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  1. 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.

  2. 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

  3. BAC Transgenic Mice Expressing a Truncated Mutant Parkin Exhibit Age-dependent Hypokinetic Motor Deficits, Dopaminergic Neuron Degeneration, and Accumulation of Proteinase K-Resistant Alpha-Synuclein

    PubMed Central

    Lu, Xiao-Hong; Fleming, Sheila M.; Meurers, Bernhard; Ackerson, Larry C.; Mortazavi, Farzad; Lo, Victor; Hernandez, Daniela; Sulzer, David; Jackson, George R.; Maidment, Nigel T.; Chesselet, Marie-Francoise; Yang, X. William

    2009-01-01

    Summary Recessive mutations in parkin are the most common cause of familial early onset Parkinson's disease (PD). Recent studies suggest that certain parkin mutants may exert dominant toxic effects to cultured cells and such dominant toxicity can lead to progressive dopaminergic (DA) neuron degeneration in Drosophila. To explore whether mutant parkin could exert similar pathogenic effects to mammalian DA neurons in vivo, we developed a Bacterial Artificial Chromosome (BAC) transgenic mouse model expressing a C-terminal truncated human mutant parkin (Parkin-Q311X) in DA neurons driven by a dopamine transporter promoter. Parkin-Q311X mice exhibit multiple late-onset and progressive hypokinetic motor deficits. Stereological analyses reveal that the mutant mice develop age-dependent DA neuron degeneration in substantia nigra accompanied by a significant loss of DA neuron terminals in the striatum. Neurochemical analyses reveal a significant reduction of the striatal dopamine level in mutant mice, which is significantly correlated with their hypokinetic motor deficits. Finally, mutant Parkin-Q311X mice, but not wild-type controls, exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in substantia nigra and co-localized with 3-nitrotyrosine, a marker for oxidative protein damage. Hence, our study provides the first mammalian genetic evidence that dominant toxicity of a parkin mutant is sufficient to elicit age-dependent hypokinetic motor deficits and DA neuron loss in vivo, and uncovers a causal relationship between dominant parkin toxicity and progressive α-synuclein accumulation in DA neurons. Our study underscores the need to further explore the putative link between parkin dominant toxicity and PD. PMID:19228951

  4. Resilience in Aging Mice.

    PubMed

    Kirkland, James L; Stout, Michael B; Sierra, Felipe

    2016-11-01

    Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context

  5. Artificially reared mice exhibit anxiety-like behavior in adulthood

    PubMed Central

    Yasuda, Hidemi; Harauma, Akiko; Kato, Maki; Ootomo, Yuki; Hatanaka, Erisa; Moriguchi, Toru

    2016-01-01

    It is important to establish experimental animal techniques that are applicable to the newborn and infant phases for nutrition and pharmacological studies. Breeding technology using the artificial suckling method without breast milk is very effective for the study of newborn nutrition. Using this method, we separated newborn mice from dams within 48 h of birth and provided them with artificial milk. We evaluated mouse anxiety levels after early postnatal maternal separation. Artificially reared mice were subjected to elevated plus-maze tests to assess emotional behavior at 9 weeks of age. Artificially reared mice showed a significantly lower frequency of entries and dipping into the open arms of the maze compared with dam-reared mice. This result indicates that the anxiety level of artificially reared mice was higher than that of dam-reared mice. Moreover, the concentration of monoamines in the brain was determined after the behavioral experiment. The hippocampal norepinephrine, serotonin, and 5-hydroxyindoleacetic acid levels in the artificially reared mice were significantly higher than those of the dam-reared mice. These results suggest that maternal-offspring interactions are extremely important for the emotional development of newborn infants during the lactation period. In future studies, it is necessary to consider the environmental factors and conditions that minimize the influence of artificial rearing on emotional behavior. PMID:26948536

  6. Practical pathology of aging mice

    PubMed Central

    Pettan-Brewer, Christina; Treuting, Piper M.

