  17. Modulation of Homology-Directed Repair in T98G Glioblastoma Cells Due to Interactions between Wildtype p53, Rad51 and HCMV IE1-72

    PubMed Central

    Kulkarni, Amit S.; Fortunato, Elizabeth A.

    2014-01-01

    Human cytomegalovirus (HCMV) is a ubiquitous pathogen capable of causing life threatening consequences in neonates and immune-compromised individuals. HCMV inflicts site-specific double strand breaks (DSBs) in the cellular genome. DNA damage infliction raises the corollary question of virus modulation of DNA repair. We recently reported HDR was stimulated in wt human foreskin fibroblasts (HFFs) during fully permissive infection or expression of the HCMV protein IE1-72 (IE72). These studies have been extended into semi-permissive T98G glioblastoma cells. T98Gs encode a mutant p53, which may contribute to their high baseline rate of HDR. We fully expected HCMV infection to increase HDR in T98Gs, similar to its effects in HFFs. Surprisingly in T98Gs HCMV infection, or sole expression of IE72, decreased HDR by two-fold. Transient expression of wt p53 in T98Gs also reduced HDR by two-fold. Dual transient expression of wt p53 and IE72 restored high baseline HDR levels. GST pulldown experiments revealed that both IE72 and wt p53 bound the important HDR protein, Rad51. We conclude that the expression of certain HCMV proteins can modulate HDR in an infected cell, dependent upon p53 status. We propose a model of the protein interactions explaining this behavior. PMID:24576846

  18. Age-related Shifts in Distortion Product Otoacoustic Emissions Peak-ratios and Amplitude Modulation Spectra

    PubMed Central

    Lai, Jesyin; Bartlett, Edward L.

    2015-01-01

    Amplitude modulation (AM) is an important temporal cue for precise speech and complex sound recognition. However, functional decline of the auditory periphery as well as degradation of central auditory processing due to aging can reduce the salience and resolution of temporal cues. Age-related deficits in central temporal processing have previously been observed at more rapid AM frequencies and various AM depths. These centrally observed changes result from cochlear changes compounded with changes along the ascending auditory pathway. In fact, a decrease in ability to detect temporally modulated sounds accurately could originate from changes in cochlear filtering properties and in cochlear mechanics due to aging. Nonetheless, few studies have examined cochlear mechanisms in AM detection. To assess integrity of the mechanical properties of the auditory periphery, distortion product otoacoustic emissions (DPOAEs) are a tool commonly used in clinics and in research. In this study, we measured DPOAEs to reveal age-related changes in peak f2/f1 ratio and degradation in AM detection by basilar membrane vibration. Two tones (f1 and f2, f2>f1) at various f2/f1 ratios and simultaneous presentation of one AM and one pure tone were used as stimuli to evoke DPOAEs. In addition of observing reduced DPOAE amplitudes and steeper slopes in the input-output DPOAE functions, higher peak f2/f1 ratios and broader f2/f1 tuning were also observed in aged animals. Aged animals generally had lower distortion product (DP) and first sideband (SB 1) responses evoked by an f1 pure tone and an f2 AM tone, regardless of whether the AM frequency was 45 Hz or 128 Hz. SB 1 thresholds, which corresponds to the smallest stimulus AM depth that can induce cochlear vibrations at the DP generator locus, were higher in aged animals as well. The results suggest that age-related changes in peak f2/f1 ratio and AM detection by basilar membrane vibration are consistent with a reduction in endocochlear

  19. Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE ε4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance.

    PubMed

    Foster, Chris M; Kennedy, Kristen M; Rodrigue, Karen M

    2017-07-19

    The present study was designed to investigate the effect of a genetic risk factor for Alzheimer's disease (AD), ApolipoproteinE ε4 (APOEε4), on the ability of the brain to modulate activation in response to cognitive challenge in a lifespan sample of healthy human adults. A community-based sample of 181 cognitively intact, healthy adults were recruited from the Dallas-Fort Worth metroplex. Thirty-one APOEε4+ individuals (48% women), derived from the parent sample, were matched based on sex, age, and years of education to 31 individuals who were APOEε4-negative (APOEε4-). Ages ranged from 20 to 86 years of age. Blood oxygen level-dependent functional magnetic resonance imaging was collected during the performance of a visuospatial distance judgment task with three parametric levels of difficulty. Multiple regression was used in a whole-brain analysis with age, APOE group, and their interaction predicting functional brain modulation in response to difficulty. Results revealed an interaction between age and APOE in a large cluster localized primarily to the bilateral precuneus. APOEε4- individuals exhibited age-invariant modulation in response to task difficulty, whereas APOEε4+ individuals showed age-related reduction of modulation in response to increasing task difficulty compared with ε4- individuals. Decreased modulation in response to cognitive challenge was associated with reduced task accuracy as well as poorer name-face associative memory performance. Findings suggest that APOEε4 is associated with a reduction in the ability of the brain to dynamically modulate in response to cognitive challenge. Coupled with a significant genetic risk factor for AD, changes in modulation may provide additional information toward identifying individuals potentially at risk for cognitive decline associated with preclinical AD.SIGNIFICANCE STATEMENT Understanding how risk factors for Alzheimer's disease (AD) affect brain function and cognition in healthy adult samples

  20. Modulation of postjunctional α-adrenergic vasoconstriction during exercise and exogenous ATP infusions in ageing humans

    PubMed Central

    Kirby, Brett S; Crecelius, Anne R; Voyles, Wyatt F; Dinenno, Frank A

    2011-01-01

    Abstract The ability to modulate sympathetic α-adrenergic vasoconstriction in contracting muscle is impaired with age. In young adults, adenosine triphosphate (ATP) has been shown to blunt sympathetic vasoconstrictor responsiveness similar to exercise. Therefore, we tested the hypothesis that modulation of postjunctional α-adrenergic vasoconstriction to exogenous ATP is impaired in ageing humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) to intra-arterial infusions of phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) during rhythmic handgrip exercise (15% MVC), a control non-exercise vasodilator condition (adenosine), and ATP infusion in seven older (64 ± 3 years) and seven young (22 ± 1 years) healthy adults. Forearm hyperaemia was matched across all vasodilatating conditions. During adenosine, forearm vasoconstrictor responses to direct α1-stimulation were lower in older compared with young adults (ΔFVC =−25 ± 3%vs.−41 ± 5%; P < 0.05), whereas the responses to α2-stimulation were not different (−35 ± 6%vs.−44 ± 8%; NS). During exercise, α1-mediated vasoconstriction was significantly blunted compared with adenosine in both young (−9 ± 2%vs.−41 ± 5%) and older adults (−15 ± 2%vs.−25 ± 3%); however, the magnitude of sympatholysis was reduced in older adults (32 ± 13 vs. 74 ± 8%; P < 0.05). Similarly, α2-mediated vasoconstriction during exercise was significantly blunted in both young (−15 ± 4%vs.−44 ± 8%) and older adults (−26 ± 3%vs.−35 ± 6%), however the magnitude of sympatholysis was reduced in older adults (19 ± 8%vs. 60 ± 10%; P < 0.05). During ATP, both α1- and α2-mediated vasoconstriction was nearly abolished in young and older adults (ΔFVC ∼−5%), and the magnitude of sympatholysis was similar in both age groups (∼85–90%). Our findings indicate that the ability to modulate postjunctional α-adrenergic vasoconstriction during

  1. Oligonol promotes anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway.

    PubMed

    Park, Seul-Ki; Seong, Rak-Kyun; Kim, Ji-Ae; Son, Seok-Jun; Kim, Younghoon; Yokozawa, Takako; Shin, Ok Sarah

    2016-02-01

    Oligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined. In this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans. Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of SIRT1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae. These data demonstrated that oligonol may act as an anti-aging molecule by modulating SIRT1/autophagy/AMPK pathways.

  2. Oligonol promotes anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway

    PubMed Central

    Park, Seul-Ki; Seong, Rak-Kyun; Kim, Ji-Ae; Son, Seok-Jun; Kim, Younghoon; Yokozawa, Takako

    2016-01-01

    BACKGROUND/OBJECTIVES Oligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined. MATERIALS/METHODS In this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans. RESULTS Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of SIRT1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae. CONCLUSIONS These data demonstrated that oligonol may act as an anti-aging molecule by modulating SIRT1/autophagy/AMPK pathways. PMID:26865910

  3. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats

    PubMed Central

    Speisman, Rachel. B.; Kumar, Ashok; Rani, Asha; Foster, Thomas C.; Ormerod, Brandi K.

    2012-01-01

    We tested whether daily exercise modulates immune and neuroimmune cytokines, hippocampus-dependent behavior and hippocampal neurogenesis in aging male F344 rats (18 mo upon arrival). Twelve weeks after conditioned running or control group assignment (n = 6 per group), the rats were trained and tested in a rapid water maze followed by an inhibitory avoidance task. The rats were BrdU-injected beginning 12 days after behavioral testing and killed 3 weeks later to quantify cytokines and neurogenesis. Daily exercise increased neurogenesis and improved immediate and 24 h water maze discrimination index (DI) scores and 24 h inhibitory avoidance retention latencies. Daily exercise decreased cortical VEGF, hippocampal IL-1β and serum MCP-1, GRO-KC and leptin levels but increased hippocampal GRO-KC and IL-18 concentrations. Serum leptin concentration correlated negatively with new neuron number and both DI scores while hippocampal IL-1β concentration correlated negatively with memory scores in both tasks. Cortical VEGF, serum GRO-KC and serum MCP-1 levels correlated negatively with immediate DI score and we found a novel positive correlation between hippocampal IL-18 and GRO-KC levels and new neuron number. Pathway analyses revealed distinct serum, hippocampal and cortical compartment cytokine relationships. Our results suggest that daily exercise potentially improves cognition in aging rats by modulating hippocampal neurogenesis and immune and neuroimmune cytokine signaling. PMID:23078985

  4. Does Human Milk Modulate Body Composition in Late Preterm Infants at Term-Corrected Age?

    PubMed

    Giannì, Maria Lorella; Consonni, Dario; Liotto, Nadia; Roggero, Paola; Morlacchi, Laura; Piemontese, Pasqua; Menis, Camilla; Mosca, Fabio

    2016-10-23

    (1) Background: Late preterm infants account for the majority of preterm births and are at risk of altered body composition. Because body composition modulates later health outcomes and human milk is recommended as the normal method for infant feeding, we sought to investigate whether human milk feeding in early life can modulate body composition development in late preterm infants; (2) Methods: Neonatal, anthropometric and feeding data of 284 late preterm infants were collected. Body composition was evaluated at term-corrected age by air displacement plethysmography. The effect of human milk feeding on fat-free mass and fat mass content was evaluated using multiple linear regression analysis; (3) Results: Human milk was fed to 68% of the infants. According to multiple regression analysis, being fed any human milk at discharge and at  term-corrected and being fed exclusively human milk at term-corrected age were positively associated with fat-free mass content(β = -47.9, 95% confidence interval (CI) = -95.7; -0.18; p = 0.049; β = -89.6, 95% CI = -131.5; -47.7; p < 0.0001; β = -104.1, 95% CI = -151.4; -56.7, p < 0.0001); (4) Conclusion: Human milk feeding appears to be associated with fat-free mass deposition in late preterm infants. Healthcare professionals should direct efforts toward promoting and supporting breastfeeding in these vulnerable infants.

  5. Does Human Milk Modulate Body Composition in Late Preterm Infants at Term-Corrected Age?

    PubMed Central

    Giannì, Maria Lorella; Consonni, Dario; Liotto, Nadia; Roggero, Paola; Morlacchi, Laura; Piemontese, Pasqua; Menis, Camilla; Mosca, Fabio

    2016-01-01

    (1) Background: Late preterm infants account for the majority of preterm births and are at risk of altered body composition. Because body composition modulates later health outcomes and human milk is recommended as the normal method for infant feeding, we sought to investigate whether human milk feeding in early life can modulate body composition development in late preterm infants; (2) Methods: Neonatal, anthropometric and feeding data of 284 late preterm infants were collected. Body composition was evaluated at term-corrected age by air displacement plethysmography. The effect of human milk feeding on fat-free mass and fat mass content was evaluated using multiple linear regression analysis; (3) Results: Human milk was fed to 68% of the infants. According to multiple regression analysis, being fed any human milk at discharge and at  term-corrected and being fed exclusively human milk at term-corrected age were positively associated with fat-free mass content(β = −47.9, 95% confidence interval (CI) = −95.7; −0.18; p = 0.049; β = −89.6, 95% CI = −131.5; −47.7; p < 0.0001; β = −104.1, 95% CI = −151.4; −56.7, p < 0.0001); (4) Conclusion: Human milk feeding appears to be associated with fat-free mass deposition in late preterm infants. Healthcare professionals should direct efforts toward promoting and supporting breastfeeding in these vulnerable infants. PMID:27782098

  6. Dynamic attentional modulation of vision across space and time after right hemisphere stroke and in ageing.

    PubMed

    Russell, Charlotte; Malhotra, Paresh; Deidda, Cristiana; Husain, Masud

    2013-01-01

    Attention modulates the availability of sensory information to conscious perception. In particular, there is evidence of pathological, spatial constriction of the effective field of vision in patients with right hemisphere damage when a central task exhausts available attentional capacity. In the current study we first examined whether this constriction might be modulated across both space and time in right hemisphere stroke patients without neglect. Then we tested healthy elderly people to determine whether non-pathological ageing also leads to spatiotemporal impairments of vision under conditions of high attention load. Right hemisphere stroke patients completed a task at fixation while attempting to discriminate letters appearing in the periphery. Attentional load of the central task was modulated by increasing task difficulty. Peripheral letters appeared simultaneously with the central task or at different times (stimulus onset asynchronies, SOAs) after it. In a second study healthy elderly volunteers were tested with a modified version of this paradigm. Under conditions of high attention load right hemisphere stroke patients have a reduced effective visual field, over a significantly extended 'attentional blink', worse for items presented to their left. In the second study, older participants were unable to discriminate otherwise salient items across the visual field (left or right) when their attention capacity was loaded on the central task. This deficit extended temporally, with peripheral discrimination ability not returning to normal for up to 450 msec. Dynamically tying up attention resources on a task at fixation can have profound effects in patient populations and in normal ageing. These results demonstrate that items can escape conscious detection across space and time, and can thereby impact significantly on visual perception in these groups. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. The autotaxin-LPA2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair.

    PubMed

    Balogh, Andrea; Shimizu, Yoshibumi; Lee, Sue Chin; Norman, Derek D; Gangwar, Ruchika; Bavaria, Mitul; Moon, ChangSuk; Shukla, Pradeep; Rao, Radakrishna; Ray, Ramesh; Naren, Anjaparavanda P; Banerjee, Souvik; Banerje, Souvik; Miller, Duane D; Balazs, Louisa; Pelus, Louis; Tigyi, Gabor

    2015-09-01

    In this study we characterized the effects of radiation injury on the expression and function of the autotaxin (ATX)-LPA2 GPCR axis. In IEC-6 crypt cells and jejunum enteroids quantitative RT-PCR showed a time- and dose-dependent upregulation of lpa2 in response to γ-irradiation that was abolished by mutation of the NF-κB site in the lpa2 promoter or by inhibition of ATM/ATR kinases with CGK-733, suggesting that lpa2 is a DNA damage response gene upregulated by ATM via NF-κB. The resolution kinetics of the DNA damage marker γ-H2AX in LPA-treated IEC-6 cells exposed to γ-irradiation was accelerated compared to vehicle, whereas pharmacological inhibition of LPA2 delayed the resolution of γ-H2AX. In LPA2-reconstituted MEF cells lacking LPA1&3 the levels of γ-H2AX decreased rapidly, whereas in Vector MEF were high and remained sustained. Inhibition of ERK1&2 or PI3K/AKT signaling axis by pertussis toxin or the C311A/C314A/L351A mutation in the C-terminus of LPA2 abrogated the effect of LPA on DNA repair. LPA2 transcripts in Lin(-)Sca-1(+)c-Kit(+) enriched for bone marrow stem cells were 27- and 5-fold higher than in common myeloid or lymphoid progenitors, respectively. Furthermore, after irradiation higher residual γ-H2AX levels were detected in the bone marrow or jejunum of irradiated LPA2-KO mice compared to WT mice. We found that γ-irradiation increases plasma ATX activity and LPA level that is in part due to the previously established radiation-induced upregulation of TNFα. These findings identify ATX and LPA2 as radiation-regulated genes that appear to play a physiological role in DNA repair. Copyright © 2015. Published by Elsevier Inc.

  8. GADD45α modulates curcumin sensitivity through c-Abl- and JNK-dependent signaling pathways in a mismatch repair-dependent manner.

    PubMed

    Naick, Hemanth; Jin, Shunqian; Baskaran, R

    2016-03-01

    Colorectal cancer is a critical health concern because of its incidence as the third most prevalent cancer in the world. Currently, 5-fluorouracil (5-FU), 6-thioguanine, and certain other genotoxic agents are mainstays of treatment; however, patients often die due to emergence of resistant population. Curcumin, a bioactive compound derived from the dietary turmeric (Curcuma longa) is an effective anticancer, anti-inflammatory, and antioxidant agent. Previously, we reported that human colorectal cancer cell lines compromised for mismatch repair (MMR) function exhibit heightened sensitivity to curcumin due to sustained curcumin-induced unrepaired DNA damage compared to proficient population counterparts. In this report, we show that the protein levels of gadd45α, whose transcript levels are increased during DNA damage and stress signals, are upregulated following curcumin treatment in a dose- and time-dependent manner. We further observed that cells compromised for Mlh1 function (HCT116 + Ch2) displayed ~twofold increased GADD45α upregulation compared to similarly treated proficient counterparts (HCT116 + Ch3). Similarly, suppression of Mlh1 using ShRNA increased GADD45α upregulation upon curcumin treatment. On the other hand, suppression of GADD45α using SiRNA-blocked curcumin-induced cell death induction in Mlh1-deficient cells. Moreover, inhibition of Abl through ST571 treatment and its downstream effector JNK through SP600125 treatment blocked GADD45α upregulation and cell death triggered by curcumin. Collective results lead us to conclude that GADD45α modulates curcumin sensitivity through activation of c-Abl > JNK signaling in a mismatch repair-dependent manner.

  9. Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation.

    PubMed

    Cerquetti, Lidia; Sampaoli, Camilla; Amendola, Donatella; Bucci, Barbara; Misiti, Silvia; Raza, Giorgio; De Paula, Ugo; Marchese, Rodolfo; Brunetti, Ercole; Toscano, Vincenzo; Stigliano, Antonio

    2010-08-01

    Mitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11beta-hydroxylase and cholesterol side chain cleavage. It also has a cytotoxic effect on the adrenocortical cells and represents a primary drug used in the adrenocortical carcinoma (ACC). H295R and SW13 cell lines were treated with mitotane 10(-5) M and ionizing radiations (IR) in combination therapy, inducing an irreversible inhibition of cell growth in both adrenocortical cancer cells. As shown in a previous report, mitotane/IR combination treatment induced a cell accumulation in the G2 phase. Here, we report the radiosensitizing properties of mitotane in two different ACC cell lines. The drug reveals the effectiveness to enhance the cytotoxic effects of IR by attenuating DNA repair and interfering on the activation of mitosis promoting factor (MPF), mainly regulated by the degradation of cyclin B1 in the mitotic process. These events may explain the inappropriate activation of cdc2, implicated in G2/M phase arrest and probably induced by the mitotane and IR in the combined treatment. Indeed, treatment with purvalanol, a cdc2-inhibitor prevents cell cycle arrest, triggering the G2/M transition. The observation that mitotane and IR in combination treatment amplifies the activation level of cyclin B/cdc2 complexes contributing to cell cycle arrest, suggests that the MPF could function as a master signal for controlling the temporal order of different mitotic events. Moreover, we report that mitotane interferes in modulation of mismatch repair (MMR) enzymes, revealing radiosensitizing drug ability.

  10. The nuclear hormone receptor coactivator NRC is a pleiotropic modulator affecting growth, development, apoptosis, reproduction, and wound repair.

    PubMed

    Mahajan, Muktar A; Das, Sharmistha; Zhu, Hong; Tomic-Canic, Marjana; Samuels, Herbert H

    2004-06-01

    Nuclear hormone receptor coregulator (NRC) is a 2,063-amino-acid coregulator of nuclear hormone receptors and other transcription factors (e.g., c-Fos, c-Jun, and NF-kappaB). We and others have generated C57BL/6-129S6 hybrid (C57/129) NRC(+/-) mice that appear outwardly normal and grow and reproduce. In contrast, homozygous deletion of the NRC gene is embryonic lethal. NRC(-/-) embryos are always smaller than NRC(+/+) embryos, and NRC(-/-) embryos die between 8.5 and 12.5 days postcoitus (dpc), suggesting that NRC has a pleotrophic effect on growth. To study this, we derived mouse embryonic fibroblasts (MEFs) from 12.5-dpc embryos, which revealed that NRC(-/-) MEFs exhibit a high rate of apoptosis. Furthermore, a small interfering RNA that targets mouse NRC leads to enhanced apoptosis of wild-type MEFs. The finding that C57/129 NRC(+/-) mice exhibit no apparent phenotype prompted us to develop 129S6 NRC(+/-) mice, since the phenotype(s) of certain gene deletions may be strain dependent. In contrast with C57/129 NRC(+/-) females, 20% of 129S6 NRC(+/-) females are infertile while 80% are hypofertile. The 129S6 NRC(+/-) males produce offspring when crossed with wild-type 129S6 females, although fertility is reduced. The 129S6 NRC(+/-) mice tend to be stunted in their growth compared with their wild-type littermates and exhibit increased postnatal mortality. Lastly, both C57/129 NRC(+/-) and 129S6 NRC(+/-) mice exhibit a spontaneous wound healing defect, indicating that NRC plays an important role in that process. Our findings reveal that NRC is a coregulator that controls many cellular and physiologic processes ranging from growth and development to reproduction and wound repair.

  11. The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair

    PubMed Central

    Alfaro, Maria P.; Pagni, Matthew; Vincent, Alicia; Atkinson, James; Hill, Michael F.; Cates, Justin; Davidson, Jeffrey M.; Rottman, Jeffrey; Lee, Ethan; Young, Pampee P.

    2008-01-01

    Cell-based therapies, using multipotent mesenchymal stem cells (MSCs) for organ regeneration, are being pursued for cardiac disease, orthopedic injuries and biomaterial fabrication. The molecular pathways that regulate MSC-mediated regeneration or enhance their therapeutic efficacy are, however, poorly understood. We compared MSCs isolated from MRL/MpJ mice, known to demonstrate enhanced regenerative capacity, to those from C57BL/6 (WT) mice. Compared with WT-MSCs, MRL-MSCs demonstrated increased proliferation, in vivo engraftment, experimental granulation tissue reconstitution, and tissue vascularity in a murine model of repair stimulation. The MRL-MSCs also reduced infarct size and improved function in a murine myocardial infarct model compared with WT-MSCs. Genomic and functional analysis indicated a downregulation of the canonical Wnt pathway in MRL-MSCs characterized by significant up-regulation of specific secreted frizzled-related proteins (sFRPs). Specific knockdown of sFRP2 by shRNA in MRL-MSCs decreased their proliferation and their engraftment in and the vascular density of MRL-MSC-generated experimental granulation tissue. These results led us to generate WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction. sFRP2-MSCs maintained their ability for multilineage differentiation in vitro and, when implanted in vivo, recapitulated the MRL phenotype. Peri-infarct intramyocardial injection of sFRP2-MSCs resulted in enhanced engraftment, vascular density, reduced infarct size, and increased cardiac function after myocardial injury in mice. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype in MSCs. PMID:19017790

  12. Type I Interferons Modulate Vascular Function, Repair, Thrombosis and Plaque Progression in Murine Models of Lupus and Atherosclerosis

    PubMed Central

    Thacker, Seth G.; Zhao, Wenpu; Smith, Carolyne K.; Luo, Wei; Wang, Hui; Vivekanandan-Giri, Anuradha; Rabquer, Bradley J.; Koch, Alisa E.; Pennathur, Subramaniam; Davidson, Anne; Eitzman, Daniel T.; Kaplan, Mariana J.

    2012-01-01

    Objectives Patients with systemic lupus erythematosus (SLE) have a striking increase in atherothrombotic cardiovascular disease (CVD), not explained by the Framingham risk equation. In vitro studies indicate that type-I Interferons (IFNs) may play prominent roles in increased CV risk in SLE. However, the in vivo relevance of these findings, with regards to the development of CVD, has not been characterized. We examined the role of type-I IFNs in endothelial dysfunction, aberrant vascular repair, and atherothrombosis in murine models of lupus and atherosclerosis. Methods Lupus-prone New Zealand Mixed-2328 mice (NZM) and atherosclerosis-prone Apolipoprotein-E-knockout mice (ApoE−/−) were compared to mice lacking type-I IFN-receptor (INZM and ApoEIFNR−/−, respectively) in their endothelial vasodilatory function, endothelial progenitor cell (EPC) function, in vivo neoangiogenesis, plaque development and occlusive thrombosis. Similar experiments were performed when NZM and ApoE−/− received an IFN-α-containing or an empty adenovirus. Results Loss of type IIFN-receptor signaling improves endothelium-dependent vasorelaxation, lipoprotein parameters, EPC numbers and function and neoangiogenesis in lupus-prone mice, independent of disease activity or gender. Further, acute exposure to IFN-α impairs endothelial vasorelaxation and EPC function in lupus-prone and non-lupus-prone mice. ApoEIFNR−/− mice have decreased atherosclerosis severity and arterial inflammatory infiltrates and increased neoangiogenesis, compared to ApoE−/− mice, while NZM and ApoE−/− mice exposed to IFN-α develop accelerated thrombosis and platelet activation. Conclusions These results support the hypothesis that type I-IFNs play key roles in the development of premature CVD in SLE and, potentially, in the general population, through pleiotropic deleterious effects on the vasculature. PMID:22549550

  13. APOE genotype modulates proton magnetic resonance spectroscopy metabolites in the aging brain.

    PubMed

    Gomar, Jesus J; Gordon, Marc L; Dickinson, Dwight; Kingsley, Peter B; Uluğ, Aziz M; Keehlisen, Lynda; Huet, Sarah; Buthorn, Justin J; Koppel, Jeremy; Christen, Erica; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

    2014-05-01

    Proton magnetic resonance spectroscopy ((1)H-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimer's disease. Additionally, we examined these measures in relation to cognition. We studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of (1)H-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained. General linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myo-inositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE × age interaction and APOE status each had a significant effect on (1)H-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE × age variable modulation of cognition was mediated by (1)H-MRS metabolites. In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers. Copyright © 2014 Society of Biological Psychiatry. All rights reserved.

  14. Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats.

    PubMed

    Casadesus, Gemma; Shukitt-Hale, Barbara; Stellwagen, Heather M; Zhu, Xiongwei; Lee, Hyoung-Gon; Smith, Mark A; Joseph, James A

    2004-01-01

    During aging, reductions in hippocampal neurogenesis are associated with memory decline indicating a causal relationship. Indeed, insulin-like growth factor-1 (IGF-1), a major activator of the extracellular receptor kinase pathway that is central in learning and memory processes, is also a key modulator of hippocampal neurogenesis. Previously, we showed that age-related declines in spatial memory tasks can be improved by antioxidant-rich diets containing blueberries. In this study, to begin to understand the mechanisms responsible for the beneficial effects of blueberries, we assessed changes in hippocampal plasticity parameters such as hippocampal neurogenesis, extracellular receptor kinase activation, and IGF-1 and IGF-1R levels in blueberry-supplemented aged animals. Our results show that all these parameters of hippocampal neuronal plasticity are increased in supplemented animals and aspects such as proliferation, extracellular receptor kinase activation and IGF-1 and IGF-1R levels correlate with improvements in spatial memory. Therefore, cognitive improvements afforded by polyphenolic-rich fruits such as blueberries appear, in part, to be mediated by their effects on hippocampal plasticity.

  15. Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine.

    PubMed

    Ferraro, Elisabetta; Pin, Fabrizio; Gorini, Stefania; Pontecorvo, Laura; Ferri, Alberto; Mollace, Vincenzo; Costelli, Paola; Rosano, Giuseppe

    2016-09-01

    The loss of muscle mass (sarcopenia) and the associated reduced muscle strength are key limiting factors for elderly people's quality of life. Improving muscle performance does not necessarily correlate with increasing muscle mass. In fact, particularly in the elderly, the main explanation for muscle weakness is a reduction of muscle quality rather than a loss of muscle mass, and the main goal to be achieved is to increase muscle strength. The effectiveness of Trimetazidine (TMZ) in preventing muscle functional impairment during ageing was assessed in our laboratory. Aged mice received TMZ or vehicle for 12 consecutive days. Muscle function was evaluated at the end of the treatment by a grip test as well as by an inverted screen test at 0, 5, 7 and 12 days of TMZ treatment. After sacrifice, muscles were stored for myofiber cross-sectional area assessment and myosin heavy chain expression evaluation by western blotting. Chronic TMZ treatment does not affect the mass of both gastrocnemius and tibialis anterior muscles, while it significantly increases muscle strength. Indeed, both latency to fall and grip force are markedly enhanced in TMZ-treated versus untreated mice. In addition, TMZ administration results in higher expression of slow myosin heavy chain isoform and increased number of small-sized myofibers. We report here some data showing that the modulation of skeletal muscle metabolism by TMZ increases muscle strength in aged mice. Reprogramming metabolism might therefore be a strategy worth to be further investigated in view of improving muscle performance in the elderly.

  16. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging.

    PubMed

    Bhasin, Shalender; Calof, Olga M; Storer, Thomas W; Lee, Martin L; Mazer, Norman A; Jasuja, Ravi; Montori, Victor M; Gao, Wenqing; Dalton, James T

    2006-03-01

    Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with beta-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.