    2011-01-01

    Old mice will have a subset of lesions as part of the progressive decline in organ function that defines aging. External and palpable lesions will be noted by the research, husbandry, or veterinary staff during testing, cage changing, or physical exams. While these readily observable lesions may cause alarm, not all cause undue distress or are life-threatening. In aging research, mice are maintained until near end of life that, depending on strain and genetic manipulation, can be upwards of 33 months. Aging research has unique welfare issues related to age-related decline, debilitation, fragility, and associated pain of chronic diseases. An effective aging research program includes the collaboration and education of the research, husbandry, and veterinary staff, and of the members of the institution animal care and use committee. This collaborative effort is critical to humanely maintaining older mice and preventing excessive censorship due to non-lethal diseases. Part of the educational process is becoming familiar with how old mice appear clinically, at necropsy and histopathologically. This baseline knowledge is important in making the determination of humane end points, defining health span, contributing causes of death and effects of interventions. The goal of this paper is to introduce investigators to age-associated diseases and lesion patterns in mice from clinical presentation to pathologic assessment. To do so, we present and illustrate the common clinical appearances, necropsy and histopathological lesions seen in subsets of the aging colonies maintained at the University of Washington. PMID:22953032

  7. Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior.

    PubMed

    Fentress, H M; Klar, R; Krueger, J J; Sabb, T; Redmon, S N; Wallace, N M; Shirey-Rice, J K; Hahn, M K

    2013-11-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET(+/-) ), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET(+/-) mouse establishes an activated state of existing surface NET proteins. The NET(+/-) mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET(+/-) mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET(+/-) mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders.

  8. Norepinephrine Transporter Heterozygous Knockout Mice Exhibit Altered Transport and Behavior

    PubMed Central

    Fentress, HM; Klar, R; Krueger, JK; Sabb, T; Redmon, SN; Wallace, NM; Shirey-Rice, JK; Hahn, MK

    2013-01-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically-driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an ~50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity, assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing, surface NET proteins. NET+/− mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris Water Maze. These data suggest recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  9. Electroencephalographic changes with age in male mice.

    PubMed

    Eleftheriou, B E; Zolovick, A J; Elias, M F

    1975-01-01

    Electroencephalographic (EEG) changes, as measured by the awake state, slow-wave sleep (SWS), rapid-eye movement (REM) patterns and ratio of REM/total sleep, were recorded in aging male mice of DBA/2J and C57BL/6J strains. Results indicate that there is a significant increase in the awake state accompanied by significant decrease in SWS with advancing age for both strains, although these changes appear more pronounced in DBA/2J mice than C57BL/6J mice. Of considerable significance is the finding that REM sleep is absent in mice of DBA/2J strain at 23.5 months of age. Based on these findings, the conclusion was reached that strain DBA/2J ages significantly faster than C57BL/6J. The difference in aging between the two strains emphasizes the need for additional studies dealing with genetic aspects of aging.

  10. Laminin α4 Deficient Mice Exhibit Decreased Capacity for Adipose Tissue Expansion and Weight Gain

    PubMed Central

    Movérare-Skrtic, Sofia; Kortesmaa, Jarkko; Soininen, Raija; Bergström, Göran; Ohlsson, Claes; Chong, Li Yen; Rozell, Björn; Emont, Margo; Cohen, Ronald N.; Brey, Eric M.; Tryggvason, Karl

    2014-01-01

    Obesity is a global epidemic that contributes to the increasing medical burdens related to type 2 diabetes, cardiovascular disease and cancer. A better understanding of the mechanisms regulating adipose tissue expansion could lead to therapeutics that eliminate or reduce obesity-associated morbidity and mortality. The extracellular matrix (ECM) has been shown to regulate the development and function of numerous tissues and organs. However, there is little understanding of its function in adipose tissue. In this manuscript we describe the role of laminin α4, a specialized ECM protein surrounding adipocytes, on weight gain and adipose tissue function. Adipose tissue accumulation, lipogenesis, and structure were examined in mice with a null mutation of the laminin α4 gene (Lama4−/−) and compared to wild-type (Lama4+/+) control animals. Lama4−/− mice exhibited reduced weight gain in response to both age and high fat diet. Interestingly, the mice had decreased adipose tissue mass and altered lipogenesis in a depot-specific manner. In particular, epididymal adipose tissue mass was specifically decreased in knock-out mice, and there was also a defect in lipogenesis in this depot as well. In contrast, no such differences were observed in subcutaneous adipose tissue at 14 weeks. The results suggest that laminin α4 influences adipose tissue structure and function in a depot-specific manner. Alterations in laminin composition offers insight into the roll the ECM potentially plays in modulating cellular behavior in adipose tissue expansion. PMID:25310607

  11. Testosterone and Dihydrotestosterone Differentially Improve Cognition in Aged Female Mice

    ERIC Educational Resources Information Center

    Benice, Ted S.; Raber, Jacob

    2009-01-01

    Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to…

  12. Dimeric acylphloroglucinols from Hypericum austrobrasiliense exhibiting antinociceptive activity in mice.

    PubMed

    Bridi, Henrique; Ccana-Ccapatinta, Gari V; Stolz, Eveline D; Meirelles, Gabriela C; Bordignon, Sérgio A L; Rates, Stela M K; von Poser, Gilsane L

    2016-02-01

    Three dimeric acylphloroglucinols, austrobrasilol A, austrobrasilol B and isoaustrobrasilol B were isolated from the flowers of Hypericum austrobrasiliense (Hypericaceae, section Trigynobrathys). Their structures were elucidated using mass spectrometry and NMR experiments (1D and 2D), and by comparison with previously reported data for other dimeric acylphloroglucinols isolated from Hypericum and Elaphoglossum genera. The three compounds were orally administered in mice at equimolar doses to uliginosin B (15mg/kg, p.o.) displaying antinociceptive activity in the hot-plate test. The compounds did not induce motor impairment in the rotarod apparatus.

  13. Dystrophin and utrophin "double knockout" dystrophic mice exhibit a spectrum of degenerative musculoskeletal abnormalities.

    PubMed

    Isaac, Christian; Wright, Adam; Usas, Arvydas; Li, Hongshuai; Tang, Ying; Mu, Xiaodong; Greco, Nicholas; Dong, Qing; Vo, Nam; Kang, James; Wang, Bing; Huard, Johnny

    2013-03-01

    Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by the lack of dystrophin expression at the sarcolemma of muscle fibers. In addition, DMD patients acquire osteopenia, fragility fractures, and scoliosis indicating that a deficiency in skeletal homeostasis coexists but little is known about the effects of DMD on bone and other connective tissues within the musculoskeletal system. Recent evidence has emerged implicating adult stem cell dysfunction in DMD myopathogenesis. Given the common mesenchymal origin of muscle and bone, we sought to investigate bone and other musculoskeletal tissues in a DMD mouse model. Here, we report that dystrophin-utrophin double knockout (dko) mice exhibit a spectrum of degenerative changes, outside skeletal muscle, in bone, articular cartilage, and intervertebral discs, in addition to reduced lifespan, muscle degeneration, spinal deformity, and cardiomyopathy previously reported. We also report these mice to have a reduced capacity for bone healing and exhibit spontaneous heterotopic ossification in the hind limb muscles. Therefore, we propose the dko mouse as a model for premature musculoskeletal aging and posit that a similar phenomenon may occur in patients with DMD.