  17. Modulating testosterone pathway: a new strategy to tackle male skin aging?

    PubMed Central

    Bernard, Philippe; Scior, Thomas; Do, Quoc Tuan

    2012-01-01

    In men, the level of testosterone decreases with age. At the skin level, the result is observed as a decrease in density and in a lower elasticity. Identifying compounds that are able to increase the level of testosterone appears to be an attractive strategy to develop new antiaging bioactive ingredients for men. Reverse pharmacognosy was successfully applied to identify new natural compounds able to modulate testosterone levels. Among several in silico hits, honokiol was retained as a candidate as it has the greatest potential to become an active ingredient. This result was then validated in vitro on aromatase and 5-alpha-reductase type 1 and 2, which are two types of enzymes implicated in the degradation of free testosterone. Indeed, honokiol was identified as an inhibitor of aromatase, with a half-maximal inhibitory concentration (IC50) of about 50 μM. In addition, honokiol was shown to be an inhibitor of 5-alpha-reductase type 1, with an IC50 of about 75 μM. Taken together, these data indicate that honokiol modulates testosterone levels, and its structure has the potential to serve as a lead for future designs of highly selective inhibitors of 5-alpha-reductase type 1. PMID:23049247

  18. Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

    PubMed Central

    Bhasin, Shalender; Calof, Olga M; Storer, Thomas W; Lee, Martin L; Mazer, Norman A; Jasuja, Ravi; Montori, Victor M; Gao, Wenqing; Dalton, James T

    2007-01-01

    SUMMARY Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging. PMID:16932274

  19. Modulating testosterone pathway: a new strategy to tackle male skin aging?

    PubMed

    Bernard, Philippe; Scior, Thomas; Do, Quoc Tuan

    2012-01-01

    In men, the level of testosterone decreases with age. At the skin level, the result is observed as a decrease in density and in a lower elasticity. Identifying compounds that are able to increase the level of testosterone appears to be an attractive strategy to develop new antiaging bioactive ingredients for men. Reverse pharmacognosy was successfully applied to identify new natural compounds able to modulate testosterone levels. Among several in silico hits, honokiol was retained as a candidate as it has the greatest potential to become an active ingredient. This result was then validated in vitro on aromatase and 5-alpha-reductase type 1 and 2, which are two types of enzymes implicated in the degradation of free testosterone. Indeed, honokiol was identified as an inhibitor of aromatase, with a half-maximal inhibitory concentration (IC(50)) of about 50 μM. In addition, honokiol was shown to be an inhibitor of 5-alpha-reductase type 1, with an IC(50) of about 75 μM. Taken together, these data indicate that honokiol modulates testosterone levels, and its structure has the potential to serve as a lead for future designs of highly selective inhibitors of 5-alpha-reductase type 1.

  20. Cold Water Swimming Beneficially Modulates Insulin Sensitivity in Middle-Aged Individuals.

    PubMed

    Gibas-Dorna, Magdalena; Chęcińska, Zuzanna; Korek, Emilia; Kupsz, Justyna; Sowińska, Anna; Krauss, Hanna

    2016-10-01

    We determined whether cold water swimming for six consecutive months results in adaptive changes in body composition and insulin sensitivity. Thirty healthy subjects aged 50.2 ± 9.4 years were exposed to cold water at least twice a week. Body composition was determined and serum glucose and insulin served to calculate beta-cell function, insulin sensitivity, and resistance using HOMA2. Compared with control subjects, swimmers were overweight, and had greater percent body fat and beta cell function. Women had lower values of BMI, fat free mass, muscle mass, visceral adipose tissue level, and greater percent body fat than men. Increased insulin sensitivity and decreased insulin secretion and resistance from beginning to middle of swim season was observed in females and in lean subjects. Findings suggest that men and women differ in regard to body composition and response to repeated cold exposure. Cold water swimming may beneficially modulate insulin sensitivity in cold acclimated lean swimmers.

  1. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats.

    PubMed

    Speisman, Rachel B; Kumar, Ashok; Rani, Asha; Foster, Thomas C; Ormerod, Brandi K

    2013-02-01

    We tested whether daily exercise modulates immune and neuroimmune cytokines, hippocampus-dependent behavior and hippocampal neurogenesis in aging male F344 rats (18mo upon arrival). Twelve weeks after conditioned running or control group assignment, the rats were trained and tested in a rapid water maze followed by an inhibitory avoidance task. The rats were BrdU-injected beginning 12days after behavioral testing and killed 3weeks later to quantify cytokines and neurogenesis. Daily exercise increased neurogenesis and improved immediate and 24h water maze discrimination index (DI) scores and 24h inhibitory avoidance retention latencies. Daily exercise decreased cortical VEGF, hippocampal IL-1β and serum MCP-1, GRO-KC and leptin levels but increased hippocampal GRO-KC and IL-18 concentrations. Serum leptin concentration correlated negatively with new neuron number and both DI scores while hippocampal IL-1β concentration correlated negatively with memory scores in both tasks. Cortical VEGF, serum GRO-KC and serum MCP-1 levels correlated negatively with immediate DI score and we found novel positive correlations between hippocampal IL-18 and GRO-KC levels and new neuron number. Pathway analyses revealed distinct serum, hippocampal and cortical compartment cytokine relationships. Our results suggest that daily exercise potentially improves cognition in aging rats by modulating hippocampal neurogenesis and immune and neuroimmune cytokine signaling. Our correlational data begin to provide a framework for systematically manipulating these immune and neuroimmune signaling molecules to test their effects on cognition and neurogenesis across lifespan in future experiments. Published by Elsevier Inc.

  2. Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

    PubMed Central

    Brennan, Lisa A.; Kantorow, Marc

    2009-01-01

    -destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr) protein repair system and other redox systems play key roles in the function and maintenance of the aging eye. PMID:18588875

  3. Dme-miR-314-3p modulation in Cr(VI) exposed Drosophila affects DNA damage repair by targeting mus309.

    PubMed

    Chandra, Swati; Khatoon, Rehana; Pandey, Ashutosh; Saini, Sanjay; Vimal, Divya; Singh, Pallavi; Chowdhuri, D Kar

    2016-03-05

    microRNAs (miRNAs) as one of the major epigenetic modulators negatively regulate mRNAs at post transcriptional level. It was therefore hypothesized that modulation of miRNAs by hexavalent Chromium [Cr(VI)], a priority environmental chemical, can affect DNA damage. In a genetically tractable model, Drosophila melanogaster, role of maximally up-regulated miRNA, dme-miR-314-3p, on DNA damage was examined by exposing the third instar larvae to 5.0-20.0 μg/ml Cr(VI) for 24 and 48 h. mus309, a Drosophila homologue of human Bloom's syndrome and predicted as one of the potential targets of this miRNA, was confirmed as its target by 5'RLM-RACE assay. A significant down-regulation of mus309 was observed in dme-miR-314-3p overexpression strain (myo-gal4>UAS-miR-314-3p) as compared with that in parental strains (myo-gal4 and UAS-miR-314-3p) and in w(1118). A significant increase in DNA damage including double strand breaks generation was observed in exposed myo-gal4>UAS-miR-314 and mus309 mutants as compared with that in parental strain and in unexposed control. A significant down-regulation of cell cycle regulation genes (CycA, CycB and cdc2) was observed in these exposed genotypes. Collectively, the study demonstrates that dme-miR-314-3p can mediate the downregulation of repair deficient gene mus309 leading to increased DNA damage and cell cycle arrest in exposed organism which may affect Cr(VI) mediated carcinogenesis.

  4. SGEF is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide

    PubMed Central

    Fortin Ensign, Shannon P.; Roos, Alison; Mathews, Ian T.; Dhruv, Harshil D.; Tuncali, Serdar; Sarkaria, Jann N.; Symons, Marc H.; Loftus, Joseph C.; Berens, Michael E.; Tran, Nhan L.

    2015-01-01

    Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide (TMZ), GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance in order to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and plays a role in promoting TWEAK-Fn14 mediated glioma invasion. Here, further investigation revealed an important role for SGEF in glioma cell survival. SGEF expression is up-regulated by TWEAK-Fn14 signaling via NF-κB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to TMZ-induced apoptosis and suppresses colony formation following TMZ treatment. Nuclear SGEF is activated following TMZ exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to TMZ treatment is hindered by SGEF knockdown. The role of SGEF in promoting chemotherapeutic resistance highlights a heretofore unappreciated driver, and suggests its candidacy for development of novel targeted therapeutics for TMZ refractory, invasive GB cells. Implication SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma. PMID:26764186

  5. Feasibility and validity of the structured attention module among economically disadvantaged preschool-age children.

    PubMed

    Bush, Hillary H; Eisenhower, Abbey; Briggs-Gowan, Margaret; Carter, Alice S

    2015-01-01

    Rooted in the theory of attention put forth by Mirsky, Anthony, Duncan, Ahearn, and Kellam (1991), the Structured Attention Module (SAM) is a developmentally sensitive, computer-based performance task designed specifically to assess sustained selective attention among 3- to 6-year-old children. The current study addressed the feasibility and validity of the SAM among 64 economically disadvantaged preschool-age children (mean age = 58 months; 55% female); a population known to be at risk for attention problems and adverse math performance outcomes. Feasibility was demonstrated by high completion rates and strong associations between SAM performance and age. Principal Factor Analysis with rotation produced robust support for a three-factor model (Accuracy, Speed, and Endurance) of SAM performance, which largely corresponded with existing theorized models of selective and sustained attention. Construct validity was evidenced by positive correlations between SAM Composite scores and all three SAM factors and IQ, and between SAM Accuracy and sequential memory. Value-added predictive validity was not confirmed through main effects of SAM on math performance above and beyond age and IQ; however, significant interactions by child sex were observed: Accuracy and Endurance both interacted with child sex to predict math performance. In both cases, the SAM factors predicted math performance more strongly for girls than for boys. There were no overall sex differences in SAM performance. In sum, the current findings suggest that interindividual variation in sustained selective attention, and potentially other aspects of attention and executive function, among young, high-risk children can be captured validly with developmentally sensitive measures.

  6. Cognitive Control Modulates Effects of Episodic Simulation on Delay Discounting in Aging

    PubMed Central

    Sasse, Laura K.; Peters, Jan; Brassen, Stefanie

    2017-01-01

    Enhancing prospective thinking by tagging the future with specific episodic events has been shown to reduce delay discounting in young age (“tag-effect”). So far, it is unclear whether such beneficial effect extends to old adulthood. Since the general ability of future thinking and cognitive control are crucial modulators of temporal discounting in young age, potential age-related decline in these functions might impact on the effect. We focused on this issue by combining functional magnetic resonance imaging (fMRI) with an established intertemporal choice task including episodic “tags” in healthy older participants. Future thinking ability was assessed using autobiographical interviews for future event simulations and a visual search task was applied to assess participants’ cognitive control ability. In contrast to previous data in young adults, the group of older participants did not benefit from tagging the future with episodic events. Older participants’ cognitive control function was directly associated with discounting rates in the episodic conditions: the less the older adults were able to focus their attention the less they benefited from the inclusion of episodic events. Consistent with this, imaging results revealed that: (a) subjective value (SV) signals in the hippocampus and the anterior cingulate cortex (ACC) as well as; (b) hippocampal-striatal coupling during the episodic condition were positively related to participants’ control capacity. Our findings highlight the critical role of executive functioning for the simultaneous integration of episodic information with future value computation in aging. Boosting delay gratification by including episodic tags might hence be limited in older individuals with pronounced decline in distraction control. PMID:28352226

  7. Cognitive Control Modulates Effects of Episodic Simulation on Delay Discounting in Aging.

    PubMed

    Sasse, Laura K; Peters, Jan; Brassen, Stefanie

    2017-01-01

    Enhancing prospective thinking by tagging the future with specific episodic events has been shown to reduce delay discounting in young age ("tag-effect"). So far, it is unclear whether such beneficial effect extends to old adulthood. Since the general ability of future thinking and cognitive control are crucial modulators of temporal discounting in young age, potential age-related decline in these functions might impact on the effect. We focused on this issue by combining functional magnetic resonance imaging (fMRI) with an established intertemporal choice task including episodic "tags" in healthy older participants. Future thinking ability was assessed using autobiographical interviews for future event simulations and a visual search task was applied to assess participants' cognitive control ability. In contrast to previous data in young adults, the group of older participants did not benefit from tagging the future with episodic events. Older participants' cognitive control function was directly associated with discounting rates in the episodic conditions: the less the older adults were able to focus their attention the less they benefited from the inclusion of episodic events. Consistent with this, imaging results revealed that: (a) subjective value (SV) signals in the hippocampus and the anterior cingulate cortex (ACC) as well as; (b) hippocampal-striatal coupling during the episodic condition were positively related to participants' control capacity. Our findings highlight the critical role of executive functioning for the simultaneous integration of episodic information with future value computation in aging. Boosting delay gratification by including episodic tags might hence be limited in older individuals with pronounced decline in distraction control.

  8. Aldynoglia cells and modulation of RhoGTPase activity as useful tools for spinal cord injury repair

    PubMed Central

    Doncel-Pérez, Ernesto; Nieto-Sampedro, Manuel

    2016-01-01

    A combined approach in spinal cord injury (SCI) therapy is the modulation of the cellular and molecular processes involved in glial scarring. Aldaynoglial cells are neural cell precursors with a high capacity to differentiate into neurons, promote axonal growth, wrapping and myelination of resident neurons. These important characteristics of aldaynoglia can be combined with specific inhibition of the RhoGTPase activity in astroglia and microglia that cause reduction of glial proliferation, retraction of glial cell processes and myelin production by oligodendrocytes. Previously we used experimental central nervous system (CNS) injury models, like spinal cord contusion and striatal lacunar infarction and observed that administration of RhoGTPase glycolipid inhibitor or aldaynoglial cells, respectively, produced a significant gain of functional recovery in treated animals. The combined therapy with neuro-regenerative properties strategy is highly desirable to treat SCI for functional potentiation of neurons and oligodendrocytes, resulting in better locomotor recovery. Here we suggest that treatment of spinal lesions with aldaynoglia from neurospheres plus local administration of a RhoGTPase inhibitor could have an additive effect and promote recovery from SCI. PMID:27630672

  9. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

    PubMed Central

    Lipinski, Marta M.; Zheng, Bin; Lu, Tao; Yan, Zhenyu; Py, Bénédicte F.; Ng, Aylwin; Xavier, Ramnik J.; Li, Cheng; Yankner, Bruce A.; Scherzer, Clemens R.; Yuan, Junying

    2010-01-01

    Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid β peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Aβ is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death. PMID:20660724

  10. Regenerative hair waves in aging mice and extra-follicular modulators Follistatin, Dkk1 and Sfrp4

    PubMed Central

    Chen, Chih-Chiang; Murray, Philip J.; Jiang, Ting Xin; Plikus, Maksim V; Chang, Yun-Ting; Lee, Oscar K.; Widelitz, Randall B.; Chuong, Cheng Ming

    2014-01-01

    Hair cycling is modulated by factors both intrinsic and extrinsic to hair follicles. Cycling defects lead to conditions such as aging associated alopecia. Recently we demonstrated that mouse skin exhibits regenerative hair waves, reflecting a coordinated regenerative behavior in follicle populations. Here, we use this model to explore the regenerative behavior of aging mouse skin. Old mice (>18 months) tracked over several months show that with progressing age hair waves slow down, wave propagation becomes restricted, and hair cycle domains fragment into smaller domains. Transplanting aged donor mouse skin to a young host can restore donor cycling within a 3mm range of the interface, suggesting that changes are due to extra-cellular factors. Therefore, hair stem cells in aged skin can be re-activated. Molecular studies show that extra-follicular modulators Bmp2, Dkk1, and Sfrp4 increase in early anagen. Further, we identify follistatin as an extra-follicular modulator which is highly expressed in late telogen and early anagen. Indeed follistatin induces hair wave propagation and its level decreases in aging mice. We present an excitable medium model to simulate the cycling behavior in aging mice and illustrate how the inter-organ macro-environment can regulate the aging process by integrating both “activator” and “inhibitor” signals. PMID:24618599

  11. Brain functional correlates of working memory: reduced load-modulated activation and deactivation in aging without hyperactivation or functional reorganization.

    PubMed

    Kaup, Allison R; Drummond, Sean P A; Eyler, Lisa T

    2014-10-01

    We aimed to identify brain functional correlates of working memory performance in aging, in hopes of facilitating understanding of mechanisms that promote better versus worse working memory in late-life. Among 64 healthy adults, aged 23 to 78, we examined the relationship between age, working memory performance, and brain functional response during task performance. We focused on the association between working memory load-modulated functional response and individual differences in performance and whether these function-performance relationships differed with age. As expected, older age was associated with poorer working memory performance. Older age was also associated with reduced load-modulated activation including in bilateral prefrontal and parietal regions and left caudate as well as reduced deactivation including in the medial prefrontal cortex. Contrary to findings of hyperactivation in aging, we found no evidence of increased activation with older age. Positive associations identified between brain response and performance did not differ with age. Our findings suggest that the neural mechanisms underlying better versus worse working memory performance are age-invariant across adulthood, and argue against a pattern of functional reorganization in aging. Results are discussed within the broader literature, in which significant heterogeneity in findings between studies has been common.

  12. Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine

    PubMed Central

    Pin, Fabrizio; Gorini, Stefania; Pontecorvo, Laura; Ferri, Alberto; Mollace, Vincenzo; Costelli, Paola; Rosano, Giuseppe

    2016-01-01

    Abstract Background The loss of muscle mass (sarcopenia) and the associated reduced muscle strength are key limiting factors for elderly people's quality of life. Improving muscle performance does not necessarily correlate with increasing muscle mass. In fact, particularly in the elderly, the main explanation for muscle weakness is a reduction of muscle quality rather than a loss of muscle mass, and the main goal to be achieved is to increase muscle strength. The effectiveness of Trimetazidine (TMZ) in preventing muscle functional impairment during ageing was assessed in our laboratory. Methods Aged mice received TMZ or vehicle for 12 consecutive days. Muscle function was evaluated at the end of the treatment by a grip test as well as by an inverted screen test at 0, 5, 7 and 12 days of TMZ treatment. After sacrifice, muscles were stored for myofiber cross‐sectional area assessment and myosin heavy chain expression evaluation by western blotting. Results Chronic TMZ treatment does not affect the mass of both gastrocnemius and tibialis anterior muscles, while it significantly increases muscle strength. Indeed, both latency to fall and grip force are markedly enhanced in TMZ‐treated versus untreated mice. In addition, TMZ administration results in higher expression of slow myosin heavy chain isoform and increased number of small‐sized myofibers. Conclusions We report here some data showing that the modulation of skeletal muscle metabolism by TMZ increases muscle strength in aged mice. Reprogramming metabolism might therefore be a strategy worth to be further investigated in view of improving muscle performance in the elderly. PMID:27239426

  13. Krikalev during Elektron repair

    NASA Image and Video Library

    2005-05-05

    ISS011-E-05509 (5 May 2005) --- Cosmonaut Sergei K. Krikalev, Expedition 11 commander representing Russia's Federal Space Agency, uses a power tool as he makes repairs to the Elektron oxygen generator in the Zvezda Service Module of the International Space Station (ISS).

  14. Krikalev during Elektron repair

    NASA Image and Video Library

    2005-05-05

    ISS011-E-05513 (5 May 2005) --- Cosmonaut Sergei K. Krikalev, Expedition 11 commander representing Russia's Federal Space Agency, poses beside the disconnected Liquid Unit #5 (BZh-5) and the O2 end-filter (BD, secondary purification unit) from the BZh5 he removed while making repairs to the Elektron oxygen generator in the Zvezda Service Module of the international space station.

  15. Krikalev during Elektron repair

    NASA Image and Video Library

    2005-05-05

    ISS011-E-05504 (5 May 2005) --- Cosmonaut Sergei K. Krikalev, Expedition 11 commander representing Russia's Federal Space Agency, uses a video camera to document repairs to the Elektron oxygen generator in the Zvezda Service Module of the International Space Station (ISS).

  16. Krikalev during Elektron repair

    NASA Image and Video Library

    2005-05-05

    ISS011-E-05510 (5 May 2005) --- Cosmonaut Sergei K. Krikalev, Expedition 11 commander representing Russia's Federal Space Agency, uses a power tool as he makes repairs to the Elektron oxygen generator in the Zvezda Service Module of the International Space Station (ISS).

  17. Performances and failure of field-aged PV modules operating in Saharan region of Algeria

    NASA Astrophysics Data System (ADS)

    Sadok, M.; Benyoucef, B.; Othmani, M.; Mehdaoui, A.

    2016-07-01

    This article deals with behaviour of PV modules, of different technologies and manufacturers, exposed for long periods in Saharan region of Algeria. These modules are exposed in Adrar in the south-western part of Algeria. The study uses experimental I-V curves of PV modules for determining their performances. The datasheet information of modules will be useful in determination of degradation rates of the modules. Three types of modules have been tested: Photowatt (PWX 500), UDTS-50 and Isofoton (I-75 and I-100 serials). Results showed that Isofoton I-100 modules present the highest degradation rate while the lowest degradation rate was reached with I-75 serial. However, these rates tallies with other studies. The visual inspection of the modules has revealed various kinds of failures and defects responsible of performances drop (EVA browning, delamination, burn marks,…).

  18. Welding/brazing for Space Station repair

    NASA Technical Reports Server (NTRS)

    Dickinson, David W.; Babel, H. W.; Conaway, H. R.; Hooper, W. H.

    1990-01-01

    Viewgraphs on welding/brazing for space station repair are presented. Topics covered include: fabrication and repair candidates; debris penetration of module panel; welded repair patch; mechanical assembly of utility fluid line; space station utility systems; Soviet aerospace fabrication - an overview; and processes under consideration.

  19. Tendon repair

    MedlinePlus

    ... the area to see if there are any injuries to nerves and blood vessels. When the repair is complete, the wound is closed. If the tendon damage is too severe, the repair and reconstruction ... to repair part of the injury. Another surgery will be done at a later ...

  20. Repair and regeneration in endodontics.

    PubMed

    Lin, L M; Rosenberg, P A

    2011-10-01

    The ideal objective of treatment of established diseases, including irreversible pulpitis and apical periodontitis, is to achieve wound healing. Wound healing can result in repair or regeneration. The ultimate goal of wound healing is to restore the original architecture and biological function of the injured tissue or organ. Although humans are equipped with powerful innate and adaptive immune defence mechanisms, many intrinsic and extrinsic factors can affect wound healing. Complete regeneration following injury in humans can occur only in the pre-natal foetus within 24 weeks of gestation. Post-natal wounds including irreversible pulpitis or apical periodontitis always heal by repair or by a combination of repair and regeneration. Somatic cells, such as fibroblasts, macrophages, cementoblasts and osteoblasts, in the pulp and periapical tissues have limited potential for regeneration following injury and lack of telomerase. Wound healing of irreversible pulpitis and apical periodontitis requires recruitment and differentiation of progenitor/stem cells into tissue-committed somatic cells. Stem cell differentiation is regulated by intrinsic factors and extrinsic micro-environmental cues. Functionality of stem cells appears to show an age-related decline because of the change in intrinsic properties and diminished signals within the extrinsic local and systemic environment that modulate the function of stem cells or their progeny. Infection induces an immuno-inflammatory response and tissue destruction, which hinders the potential of tissue regeneration. Therefore, prevention, early detection and treatment of inflammation/infection of pulpal and periapical disease can enhance regeneration and minimize the repair of pulpal and periapical tissues after endodontic therapy. © 2011 International Endodontic Journal.

  1. Occupational Home Economics Education Series. Care and Independent Living Services for Aging. Competency Based Teaching Module.

    ERIC Educational Resources Information Center

    Wheeler-Liston, Carol; And Others

    This large training module is intended to help prepare home helpers or others who can provide direct care and can utilize resources to assist older persons. The document presents first a general discussion of the background and rationale behind a series of occupational home economics modules. In addition, the particular module on serving the aging…

  2. Occupational Home Economics Education Series. Care and Independent Living Services for Aging. Competency Based Teaching Module.

    ERIC Educational Resources Information Center

    Wheeler-Liston, Carol; And Others

    This large training module is intended to help prepare home helpers or others who can provide direct care and can utilize resources to assist older persons. The document presents first a general discussion of the background and rationale behind a series of occupational home economics modules. In addition, the particular module on serving the aging…

  3. [Congenital heart disease in adults: residua, sequelae, and complications of cardiac defects repaired at an early age].

    PubMed

    Oliver Ruiz, José María

    2003-01-01

    Nowadays, it is estimated that 85% of the infants born with congenital heart disease (CHD) will survive to adulthood, thanks mainly to surgical or therapeutic procedures performed during infancy or childhood. The clinical profile and disease pattern of adults with CHD is changing. The prevalence of certain adult CHDs, such as tetralogy of Fallot, transposition of the great arteries or univentricular heart, is rising, but these conditions have practically become new diseases as a result of therapy. Most surviving patients present residua, sequelae, or complications, which can progress during adult life. These disorders can present electrophysiological disturbances, valvular disease, persistent shunts, myocardial dysfunction, pulmonary or systemic vascular disease, problems caused by prosthetic materials, infectious complications, thromboembolic events, or extravascular disorders involving multiple organs or systems. In tetralogy of Fallot, the most striking problems that affect long-term prognosis are pulmonary valve regurgitation, right ventricle dysfunction, and atrial or ventricular arrhythmias. The main problems appearing after physiological atrial repair of transposition of the great arteries are related to right ventricular function, since it is structurally unprepared for systemic circulation, and atrial arrhythmias. Surgical repair of univentricular heart using Fontan techniques should be considered a palliative procedure that does not modify the underlying structural disorder and exposes the postoperative patient to severe complications and problems. The increase in the number of patients with CHD who will reach adulthood in the coming decades makes it necessary to carefully consider the new healthcare demands that are being generated, who should be responsible for them, and how and where solutions can be found.

  4. Comparison of functional gains after arthroscopic rotator cuff repair in patients over 70 years of age versus patients under 50 years of age: a prospective multicenter study.

    PubMed

    Moraiti, Constantina; Valle, Pablo; Maqdes, Ali; Boughebri, Omar; Dib, Chourky; Giakas, Giannis; Kany, Jean; Elkholti, Kamil; Garret, Jérôme; Katz, Denis; Leclère, Franck Marie; Valenti, Philippe

    2015-02-01

    To assess rotator cuff rupture characteristics and evaluate healing and the functional outcome after arthroscopic repair in patients older than 70 years versus patients younger than 50 years. We conducted a multicenter, prospective, comparative study of 40 patients younger than 50 years (group A) and 40 patients older than 70 years (group B) treated with arthroscopic rotator cuff repair. Patients older than 70 years were operated on only if symptoms persisted after 6 months of conservative treatment, whereas patients younger than 50 years were operated on regardless of any persistent symptoms. Imaging consisted of preoperative magnetic resonance imaging and postoperative ultrasound. Preoperative and postoperative function was evaluated with Constant and modified Constant scores. Patient satisfaction was also assessed. The evaluations were performed at least 1 year postoperatively. No patient was lost to follow-up. The incidence of both supraspinatus and infraspinatus tears was greater in group B. Greater retraction in the frontal plane and greater fatty infiltration were observed in group B. The Constant score was significantly improved in both groups (51 ± 12.32 preoperatively v 77.18 ± 11.02 postoperatively in group A and 48.8 ± 10.97 preoperatively v 74.6 ± 12.02 postoperatively in group B, P < .05). The improvement was similar in both groups. The modified Constant score was also significantly improved in both groups (57.48 ± 18.23 preoperatively v 81.35 ± 19.75 postoperatively in group A and 63.09 ± 14.96 preoperatively v 95.62 ± 17.61 postoperatively in group B, P < .05). The improvement was greater for group B (P < .05). Partial rerupture of the rotator cuff occurred in 2 cases in group A and 5 cases in group B. Complete rerupture was observed in 2 patients in group B. In group A, 29 patients (72.5%) were very satisfied, 8 (20%) were satisfied, and 3 (7.5%) were less satisfied. In group B, 33 patients (82.5%) were very satisfied, 6 (15%) were

  5. Meta-analysis on blood transcriptomic studies identifies consistently coexpressed protein–protein interaction modules as robust markers of human aging

    PubMed Central

    van den Akker, Erik B; Passtoors, Willemijn M; Jansen, Rick; van Zwet, Erik W; Goeman, Jelle J; Hulsman, Marc; Emilsson, Valur; Perola, Markus; Willemsen, Gonneke; Penninx, Brenda WJH; Heijmans, Bas T; Maier, Andrea B; Boomsma, Dorret I; Kok, Joost N; Slagboom, Pieternella E; Reinders, Marcel JT; Beekman, Marian

    2014-01-01

    The bodily decline that occurs with advancing age strongly impacts on the prospects for future health and life expectancy. Despite the profound role of age in disease etiology, knowledge about the molecular mechanisms driving the process of aging in humans is limited. Here, we used an integrative network-based approach for combining multiple large-scale expression studies in blood (2539 individuals) with protein–protein Interaction (PPI) data for the detection of consistently coexpressed PPI modules that may reflect key processes that change throughout the course of normative aging. Module detection followed by a meta-analysis on chronological age identified fifteen consistently coexpressed PPI modules associated with chronological age, including a highly significant module (P = 3.5 × 10−38) enriched for ‘T-cell activation’ marking age-associated shifts in lymphocyte blood cell counts (R2 = 0.603; P = 1.9 × 10−10). Adjusting the analysis in the compendium for the ‘T-cell activation’ module showed five consistently coexpressed PPI modules that robustly associated with chronological age and included modules enriched for ‘Translational elongation’, ‘Cytolysis’ and ‘DNA metabolic process’. In an independent study of 3535 individuals, four of five modules consistently associated with chronological age, underpinning the robustness of the approach. We found three of five modules to be significantly enriched with aging-related genes, as defined by the GenAge database, and association with prospective survival at high ages for one of the modules including ASF1A. The hereby-detected age-associated and consistently coexpressed PPI modules therefore may provide a molecular basis for future research into mechanisms underlying human aging. PMID:24119000

  6. Studies of dentate granule cell modulation: paired-pulse responses in freely moving rats at three ages.

    PubMed

    Bronzino, J D; Blaise, J H; Austin-LaFrance, R J; Morgane, P J

    1996-10-23

    Dentate granule cell population responses to paired-pulse stimulations applied to the perforant pathway across a range of interpulse intervals (IPI) were examined in freely moving rats at 15, 30, and 90 days of age. The profile of the paired-pulse index (PPI), a measure of the type and degree of modulation of dentate granule cell excitability, was shown to change significantly as a function of age.

  7. Effects of reverberation on speech recognition in stationary and modulated noise by school-aged children and young adults

    PubMed Central

    Wróblewski, Marcin; Lewis, Dawna E.; Valente, Daniel L.; Stelmachowicz, Patricia G.

    2012-01-01

    Objectives The purpose of this study was to determine how combinations of reverberation and noise, typical of many elementary school classroom environments, affect normal-hearing school-aged children’s speech recognition in stationary and amplitude-modulated noise, and to compare their performance to that of normal-hearing young adults. Additionally, the magnitude of release from masking in the modulated noise relative to stationary noise was compared across age in non-reverberant and reverberant listening conditions. Finally, for all noise and reverberation combinations the degree of change in predicted performance at 70% correct was obtained for all age groups using a best-fit cubic polynomial. Design Bamford-Kowal-Bench sentences and noise were convolved with binaural room impulse responses representing non-reverberant and reverberant environments to create test materials representative of both audiology clinics and school classroom environments. Speech recognition of 48 school-aged children and 12 adults was measured in speech-shaped and amplitude modulated speech-shaped noise, in the following three virtual listening environments: non-reverberant, reverberant at a 2 m distance, and reverberant at a 6 m distance. Results Speech recognition decreased in the reverberant conditions and with decreasing age. Release from masking in modulated relative to stationary noise decreased with age and was reduced by reverberation. In the non-reverberant condition, participants showed similar amounts of masking release across ages. The slopes of performance-intensity functions increased with age, with the exception of the non-reverberant modulated masker condition. The slopes were steeper in the stationary masker conditions, where they also decreased with reverberation and distance. In the presence of a modulated masker, the slopes did not differ between the two reverberant conditions. Conclusions The results of this study reveal systematic developmental changes in speech

  8. Modulation of gene expression as a new skin anti-aging strategy.

    PubMed

    Talbourdet, Sylvie; Sadick, Neil S; Lazou, Kristell; Bonnet-Duquennoy, Mathilde; Kurfurst, Robin; Neveu, Michele; Heusèle, Catherine; André, Patrice; Schnebert, Sylvianne; Draelos, Zoe D; Perrier, Eric

    2007-06-01

    human epidermis model showed that some genes modulated by treatment with the Malva sylvestris extract are also regulated by RA treatment indicating a similar activity at the mRNA level. In the single-center study, a facial skin care product containing the Aframomum angustifolium seed extract significantly improved the homogeneity of the skin. The areas of the detected objects (skin imperfections) decreased significantly on each studied area of the face and the variance decreased significantly over the entire face. In the 2-center study, 28% percent of the subjects reported a greater than 50% overall global improvement in their skin by the end of the study compared to 11% of the subjects after 4 weeks of treatment. Seventy-six percent of subjects said they would purchase the cream. The authors developed a low-density DNA chip method that permitted the study of the transcriptional effect of Malva Sylvestris extract and of Aframomum angustrifolium seed extract. The gene expression profiles obtained demonstrate the anti-aging properties of these compounds. An in vivo single-center study, performed and analyzed with an assay based on image processing analysis, demonstrated the antiwrinkle activity of a formulation containing the Aframomum angustifolium seed extract. The data obtained in the 2-center study suggests that the cosmeceutical containing Aframomum angustifolium seed extract produces a global rejuvenation effect in terms of redness, pigmentation, and fine lines similar to that noted utilizing an intense pulse light source.

  9. Over-the-counter anti-ageing topical agents and their ability to protect and repair photoaged skin.

    PubMed

    Bradley, Eleanor J; Griffiths, Christopher E M; Sherratt, Michael J; Bell, Mike; Watson, Rachel E B

    2015-03-01

    Ultraviolet radiation (UVR)-induced photoageing of the skin is associated with characteristic clinical features including a sallow complexion, deep, coarse wrinkles and a loss of elasticity. Remodelling of the dermal extracellular matrix (ECM) with changes to fibrillar collagens, elastic fibres and glycosaminoglycans is likely to be a major contributing factor to these particular clinical signs. Over-the-counter (OTC) topical formulations are one popular management strategy for preventing and/or repairing photoaged skin, most commonly targeting wrinkles as these are often the most concerning clinical feature. Due to the cosmetic nature of such formulations, evidence of their clinical efficacy and mechanism of action is often limited. However, these formulations usually contain putative active ingredients which individually have been subject to in vitro and in vivo investigation for efficacy as photoageing interventions. This review highlights commonly found ingredients within OTC formulations and assesses the evidence for: (i) their efficacy in clinically and histologically improving photoaged skin; (ii) the potential mechanisms of action; and (iii) their ability to act synergistically with complementary ingredients to enhance the clinical outcome.

  10. Cell senescence in the aging kidney.

    PubMed

    Yang, Haichun; Fogo, Agnes B

    2010-09-01

    Pedigree genetics and environment modulate the biological process of aging. The permanent and irreversible growth arrest of cell senescence is a central paradigm of aging. Various pathophysiologic pressures such as oxidative stress and mitochondrial injury can also induce senescence. Senescent cells secrete altered levels of growth factors, show increased susceptibility to apoptosis, and associate with delayed repair and regeneration in the aging kidney. Here we discuss new progress in understanding renal aging, focusing on mechanisms of cell senescence and possible interventions to modulate age-related organ damage.

  11. Matrix factorization reveals aging-specific co-expression gene modules in the fat and muscle tissues in nonhuman primates

    PubMed Central

    Wang, Yongcui; Zhao, Weiling; Zhou, Xiaobo

    2016-01-01

    Accurate identification of coherent transcriptional modules (subnetworks) in adipose and muscle tissues is important for revealing the related mechanisms and co-regulated pathways involved in the development of aging-related diseases. Here, we proposed a systematically computational approach, called ICEGM, to Identify the Co-Expression Gene Modules through a novel mathematical framework of Higher-Order Generalized Singular Value Decomposition (HO-GSVD). ICEGM was applied on the adipose, and heart and skeletal muscle tissues in old and young female African green vervet monkeys. The genes associated with the development of inflammation, cardiovascular and skeletal disorder diseases, and cancer were revealed by the ICEGM. Meanwhile, genes in the ICEGM modules were also enriched in the adipocytes, smooth muscle cells, cardiac myocytes, and immune cells. Comprehensive disease annotation and canonical pathway analysis indicated that immune cells, adipocytes, cardiomyocytes, and smooth muscle cells played a synergistic role in cardiac and physical functions in the aged monkeys by regulation of the biological processes associated with metabolism, inflammation, and atherosclerosis. In conclusion, the ICEGM provides an efficiently systematic framework for decoding the co-expression gene modules in multiple tissues. Analysis of genes in the ICEGM module yielded important insights on the cooperative role of multiple tissues in the development of diseases. PMID:27703186

  12. Matrix factorization reveals aging-specific co-expression gene modules in the fat and muscle tissues in nonhuman primates

    NASA Astrophysics Data System (ADS)

    Wang, Yongcui; Zhao, Weiling; Zhou, Xiaobo

    2016-10-01

    Accurate identification of coherent transcriptional modules (subnetworks) in adipose and muscle tissues is important for revealing the related mechanisms and co-regulated pathways involved in the development of aging-related diseases. Here, we proposed a systematically computational approach, called ICEGM, to Identify the Co-Expression Gene Modules through a novel mathematical framework of Higher-Order Generalized Singular Value Decomposition (HO-GSVD). ICEGM was applied on the adipose, and heart and skeletal muscle tissues in old and young female African green vervet monkeys. The genes associated with the development of inflammation, cardiovascular and skeletal disorder diseases, and cancer were revealed by the ICEGM. Meanwhile, genes in the ICEGM modules were also enriched in the adipocytes, smooth muscle cells, cardiac myocytes, and immune cells. Comprehensive disease annotation and canonical pathway analysis indicated that immune cells, adipocytes, cardiomyocytes, and smooth muscle cells played a synergistic role in cardiac and physical functions in the aged monkeys by regulation of the biological processes associated with metabolism, inflammation, and atherosclerosis. In conclusion, the ICEGM provides an efficiently systematic framework for decoding the co-expression gene modules in multiple tissues. Analysis of genes in the ICEGM module yielded important insights on the cooperative role of multiple tissues in the development of diseases.

  13. Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression

    PubMed Central

    Yabumoto, Chizuru; Akazawa, Hiroshi; Yamamoto, Rie; Yano, Masamichi; Kudo-Sakamoto, Yoko; Sumida, Tomokazu; Kamo, Takehiro; Yagi, Hiroki; Shimizu, Yu; Saga-Kamo, Akiko; Naito, Atsuhiko T.; Oka, Toru; Lee, Jong-Kook; Suzuki, Jun-ichi; Sakata, Yasushi; Uejima, Etsuko; Komuro, Issei

    2015-01-01

    Disruption of angiotensin II type 1 (AT1) receptor prolonged life span in mice. Since aging-related decline in skeletal muscle function was retarded in Atgr1a−/− mice, we examined the role of AT1 receptor in muscle regeneration after injury. Administration of AT1 receptor blocker irbesartan increased the size of regenerating myofibers, decreased fibrosis, and enhanced functional muscle recovery after cryoinjury. We recently reported that complement C1q, secreted by macrophages, activated Wnt/β-catenin signaling and promoted aging-related decline in regenerative capacity of skeletal muscle. Notably, irbesartan induced M2 polarization of macrophages, but reduced C1q expression in cryoinjured muscles and in cultured macrophage cells. Irbesartan inhibited up-regulation of Axin2, a downstream gene of Wnt/β-catenin pathway, in cryoinjured muscles. In addition, topical administration of C1q reversed beneficial effects of irbesartan on skeletal muscle regeneration after injury. These results suggest that AT1 receptor blockade improves muscle repair and regeneration through down-regulation of the aging-promoting C1q-Wnt/β-catenin signaling pathway. PMID:26571361

  14. Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice

    PubMed Central

    Cho, Si-Young; Kim, Juewon; Lee, Ji Hae; Sim, Ji Hyun; Cho, Dong-Hyun; Bae, Il-Hong; Lee, Hyunbok; Seol, Min A.; Shin, Hyun Mu; Kim, Tae-Joo; Kim, Dae-Yong; Lee, Su-Hyung; Shin, Song Seok; lm, Sin-Hyeog; Kim, Hang-Rae

    2016-01-01

    Age-associated immunological dysfunction (immunosenescence) is closely linked to perturbation of the gut microbiota. Here, we investigated whether syringaresinol (SYR), a polyphenolic lignan, modulates immune aging and the gut microbiota associated with this effect in middle-aged mice. Compared with age-matched control mice, SYR treatment delayed immunosenescence by enhancing the numbers of total CD3+ T cells and naïve T cells. SYR treatment induced the expression of Bim as well as activation of FOXO3 in Foxp3+ regulatory T cells (Tregs). Furthermore, SYR treatment significantly enhanced the Firmicutes/Bacteroidetes ratio compared with that in age-matched controls by increasing beneficial bacteria, Lactobacillus and Bifidobacterium, while reducing the opportunistic pathogenic genus, Akkermansia. In addition, SYR treatment reduced the serum level of lipopolysaccharide-binding protein, an inflammatory marker, and enhanced humoral immunity against influenza vaccination to the level of young control mice. Taken together, these findings suggest that SYR may rejuvenate the immune system through modulation of gut integrity and microbiota diversity as well as composition in middle-aged mice, which may delay the immunosenescence associated with aging. PMID:27976725

  15. Effect of ATP-dependent channel modulators on ischemia-induced arrhythmia change depending on age and gender.

    PubMed

    Bozdogan, Ömer; Kaya, Salih Tunç; Yasar, Selçuk; Orallar, Hayriye

    2013-10-01

    The number of ATP-dependent potassium channels in myocardial cells has been previously shown to change depending on gender and age. Different effects of the ATP-dependent potassium channel blocker, glybenclamide and ATP-dependent potassium channel opener, pinacidil on ischemia or reperfusion-induced arrhythmia observed in various research might depend on different ages and genders of the animals used. The aim of this study is to research the effect of ATP-dependent potassium channel modulators on ischemia-induced arrhythmia in animals of different ages and genders. Sprague-Dawley rats of different ages and genders were used in this study. Ischemia was produced by the ligation of the left coronary artery for 30 min. Electrocardiogram (ECG), blood pressure, infarct area and blood glucose were determined during the 30 min of ischemia. An arrhythmia score from an ECG recorded during 30 min of ischemia was determined by examining the duration and type of arrhythmia. Different effects of glybenclamide and pinacidil on the arrhythmias were observed in male and female young and middle-age rats. Pinacidil decreased the infarct zone in younger female rats, but differences in the type and length of ischemia-induced arrhythmias between females and males disappeared in older age. The results of this study showed that the effect of ATP-dependent potassium channel modulators on ischemia-induced arrhythmia changed due to the age and gender of rats.

  16. Language-related activations in the left prefrontal regions are differentially modulated by age, proficiency, and task demands.

    PubMed

    Tatsuno, Yoshinori; Sakai, Kuniyoshi L

    2005-02-16

    It remains to be elucidated how cortical activations are modulated by factors of age, proficiency, and language task demands when mastering first language (L1) and a second language (L2). Using functional magnetic resonance imaging, we tested subjects aged 13 (the age 13 group) and 19 (the age 19 group), thereby comparing the cortical activations involved in past-tense verb identification with those involved in verb matching. We found that the activation in the dorsal triangular part of the left inferior frontal gyrus (IFG) was lower, corresponding to a higher proficiency in English (L2) in the older subjects, suggesting that the proficiency level plays a major role in the activation of this region during L2 acquisition. Moreover, the lower activation in the triangular and orbital parts of the left IFG (F3t/F3O) for the irregular past tense corresponding to a higher proficiency in L2, together with the nonsignificant activation for the regular past tense when its performance almost reached perfection for age 19, suggests that the modulation of the left F3t/F3O activation reflects language task demands for identifying correct past-tense forms. On the other hand, the left F3t/F3O activation in Japanese (L1) for age 13 was significantly greater than that for age 19, despite the matched performances in L1. These results suggest that the left IFG subserves language-specific functions that are critically required when mastering any language.

  17. Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice.

    PubMed

    Cho, Si-Young; Kim, Juewon; Lee, Ji Hae; Sim, Ji Hyun; Cho, Dong-Hyun; Bae, Il-Hong; Lee, Hyunbok; Seol, Min A; Shin, Hyun Mu; Kim, Tae-Joo; Kim, Dae-Yong; Lee, Su-Hyung; Shin, Song Seok; Lm, Sin-Hyeog; Kim, Hang-Rae

    2016-12-15

    Age-associated immunological dysfunction (immunosenescence) is closely linked to perturbation of the gut microbiota. Here, we investigated whether syringaresinol (SYR), a polyphenolic lignan, modulates immune aging and the gut microbiota associated with this effect in middle-aged mice. Compared with age-matched control mice, SYR treatment delayed immunosenescence by enhancing the numbers of total CD3(+) T cells and naïve T cells. SYR treatment induced the expression of Bim as well as activation of FOXO3 in Foxp3(+) regulatory T cells (Tregs). Furthermore, SYR treatment significantly enhanced the Firmicutes/Bacteroidetes ratio compared with that in age-matched controls by increasing beneficial bacteria, Lactobacillus and Bifidobacterium, while reducing the opportunistic pathogenic genus, Akkermansia. In addition, SYR treatment reduced the serum level of lipopolysaccharide-binding protein, an inflammatory marker, and enhanced humoral immunity against influenza vaccination to the level of young control mice. Taken together, these findings suggest that SYR may rejuvenate the immune system through modulation of gut integrity and microbiota diversity as well as composition in middle-aged mice, which may delay the immunosenescence associated with aging.

  18. Retinoic acid modulates intrahippocampal levels of corticosterone in middle-aged mice: consequences on hippocampal plasticity and contextual memory.

    PubMed

    Bonhomme, Damien; Pallet, Véronique; Dominguez, Gaelle; Servant, Laure; Henkous, Nadia; Lafenêtre, Pauline; Higueret, Paul; Béracochéa, Daniel; Touyarot, Katia

    2014-01-01

    It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for cognitive functions in adulthood. RA hyposignaling and hyperactivity of glucocorticoid (GC) pathway appear concomitantly during aging and would contribute to the deterioration of hippocampal synaptic plasticity and functions. Furthermore, recent data have evidenced counteracting effects of retinoids on GC signaling pathway. In the present study, we addressed the following issue: whether the stimulation of RA pathway could modulate intrahippocampal corticosterone (CORT) levels in middle-aged mice and thereby impact on hippocampal plasticity and cognitive functions. We firstly investigated the effects of vitamin A supplementation and RA treatment in middle-aged mice, on contextual serial discrimination task, a paradigm which allows the detection of early signs of age-related hippocampal-dependent memory dysfunction. We then measured intrahippocampal CORT concentrations by microdialysis before and after a novelty-induced stress. Our results show that both RA treatment and vitamin A supplementation improve "episodic-like" memory in middle-aged mice but RA treatment appears to be more efficient. Moreover, we show that the beneficial effect of RA on memory is associated to an increase in hippocampal PSD-95 expression. In addition, intrahippocampal CORT levels are reduced after novelty-induced stress in RA-treated animals. This effect cannot be related to a modulation of hippocampal 11β-HSD1 expression. Interestingly, RA treatment induces a modulation of RA receptors RARα and RARβ expression in middle-aged mice, a finding which has been correlated with the amplitude of intrahippocampal CORT levels after novelty-induced stress. Taken together, our results suggest that the preventive action of RA treatment on age-related memory deficits in middle-aged mice could be, at least in part, due to an inhibitory effect of retinoids on GC activity.

  19. Retinoic acid modulates intrahippocampal levels of corticosterone in middle-aged mice: consequences on hippocampal plasticity and contextual memory

    PubMed Central

    Bonhomme, Damien; Pallet, Véronique; Dominguez, Gaelle; Servant, Laure; Henkous, Nadia; Lafenêtre, Pauline; Higueret, Paul; Béracochéa, Daniel; Touyarot, Katia

    2014-01-01

    It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for cognitive functions in adulthood. RA hyposignaling and hyperactivity of glucocorticoid (GC) pathway appear concomitantly during aging and would contribute to the deterioration of hippocampal synaptic plasticity and functions. Furthermore, recent data have evidenced counteracting effects of retinoids on GC signaling pathway. In the present study, we addressed the following issue: whether the stimulation of RA pathway could modulate intrahippocampal corticosterone (CORT) levels in middle-aged mice and thereby impact on hippocampal plasticity and cognitive functions. We firstly investigated the effects of vitamin A supplementation and RA treatment in middle-aged mice, on contextual serial discrimination task, a paradigm which allows the detection of early signs of age-related hippocampal-dependent memory dysfunction. We then measured intrahippocampal CORT concentrations by microdialysis before and after a novelty-induced stress. Our results show that both RA treatment and vitamin A supplementation improve “episodic-like” memory in middle-aged mice but RA treatment appears to be more efficient. Moreover, we show that the beneficial effect of RA on memory is associated to an increase in hippocampal PSD-95 expression. In addition, intrahippocampal CORT levels are reduced after novelty-induced stress in RA-treated animals. This effect cannot be related to a modulation of hippocampal 11β-HSD1 expression. Interestingly, RA treatment induces a modulation of RA receptors RARα and RARβ expression in middle-aged mice, a finding which has been correlated with the amplitude of intrahippocampal CORT levels after novelty-induced stress. Taken together, our results suggest that the preventive action of RA treatment on age-related memory deficits in middle-aged mice could be, at least in part, due to an inhibitory effect of retinoids on GC activity. PMID:24570662

  20. Age of acquisition modulates neural activity for both regular and irregular syntactic functions

    PubMed Central

    Hernandez, Arturo E.; Hofmann, Juliane; Kotz, Sonja A.

    2007-01-01

    Studies have found that neural activity is greater for irregular grammatical items than regular items. Findings with monolingual Spanish speakers have revealed a similar effect when making gender decisions for visually presented nouns. The current study extended previous studies by looking at the role of regularity in modulating differences in groups that differ in the age of acquisition of a language. Early and late learners of Spanish matched on measures of language proficiency were asked to make gender decisions to regular (-o for masculine and –a for feminine) and irregular items (which can end in e,l,n,r,s,t and z). Results revealed increased activity in left BA 44 for irregular compared to regular items in separate comparisons for both early and late learners. In addition, within group-comparisons revealed that neural activity for irregulars extended into left BA 47 for late learners and into left BA 6 for early learners. Direct comparisons between-groups revealed increased activity in left BA 44/45 for irregular items indicating the need for more extensive syntactic processing in late learners. The results revealed that processing of irregular grammatical gender leads to increased activity in left BA 44 and adjacent areas in the left IFG regardless of when a language is learned. Furthermore, these findings suggest differential recruitment of brain areas associated with grammatical processing in late learners. The results are discussed with regard to a model which considers L2 learning as emerging from the competitive interplay between two languages. PMID:17490895

  1. Clubfoot repair

    MedlinePlus

    ... Clubfoot release; Talipes equinovarus - repair; Tibialis anterior tendon transfer ... complete blood count and check electrolytes or clotting factors) Always tell your child's provider: What drugs your ...

  2. Soft-tissue profile growth in patients with repaired complete unilateral cleft lip and palate: A cephalometric comparison with normal controls at ages 7, 11, and 18 years.

    PubMed

    Moreira, Iris; Suri, Sunjay; Ross, Bruce; Tompson, Bryan; Fisher, David; Lou, Wendy

    2014-03-01

    In this retrospective longitudinal study, we aimed to study differences in the soft-tissue profiles in growing children with clefts in comparison with controls through the period of facial growth from 7 to 18 years. Lateral cephalometric measurements made at 7 years (T1), 11.1 years (T2), and 17.9 years (T3) of age of 70 white children (35 boys, 35 girls) with complete unilateral cleft lip and palate (UCLP) who received primary lip and palate repair surgeries at The Hospital for Sick Children, Toronto, were compared with those of a control group of similar ages, sexes, and racial backgrounds, and having skeletal Class I facial growth, selected from the Burlington Growth Study. None of the included subjects had received any surgeries other than the primary lip and palate repairs, and none had undergone nasal septum surgery or nasal molding during infancy. Between-group comparisons were made at each time point using generalized linear models adjusted for age and sex effects. Longitudinal comparisons across all time points were conducted using the mixed model approach, adjusting for these effects and their interactions with time. Bimaxillary retrognathism, progressive maxillary retrognathism, and increasing lower anterior face height with downward and backward growth rotation of the mandible in the UCLP group were seen. Unlike the hard-tissue face height ratio, their soft-tissue face height ratio was not affected. The upper lips in the UCLP group were shorter by 1.81 mm at T2 (P <0.001) and by 1.16 mm at T3 (P = 0.018), whereas their lower lips were 2.21 mm longer at T3 (P = 0.003). A reduced upper lip to lower lip length ratio at T2 and T3 (P <0.001) resulted. Their upper lips were relatively retruded by 1.44 mm at T1, 1.66 mm at T2, and 1.86 mm at T3 (all, P <0.001), and their lower lips were relatively protruded by 1.07 mm at T1 (P = 0.003), 1.40 mm at T2 (P <0.001), and 1.62 mm at T3 (P <0.001). Nose depths in the UCLP group were shallower by at least 1 mm

  3. Potential force dynamics of heart rate variability reflect cardiac autonomic modulation with respect to posture, age, and breathing pattern.

    PubMed

    Mahananto, Faizal; Igasaki, Tomohiko; Murayama, Nobuki

    2015-09-01

    Various physiological and pathological conditions are correlated with cardiac autonomic function. Heart rate variability is a marker of cardiac autonomic modulation and can be measured by several methods. However, the available methods are sensitive to breathing patterns. To quantify cardiac autonomic modulation by observing the potential force dynamics of the R-R interval time series in healthy individuals. We propose two "potentials of unbalanced complex kinetic" (PUCK) parameters to quantify the characteristics of the potential force dynamics of R-R interval time series: potential strength (slope) and fluctuation size (slope standard deviations [SSD1, SSD2]). We applied this method to the series of R-R intervals obtained from 30 healthy subjects in an experimental condition that elicited cardiac autonomic (i.e., sympathetic and vagal) activation (in supine, sitting, and standing positions). Subjects were categorized into three groups by decade (i.e., 20 s, 30 s, and 40 s) to verify the cardiac autonomic differences by age. Two respiration patterns were introduced to check the influence of the pattern into the analytical results. Sympathetic modulation activation significantly increased the slope and reduced SSD1 and SSD2; these trends were confirmed in all groups. The slope is concordant with the result of the low frequency/high frequency (LF/HF) ratio in frequency components as an indicator of sympathetic modulation. No trend was observed in slope among age groups. However, SSD1 and SSD2 in the 40 s group were significantly decreased in the supine and sitting positions. The results with respect to respiration frequency showed lower sympathetic modulation as shown in the LF/HF ratio and slope, whereas higher vagal modulation as shown in the HF appeared with a longer breathing rate. PUCK can quantify the cardiac autonomic modulation in the experimental conditions of different postures. SSD1 and SSD2 are more sensitive to age than frequency components and are

  4. DNA repair in cultured keratinocytes

    SciTech Connect

    Liu, S.C.; Parsons, S.; Hanawalt, P.C.

    1983-07-01

    Most of our understanding of DNA repair mechanisms in human cells has come from the study of these processes in cultured fibroblasts. The unique properties of keratinocytes and their pattern of terminal differentiation led us to a comparative examination of their DNA repair properties. The relative repair capabilities of the basal cells and the differentiated epidermal keratinocytes as well as possible correlations of DNA repair capacity with respect to age of the donor have been examined. In addition, since portions of human skin are chronically exposed to sunlight, the repair response to ultraviolet (UV) irradiation (254 nm) when the cells are conditioned by chronic low-level UV irradiation has been assessed. The comparative studies of DNA repair in keratinocytes from infant and aged donors have revealed no significant age-related differences for repair of UV-induced damage to DNA. Sublethal UV conditioning of cells from infant skin had no appreciable effect on either the repair or normal replication response to higher, challenge doses of UVL. However, such conditioning resulted in attenuated repair in keratinocytes from adult skin after UV doses above 25 J/m2. In addition, a surprising enhancement in replication was seen in conditioned cells from adult following challenge UV doses.

  5. The somatotropic axis may not modulate ageing and longevity in humans.

    PubMed

    Le Bourg, Éric

    2016-04-01

    Studies in nematodes and mice have shown that the somatotropic axis can modulate their longevity and it has been argued that it could also modulate human longevity. Thus, like nematodes and mice, human beings should live longer when facing starvation and genetic variation of the somatotropic axis should be linked to longevity. This article argues that, because the life-history strategies of humans are very different from those of mice, these hypotheses are not warranted.

  6. Flavonoid Chrysin prevents age-related cognitive decline via attenuation of oxidative stress and modulation of BDNF levels in aged mouse brain.

    PubMed

    Souza, Leandro Cattelan; Antunes, Michelle Silva; Filho, Carlos Borges; Del Fabbro, Lucian; de Gomes, Marcelo Gomes; Goes, André Tiago Rossito; Donato, Franciele; Prigol, Marina; Boeira, Silvana Peterini; Jesse, Cristiano R

    2015-07-01

    In this study, the effect of Chrysin (5,7-dihydroxyflavone), an important member of the flavonoid family, on memory impairment, oxidative stress and BDNF reduction generated by aging in mice were investigated. Young and aged mice were treated daily per 60days with Chrysin (1 and 10mg/kg; per oral, p.o.) or veichle (10ml/kg; p.o.). Mice were trained and tested in Morris Water Maze task. After the behavioural test, the levels of reactive species (RS), the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as the activity of Na(+), K(+)-ATPase and the levels of brain-derived neurotrophic factor (BDNF) were determined in the prefrontal cortex (PFC) and hippocampus (HC) of mice. Results demonstrated that the age-related memory decline was partially protected by Chrysin at a dose of 1mg/kg, and normalized at the dose of 10mg/kg (p<0.001). Treatment with Chrysin significantly attenuated the increase of RS levels and the inhibition of SOD, CAT and GPx activities of aged mice. Inhibition of Na(+), K(+)-ATPase activity in PFC and HP of aged mice was also attenuated by Chrysin treatment. Moreover, Chrysin marked mitigated the decrease of BDNF levels in the PFC and HC of aged mice. These results demonstrated that flavonoid Chrysin, an antioxidant compound, was able to prevent age-associated memory probably by their free radical scavenger action and modulation of BDNF production. Thus, this study indicates that Chrysin may represent a new pharmacological approach to alleviate the age-related declines during normal age, acting as an anti-aging agent.

  7. L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation.

    PubMed

    Wagner, Waldemar; Ciszewski, Wojciech M; Kania, Katarzyna D

    2015-07-25

    lower mRNA levels of monocarboxylate transporter 4. Finally, the enhancement of DNA repair and cell survival by lactate was suppressed by pharmacologically inhibiting monocarboxylate transporters using the inhibitor α-cyano-4-hydroxycinnamic acid (α-CHCA). Our data indicate that L- and D-lactate present in the uterine cervix may participate in the modulation of cellular DNA damage repair processes and in the resistance of cervical carcinoma cells to anticancer therapy.

  8. Children with repaired bilateral cleft lip/palate: effect of age at premaxillary osteotomy on facial growth.

    PubMed

    Padwa, B L; Sonis, A; Bagheri, S; Mulliken, J B

    1999-10-01

    This study compared facial growth in three groups of patients with bilateral complete cleft lip/palate: those who had (1) no premaxillary osteotomy, (2) premaxillary osteotomy before age 8 years, and (3) premaxillary osteotomy after age 8 years. Of 24 children with bilateral complete cleft lip/palate, 7 had early premaxillary osteotomy (mean age, 6.1; range, 3.7 to 7.6 years), 10 had late osteotomy (mean age, 11.2; range, 8.3 to 20.7 years), and 7 did not require premaxillary repositioning and served as controls (mean age, 12.4; range, 6.4 to 17.8 years). Presurgical and postsurgical lateral cephalograms were digitized using the Dentofacial Planner software; most current lateral cephalograms comprised the control group. Forty-one bony and 25 soft-tissue landmarks were digitized, and 8 angles were measured: SNA, (sella-nasion-A point), SNPg (sella-nasion-pogonion), ANB (A point-nasion-B point), NAPg (nasion-A point-pogonion), ST convexity (glabella-subnasale-soft-tissue pogonion), Sn-G vertical (line perpendicular to the horizontal plane dropped from glabella and distance measured from subnasale to this vertical), Cm-Sn-Ls (columella-subnasale-abial superioris), and Sn-Gn-C (subnasale-soft-tissue gnathion-chin point). Statistical difference in mean preoperative and postoperative values were measured with analysis of variance. Tests of significance were adjusted for multiple comparisons using the Bonferroni correction. Mean age at follow-up for early, late, and control groups was 11.8, 14.0, and 12.4 years, respectively. Mean follow-up for early and late groups was 5.7 and 2.8 years. There was a significant preoperative difference among the three groups for mean SNA (p < 0.01), ANB (p < 0.01), and NAPg (p < 0.01). Bonferroni analyses revealed that the early group had significantly greater SNA, ANB, and NAPg angles than the late (p < 0.01) and control groups (p < 0.05). There was a significant postoperative difference among groups for ANB (p < 0.05); Bonferroni

  9. Immunoengineering nerve repair

    PubMed Central

    Mokarram, Nassir; Dymanus, Kyle; Srinivasan, Akhil; Tipton, John; Chu, Jason; English, Arthur W.; Bellamkonda, Ravi V.

    2017-01-01

    Injuries to the peripheral nervous system are major sources of disability and often result in painful neuropathies or the impairment of muscle movement and/or normal sensations. For gaps smaller than 10 mm in rodents, nearly normal functional recovery can be achieved; for longer gaps, however, there are challenges that have remained insurmountable. The current clinical gold standard used to bridge long, nonhealing nerve gaps, the autologous nerve graft (autograft), has several drawbacks. Despite best efforts, engineering an alternative “nerve bridge” for peripheral nerve repair remains elusive; hence, there is a compelling need to design new approaches that match or exceed the performance of autografts across critically sized nerve gaps. Here an immunomodulatory approach to stimulating nerve repair in a nerve-guidance scaffold was used to explore the regenerative effect of reparative monocyte recruitment. Early modulation of the immune environment at the injury site via fractalkine delivery resulted in a dramatic increase in regeneration as evident from histological and electrophysiological analyses. This study suggests that biasing the infiltrating inflammatory/immune cellular milieu after injury toward a proregenerative population creates a permissive environment for repair. This approach is a shift from the current modes of clinical and laboratory methods for nerve repair, which potentially opens an alternative paradigm to stimulate endogenous peripheral nerve repair. PMID:28611218

  10. Adults' age-related differences in strategy perseveration are modulated by response-stimulus intervals and problem features.

    PubMed

    Lemaire, Patrick; Brun, Fleur

    2014-10-01

    Ageing results in the tendency of older adults to repeat the same strategy across consecutive problems more often than young adults, even when such strategy perseveration is not appropriate. Here, we examined how these age-related differences in strategy perseveration are modulated by response-stimulus intervals and problem characteristics. We asked participants to select the best strategy while accomplishing a computational estimation task (i.e., provide approximate sums to two-digit addition problems like 38 + 74). We found that participants repeated the same strategy across consecutive problems more often when the duration between their response and next problem display was short (300 ms) than when it was long (1300 ms). We also found more strategy perseverations in older than in young adults under short Response-Stimulus Intervals, but not under long Response-Stimulus Intervals. Finally, age-related differences in strategy perseveration decreased when problem features helped participants to select the best strategy. These modulations of age-related differences in strategy perseveration by response-stimulus intervals and characteristics of target problems are important for furthering our understanding of mechanisms underlying strategy perseveration and, more generally, ageing effects on strategy selection.

  11. Cobbler's Technique for Iridodialysis Repair

    PubMed Central

    Pandav, Surinder Singh; Gupta, Parul Chawla; Singh, Rishi Raj; Das, Kalpita; Kaushik, Sushmita; Raj, Srishti; Ram, Jagat

    2016-01-01

    We describe a novel “Cobbler's technique” for iridodialysis repair in the right eye of a patient aged 18 years, with a traumatic iridodialysis secondary to open globe injury with an iron rod. Our technique is simple with easy surgical maneuvers, that is, effective for repairing iridodialysis. The “Cobbler's technique” allows a maximally functional and cosmetic result for iridodialysis. PMID:26957855

  12. Human Apurinic/Apyrimidinic Endonuclease (APE1) Is Acetylated at DNA Damage Sites in Chromatin, and Acetylation Modulates Its DNA Repair Activity

    PubMed Central

    Roychoudhury, Shrabasti; Nath, Somsubhra; Song, Heyu; Hegde, Muralidhar L.; Bellot, Larry J.; Mantha, Anil K.; Sengupta, Shiladitya; Ray, Sutapa; Natarajan, Amarnath

    2016-01-01

    ABSTRACT Apurinic/apyrimidinic (AP) sites, the most frequently formed DNA lesions in the genome, inhibit transcription and block replication. The primary enzyme that repairs AP sites in mammalian cells is the AP endonuclease (APE1), which functions through the base excision repair (BER) pathway. Although the mechanism by which APE1 repairs AP sites in vitro has been extensively investigated, it is largely unknown how APE1 repairs AP sites in cells. Here, we show that APE1 is acetylated (AcAPE1) after binding to the AP sites in chromatin and that AcAPE1 is exclusively present on chromatin throughout the cell cycle. Positive charges of acetylable lysine residues in the N-terminal domain of APE1 are essential for chromatin association. Acetylation-mediated neutralization of the positive charges of the lysine residues in the N-terminal domain of APE1 induces a conformational change; this in turn enhances the AP endonuclease activity of APE1. In the absence of APE1 acetylation, cells accumulated AP sites in the genome and showed higher sensitivity to DNA-damaging agents. Thus, mammalian cells, unlike Saccharomyces cerevisiae or Escherichia coli cells, require acetylation of APE1 for the efficient repair of AP sites and base damage in the genome. Our study reveals that APE1 acetylation is an integral part of the BER pathway for maintaining genomic integrity. PMID:27994014

  13. Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

    PubMed Central

    Lunetta, Kathryn L.; Pervjakova, Natalia; Chasman, Daniel I.; Stolk, Lisette; Finucane, Hilary K.; Sulem, Patrick; Bulik-Sullivan, Brendan; Esko, Tõnu; Johnson, Andrew D.; Elks, Cathy E.; Franceschini, Nora; He, Chunyan; Altmaier, Elisabeth; Brody, Jennifer A.; Franke, Lude L.; Huffman, Jennifer E.; Keller, Margaux F.; McArdle, Patrick F.; Nutile, Teresa; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Smith, Jennifer A.; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke-Jan; Mangino, Massimo; Smith, Albert V.; Tanaka, Toshiko; Abecasis, Goncalo; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Arndt, Volker; Arnold, Alice M.; Barbieri, Caterina; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bernstein, Leslie; Bielinski, Suzette J.; Blomqvist, Carl; Boerwinkle, Eric; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne-Lise; Boutin, Thibaud S; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Campbell, Archie; Campbell, Harry; Chanock, Stephen J.; Chapman, J. Ross; Chen, Yii-Der Ida; Chenevix-Trench, Georgia; Couch, Fergus J.; Coviello, Andrea D.; Cox, Angela; Czene, Kamila; Darabi, Hatef; De Vivo, Immaculata; Demerath, Ellen W.; Dennis, Joe; Devilee, Peter; Dörk, Thilo; dos-Santos-Silva, Isabel; Dunning, Alison M.; Eicher, John D.; Fasching, Peter A.; Faul, Jessica D.; Figueroa, Jonine; Flesch-Janys, Dieter; Gandin, Ilaria; Garcia, Melissa E.; García-Closas, Montserrat; Giles, Graham G.; Girotto, Giorgia G.; Goldberg, Mark S.; González-Neira, Anna; Goodarzi, Mark O.; Grove, Megan L.; Gudbjartsson, Daniel F.; Guénel, Pascal; Guo, Xiuqing; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Henderson, Brian E.; Hocking, Lynne J.; Hofman, Albert; Homuth, Georg; Hooning, Maartje J.; Hopper, John L.; Hu, Frank B.; Huang, Jinyan; Humphreys, Keith; Hunter, David J.; Jakubowska, Anna; Jones, Samuel E.; Kabisch, Maria; Karasik, David; Knight, Julia A.; Kolcic, Ivana; Kooperberg, Charles; Kosma, Veli-Matti; Kriebel, Jennifer; Kristensen, Vessela; Lambrechts, Diether; Langenberg, Claudia; Li, Jingmei; Li, Xin; Lindström, Sara; Liu, Yongmei; Luan, Jian’an; Lubinski, Jan; Mägi, Reedik; Mannermaa, Arto; Manz, Judith; Margolin, Sara; Marten, Jonathan; Martin, Nicholas G.; Masciullo, Corrado; Meindl, Alfons; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L.; Müller-Nurasyid, Martina; Nalls, Michael; Neale, Ben M.; Nevanlinna, Heli; Neven, Patrick; Newman, Anne B.; Nordestgaard, Børge G.; Olson, Janet E.; Padmanabhan, Sandosh; Peterlongo, Paolo; Peters, Ulrike; Petersmann, Astrid; Peto, Julian; Pharoah, Paul D.P.; Pirastu, Nicola N.; Pirie, Ailith; Pistis, Giorgio; Polasek, Ozren; Porteous, David; Psaty, Bruce M.; Pylkäs, Katri; Radice, Paolo; Raffel, Leslie J.; Rivadeneira, Fernando; Rudan, Igor; Rudolph, Anja; Ruggiero, Daniela; Sala, Cinzia F.; Sanna, Serena; Sawyer, Elinor J.; Schlessinger, David; Schmidt, Marjanka K.; Schmidt, Frank; Schmutzler, Rita K.; Schoemaker, Minouk J.; Scott, Robert A.; Seynaeve, Caroline M.; Simard, Jacques; Sorice, Rossella; Southey, Melissa C.; Stöckl, Doris; Strauch, Konstantin; Swerdlow, Anthony; Taylor, Kent D.; Thorsteinsdottir, Unnur; Toland, Amanda E.; Tomlinson, Ian; Truong, Thérèse; Tryggvadottir, Laufey; Turner, Stephen T.; Vozzi, Diego; Wang, Qin; Wellons, Melissa; Willemsen, Gonneke; Wilson, James F.; Winqvist, Robert; Wolffenbuttel, Bruce B.H.R.; Wright, Alan F.; Yannoukakos, Drakoulis; Zemunik, Tatijana; Zheng, Wei; Zygmunt, Marek; Bergmann, Sven; Boomsma, Dorret I.; Buring, Julie E.; Ferrucci, Luigi; Montgomery, Grant W.; Gudnason, Vilmundur; Spector, Tim D.; van Duijn, Cornelia M; Alizadeh, Behrooz Z.; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F.; Gasparini, Paolo P.; Gieger, Christian; Harris, Tamara B.; Hayward, Caroline; Kardia, Sharon L.R.; Kraft, Peter; McKnight, Barbara; Metspalu, Andres; Morrison, Alanna C.; Reiner, Alex P.; Ridker, Paul M.; Rotter, Jerome I.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Weir, David R.; Yerges-Armstrong, Laura M.; Price, Alkes L.; Stefansson, Kari; Visser, Jenny A.; Ong, Ken K.; Chang-Claude, Jenny; Murabito, Joanne M.; Perry, John R.B.; Murray, Anna

    2015-01-01

    Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms. PMID:26414677

  14. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

    PubMed

    Day, Felix R; Ruth, Katherine S; Thompson, Deborah J; Lunetta, Kathryn L; Pervjakova, Natalia; Chasman, Daniel I; Stolk, Lisette; Finucane, Hilary K; Sulem, Patrick; Bulik-Sullivan, Brendan; Esko, Tõnu; Johnson, Andrew D; Elks, Cathy E; Franceschini, Nora; He, Chunyan; Altmaier, Elisabeth; Brody, Jennifer A; Franke, Lude L; Huffman, Jennifer E; Keller, Margaux F; McArdle, Patrick F; Nutile, Teresa; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M; Schick, Ursula M; Smith, Jennifer A; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke-Jan; Mangino, Massimo; Smith, Albert V; Tanaka, Toshiko; Abecasis, Gonçalo R; Andrulis, Irene L; Anton-Culver, Hoda; Antoniou, Antonis C; Arndt, Volker; Arnold, Alice M; Barbieri, Caterina; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bernstein, Leslie; Bielinski, Suzette J; Blomqvist, Carl; Boerwinkle, Eric; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Borresen-Dale, Anne-Lise; Boutin, Thibaud S; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Campbell, Archie; Campbell, Harry; Chanock, Stephen J; Chapman, J Ross; Chen, Yii-Der Ida; Chenevix-Trench, Georgia; Couch, Fergus J; Coviello, Andrea D; Cox, Angela; Czene, Kamila; Darabi, Hatef; De Vivo, Immaculata; Demerath, Ellen W; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M; Eicher, John D; Fasching, Peter A; Faul, Jessica D; Figueroa, Jonine; Flesch-Janys, Dieter; Gandin, Ilaria; Garcia, Melissa E; García-Closas, Montserrat; Giles, Graham G; Girotto, Giorgia G; Goldberg, Mark S; González-Neira, Anna; Goodarzi, Mark O; Grove, Megan L; Gudbjartsson, Daniel F; Guénel, Pascal; Guo, Xiuqing; Haiman, Christopher A; Hall, Per; Hamann, Ute; Henderson, Brian E; Hocking, Lynne J; Hofman, Albert; Homuth, Georg; Hooning, Maartje J; Hopper, John L; Hu, Frank B; Huang, Jinyan; Humphreys, Keith; Hunter, David J; Jakubowska, Anna; Jones, Samuel E; Kabisch, Maria; Karasik, David; Knight, Julia A; Kolcic, Ivana; Kooperberg, Charles; Kosma, Veli-Matti; Kriebel, Jennifer; Kristensen, Vessela; Lambrechts, Diether; Langenberg, Claudia; Li, Jingmei; Li, Xin; Lindström, Sara; Liu, Yongmei; Luan, Jian'an; Lubinski, Jan; Mägi, Reedik; Mannermaa, Arto; Manz, Judith; Margolin, Sara; Marten, Jonathan; Martin, Nicholas G; Masciullo, Corrado; Meindl, Alfons; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L; Müller-Nurasyid, Martina; Nalls, Michael; Neale, Benjamin M; Nevanlinna, Heli; Neven, Patrick; Newman, Anne B; Nordestgaard, Børge G; Olson, Janet E; Padmanabhan, Sandosh; Peterlongo, Paolo; Peters, Ulrike; Petersmann, Astrid; Peto, Julian; Pharoah, Paul D P; Pirastu, Nicola N; Pirie, Ailith; Pistis, Giorgio; Polasek, Ozren; Porteous, David; Psaty, Bruce M; Pylkäs, Katri; Radice, Paolo; Raffel, Leslie J; Rivadeneira, Fernando; Rudan, Igor; Rudolph, Anja; Ruggiero, Daniela; Sala, Cinzia F; Sanna, Serena; Sawyer, Elinor J; Schlessinger, David; Schmidt, Marjanka K; Schmidt, Frank; Schmutzler, Rita K; Schoemaker, Minouk J; Scott, Robert A; Seynaeve, Caroline M; Simard, Jacques; Sorice, Rossella; Southey, Melissa C; Stöckl, Doris; Strauch, Konstantin; Swerdlow, Anthony; Taylor, Kent D; Thorsteinsdottir, Unnur; Toland, Amanda E; Tomlinson, Ian; Truong, Thérèse; Tryggvadottir, Laufey; Turner, Stephen T; Vozzi, Diego; Wang, Qin; Wellons, Melissa; Willemsen, Gonneke; Wilson, James F; Winqvist, Robert; Wolffenbuttel, Bruce B H R; Wright, Alan F; Yannoukakos, Drakoulis; Zemunik, Tatijana; Zheng, Wei; Zygmunt, Marek; Bergmann, Sven; Boomsma, Dorret I; Buring, Julie E; Ferrucci, Luigi; Montgomery, Grant W; Gudnason, Vilmundur; Spector, Tim D; van Duijn, Cornelia M; Alizadeh, Behrooz Z; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F; Gasparini, Paolo P; Gieger, Christian; Harris, Tamara B; Hayward, Caroline; Kardia, Sharon L R; Kraft, Peter; McKnight, Barbara; Metspalu, Andres; Morrison, Alanna C; Reiner, Alex P; Ridker, Paul M; Rotter, Jerome I; Toniolo, Daniela; Uitterlinden, André G; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J; Weir, David R; Yerges-Armstrong, Laura M; Price, Alkes L; Stefansson, Kari; Visser, Jenny A; Ong, Ken K; Chang-Claude, Jenny; Murabito, Joanne M; Perry, John R B; Murray, Anna

    2015-11-01

    Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

  15. ATP binding and hydrolysis by Saccharomyces cerevisiae Msh2-Msh3 are differentially modulated by mismatch and double-strand break repair DNA substrates.

    PubMed

    Kumar, Charanya; Eichmiller, Robin; Wang, Bangchen; Williams, Gregory M; Bianco, Piero R; Surtees, Jennifer A

    2014-06-01

    In Saccharomyces cerevisiae, Msh2-Msh3-mediated mismatch repair (MMR) recognizes and targets insertion/deletion loops for repair. Msh2-Msh3 is also required for 3' non-homologous tail removal (3'NHTR) in double-strand break repair. In both pathways, Msh2-Msh3 binds double-strand/single-strand junctions and initiates repair in an ATP-dependent manner. However, we recently demonstrated that the two pathways have distinct requirements with respect to Msh2-Msh3 activities. We identified a set of aromatic residues in the nucleotide binding pocket (FLY motif) of Msh3 that, when mutated, disrupted MMR, but left 3'NHTR largely intact. One of these mutations, msh3Y942A, was predicted to disrupt the nucleotide sandwich and allow altered positioning of ATP within the pocket. To develop a mechanistic understanding of the differential requirements for ATP binding and/or hydrolysis in the two pathways, we characterized Msh2-Msh3 and Msh2-msh3Y942A ATP binding and hydrolysis activities in the presence of MMR and 3'NHTR DNA substrates. We observed distinct, substrate-dependent ATP hydrolysis and nucleotide turnover by Msh2-Msh3, indicating that the MMR and 3'NHTR DNA substrates differentially modify the ATP binding/hydrolysis activities of Msh2-Msh3. Msh2-msh3Y942A retained the ability to bind DNA and ATP but exhibited altered ATP hydrolysis and nucleotide turnover. We propose that both ATP and structure-specific repair substrates cooperate to direct Msh2-Msh3-mediated repair and suggest an explanation for the msh3Y942A separation-of-function phenotype.

  16. ATP binding and hydrolysis by Saccharomyces cerevisiae Msh2-Msh3 are differentially modulated by Mismatch and Double-strand Break Repair DNA substrates

    PubMed Central

    Kumar, Charanya; Eichmiller, Robin; Wang, Bangchen; Williams, Gregory M.; Bianco, Piero R.; Surtees, Jennifer A.

    2014-01-01

    In Saccharomyces cerevisiae, Msh2-Msh3-mediated mismatch repair (MMR) recognizes and targets insertion/deletion loops for repair. Msh2-Msh3 is also required for 3′ non-homologous tail removal (3′NHTR) in double-strand break repair. In both pathways, Msh2-Msh3 binds double-strand/single-strand junctions and initiates repair in an ATP-dependent manner. However, we recently demonstrated that the two pathways have distinct requirements with respect to Msh2-Msh3 activities. We identified a set of aromatic residues in the nucleotide binding pocket (FLY motif) of Msh3 that, when mutated, disrupted MMR, but left 3′ NHTR largely intact. One of these mutations, msh3Y942A, was predicted to disrupt the nucleotide sandwich and allow altered positioning of ATP within the pocket. To develop a mechanistic understanding of the differential requirements for ATP binding and/or hydrolysis in the two pathways, we characterized Msh2-Msh3 and Msh2-msh3Y942A ATP binding and hydrolysis activities in the presence of MMR and 3′ NHTR DNA substrates. We observed distinct, substrate-dependent ATP hydrolysis and nucleotide turnover by Msh2-Msh3, indicating that the MMR and 3′ NHTR DNA substrates differentially modify the ATP binding/hydrolysis activities of Msh2-Msh3. Msh2-msh3Y942A retained the ability to bind DNA and ATP but exhibited altered ATP hydrolysis and nucleotide turnover. We propose that both ATP and structure-specific repair substrates cooperate to direct Msh2-Msh3-mediated repair and suggest an explanation for the msh3Y942A separation-of-function phenotype. PMID:24746922

  17. A relationship to survival is seen by combining the factors of mismatch repair status, tumor location and age of onset in colorectal cancer patients.

    PubMed

    Li, Pan; Xiao, Zhitao; Braciak, Todd A; Ou, Qingjian; Chen, Gong; Oduncu, Fuat S

    2017-01-01

    The progression of colorectal cancer (CRC) may differ depending on the location of the tumor and the age of onset of the disease. Previous studies also suggested that the molecular basis of CRC varies with tumor location, which could affect the clinical management of patients. Therefore, we performed survival analysis looking at different age groups and mismatch repair status (MMR) of CRC patients according to primary tumor location in an attempt to identify subgroups of CRC that might help in the prognosis of disease. A group of 2233 patients operated on to remove their CRC tumors were analyzed (521 with right colon cancer, 740 with left colon cancer and 972 with rectal cancer). The expression of four MMR genes was assessed by immunohistochemistry (IHC), independent of clinical criteria. From the data collected, a predictive model for overall survival (OS) could be constructed for some associations of tumor location and age of onset using Kaplan-Meier, logistic and Cox regression analysis. When tumor location was considered as the lone factor, we found no statistical difference in overall survival (OS) between right cancer (68%), left cancer (67%) or rectal cancer tumor locations (71%) (HR: 1.17, 95%CI (confidence interval): 0.97-1.43, P = 0.057). When age of onset was considered, middle age (40-59 years) and older (60-85 years) patients were found to have higher OS than younger onset cancer (20-39 years) patients (69% vs 71% vs 59%, HR: 1.07, 95% confidence interval (CI): 0.91-1.25, P = 0.008). When both age of onset and tumor location were considered in combination as disease factors, we found that the subgroup of patients with left colon cancer from middle age (69%) and older (67%) aged patients had higher OS than younger (54%) patients (HR: 0.89, 95%CI: 0.68-1.16, P = 0.048). However in patients with right colon cancers, we found no statistical difference is OS between younger, middle age or older grouped patients (60% vs 71% vs 67%, HR: 0.84, 95% CI: 0

  18. A relationship to survival is seen by combining the factors of mismatch repair status, tumor location and age of onset in colorectal cancer patients

    PubMed Central

    Li, Pan; Xiao, Zhitao; Braciak, Todd A.; Ou, Qingjian; Chen, Gong; Oduncu, Fuat S.

    2017-01-01

    Background The progression of colorectal cancer (CRC) may differ depending on the location of the tumor and the age of onset of the disease. Previous studies also suggested that the molecular basis of CRC varies with tumor location, which could affect the clinical management of patients. Therefore, we performed survival analysis looking at different age groups and mismatch repair status (MMR) of CRC patients according to primary tumor location in an attempt to identify subgroups of CRC that might help in the prognosis of disease. Methods A group of 2233 patients operated on to remove their CRC tumors were analyzed (521 with right colon cancer, 740 with left colon cancer and 972 with rectal cancer). The expression of four MMR genes was assessed by immunohistochemistry (IHC), independent of clinical criteria. From the data collected, a predictive model for overall survival (OS) could be constructed for some associations of tumor location and age of onset using Kaplan-Meier, logistic and Cox regression analysis. Results When tumor location was considered as the lone factor, we found no statistical difference in overall survival (OS) between right cancer (68%), left cancer (67%) or rectal cancer tumor locations (71%) (HR: 1.17, 95%CI (confidence interval): 0.97–1.43, P = 0.057). When age of onset was considered, middle age (40–59 years) and older (60–85 years) patients were found to have higher OS than younger onset cancer (20–39 years) patients (69% vs 71% vs 59%, HR: 1.07, 95% confidence interval (CI): 0.91–1.25, P = 0.008). When both age of onset and tumor location were considered in combination as disease factors, we found that the subgroup of patients with left colon cancer from middle age (69%) and older (67%) aged patients had higher OS than younger (54%) patients (HR: 0.89, 95%CI: 0.68–1.16, P = 0.048). However in patients with right colon cancers, we found no statistical difference is OS between younger, middle age or older grouped patients (60% vs

  19. Spirulina Protects against Hepatic Inflammation in Aging: An Effect Related to the Modulation of the Gut Microbiota?

    PubMed Central

    Neyrinck, Audrey M.; Taminiau, Bernard; Walgrave, Hannah; Daube, Georges; Cani, Patrice D.; Bindels, Laure B.; Delzenne, Nathalie M.

    2017-01-01

    Aging predisposes to hepatic dysfunction and inflammation that can contribute to the development of non-alcoholic fatty liver disease. Spirulina, a cyanobacterium used as a food additive or food supplement, has been shown to impact immune function. We have tested the potential hepatoprotective effect of a Spirulina in aged mice and to determine whether these effects can be related to a modulation of the gut microbiota. Old mice have been fed a standard diet supplemented with or without 5% Spirulina for six weeks. Among several changes of gut microbiota composition, an increase in Roseburia and Lactobacillus proportions occurs upon Spirulina treatment. Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice. Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice. We conclude that the oral administration of a Spirulina is able to modulate the gut microbiota and to activate the immune system in the gut, a mechanism that may be involved in the improvement of the hepatic inflammation in aged mice. Those data open the way to new therapeutic tools in the management of immune alterations in aging, based on gut microbe-host interactions. PMID:28632181

  20. Age-related disruption of autophagy in dermal fibroblasts modulates extracellular matrix components

    SciTech Connect

    Tashiro, Kanae; Shishido, Mayumi; Fujimoto, Keiko; Hirota, Yuko; Yo, Kazuyuki; Gomi, Takamasa; Tanaka, Yoshitaka

    2014-01-03

    Highlights: •Autophagosomes accumulate in aged dermal fibroblasts. •Autophagic degradation is impaired in aged dermal fibroblasts. •Autophagy disruption affects extracellular matrix components in dermal fibroblasts. -- Abstract: Autophagy is an intracellular degradative system that is believed to be involved in the aging process. The contribution of autophagy to age-related changes in the human skin is unclear. In this study, we examined the relationship between autophagy and skin aging. Transmission electron microscopy and immunofluorescence microscopy analyses of skin tissue and cultured dermal fibroblasts derived from women of different ages revealed an increase in the number of nascent double-membrane autophagosomes with age. Western blot analysis showed that the amount of LC3-II, a form associated with autophagic vacuolar membranes, was significantly increased in aged dermal fibroblasts compared with that in young dermal fibroblasts. Aged dermal fibroblasts were minimally affected by inhibition of autophagic activity. Although lipofuscin autofluorescence was elevated in aged dermal fibroblasts, the expression of Beclin-1 and Atg5—genes essential for autophagosome formation—was similar between young and aged dermal fibroblasts, suggesting that the increase of autophagosomes in aged dermal fibroblasts was due to impaired autophagic flux rather than an increase in autophagosome formation. Treatment of young dermal fibroblasts with lysosomal protease inhibitors, which mimic the condition of aged dermal fibroblasts with reduced autophagic activity, altered the fibroblast content of type I procollagen, hyaluronan and elastin, and caused a breakdown of collagen fibrils. Collectively, these findings suggest that the autophagy pathway is impaired in aged dermal fibroblasts, which leads to deterioration of dermal integrity and skin fragility.

  1. Aneurysm Repair

    MedlinePlus

    ... repair of abdominal aortic aneurysms Cardiologists at the Texas Heart Institute were among the first to use ... comments. Terms of Use and Privacy Policy © Copyright Texas Heart Institute All rights reserved.

  2. Nitric oxide production by peritoneal macrophages from aged rats: A short term and direct modulation by citrulline.

    PubMed

    Breuillard, Charlotte; Curis, Emmanuel; Le Plénier, Servane; Cynober, Luc; Moinard, Christophe

    2017-02-01

    Citrulline has anti-inflammatory properties and exerts beneficial effects on various impaired functions in aging. However, there are few data on citrulline action on immune function in aged populations. The objective of the study was to evaluate citrulline ability, after in vivo and in vitro administration, to modulate macrophage functions in aged rats and the possible pathways involved. Twenty-one-month-old Sprague-Dawley rats (n = 27) received a citrulline supplementation at 5 g/kg/d for 5 days, or an isonitrogenous diet, and peritoneal macrophages were cultured with or without LPS. In the in vitro study, macrophages from 22-month-old rats (n = 16) were cultured with or without LPS, citrulline and inhibitors of different inflammatory pathways (n = 8/conditions). Nitric oxide (NO) and tumor necrosis factor α (TNFα) production were measured in both in vivo and in vitro studies. Citrulline decreased NO production variability by peritoneal macrophages after in vivo administration (p = 0.0034) and downregulated NO production by 22% after in vitro administration (95% CI: [6%; 35%]; p = 0.0394), without any direct effect on TNFα production. None of the transductional pathways explored seem to be involved. Citrulline slightly modulates NO production in vivo and in vitro, suggesting a possible action through modulation of arginine metabolism in macrophages rather than a direct transductional effect. The pleiotropic effects of citrulline in aging could be due, at least in part, to the anti-inflammatory effect of citrulline. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  3. Biology of frailty: Modulation of ageing genes and its importance to prevent age-associated loss of function.