  14. Absence of cytoglobin promotes multiple organ abnormalities in aged mice

    PubMed Central

    Thuy, Le Thi Thanh; Van Thuy, Tuong Thi; Matsumoto, Yoshinari; Hai, Hoang; Ikura, Yoshihiro; Yoshizato, Katsutoshi; Kawada, Norifumi

    2016-01-01

    Cytoglobin (Cygb) was identified in hepatic stellate cells (HSCs) and pericytes of all organs; however, the effects of Cygb on cellular functions remain unclear. Here, we report spontaneous and age-dependent malformations in multiple organs of Cygb−/− mice. Twenty-six percent of young Cygb−/− mice (<1 year old) showed heart hypertrophy, cystic disease in the kidney or ovary, loss of balance, liver fibrosis and lymphoma. Furthermore, 71.3% (82/115) of aged Cygb−/− mice (1–2 years old) exhibited abnormalities, such as heart hypertrophy and cancer development in multiple organs; by contrast, 5.8% (4/68) of aged wild-type (WT) mice had abnormalities (p < 0.0001). Interestingly, serum and urine analysis demonstrated that the concentration of nitric oxide metabolites increased significantly in Cygb−/− mice, resulting in an imbalance in the oxidative stress and antioxidant defence system that was reversed by NG-monomethyl-L-arginine treatment. A senescent phenotype and evidence of DNA damage were found in primary HSCs and the liver of aged Cygb−/− mice. Moreover, compared with HSC+/+, HSC−/− showed high expression of Il-6 and chemokine mRNA when cocultured with mouse Hepa 1–6 cells. Thus, the absence of Cygb in pericytes provokes organ abnormalities, possibly via derangement of the nitric oxide and antioxidant defence system and through accelerated cellular senescence. PMID:27146058

  15. Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

    PubMed

    Liu, Peng; Xing, Bo; Chu, Zheng; Liu, Fei; Lei, Gang; Zhu, Li; Gao, Ya; Chen, Teng; Dang, Yong-Hui

    2016-09-26

    Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc.

  16. Unexpected regeneration in middle-aged mice.

    PubMed

    Reines, Brandon; Cheng, Lily I; Matzinger, Polly

    2009-02-01

    Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight.

  17. Unexpected Regeneration in Middle-Aged Mice

    PubMed Central

    Cheng, Lily I.; Matzinger, Polly

    2009-01-01

    Abstract Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5–11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight. PMID:19226206

  18. 77 FR 4858 - Culturally Significant Objects Imported for Exhibition Determinations: “Byzantium and Islam: Age...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-31

    ... Culturally Significant Objects Imported for Exhibition Determinations: ``Byzantium and Islam: Age of... determinations made by ] the Department of State pertaining to the exhibition ``Byzantium and Islam: Age of... Islam: Age of Transition (7th-9th Century),'' imported from abroad for temporary exhibition within...

  19. Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders

    PubMed Central

    Berkowicz, Susan R.; Featherby, Travis J.; Whisstock, James C.; Bird, Phillip I.

    2016-01-01

    Background: Brinps 1–3, and Astrotactins (Astn) 1 and 2, are members of the Membrane Attack Complex/Perforin (MACPF) superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1−/− mice exhibit behavior reminiscent of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Method: We created Brinp2−/− mice and Brinp3−/− mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behavior. Additionally, Brinp2−/−Brinp3−/− double knock-out mice were generated by interbreeding Brinp2−/− and Brinp3−/− mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioral examination. Brinp1−/−Brinp2−/−Brinp3−/− triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1−/− mice, and examined by weight and histological analysis. Results: Brinp2−/− and Brinp3−/− mice differ in their behavior: Brinp2−/− mice are hyperactive, whereas Brinp3−/− mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3−/− mice also show evidence of altered sociability. Both Brinp2−/− and Brinp3−/− mice have normal short-term memory, olfactory responses, pre-pulse inhibition, and motor learning. The double knock-out mice show behaviors of Brinp2−/− and Brinp3−/− mice, without evidence of new or exacerbated phenotypes. Conclusion: Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2−/− and Brinp3−/− genes do not compensate in the mammalian brain and likely have

  20. TRPA1 contributes to chronic pain in aged mice with CFA-induced arthritis

    PubMed Central

    Garrison, Sheldon R.; Stucky, Cheryl L.

    2014-01-01

    Objective Investigate age-related differences in mechanical sensitivity and determine the contribution of transient receptor potential ankyrin 1 (TRPA1) to mechanical hypersensitivity during chronic inflammation in young and aged animals. Methods Mechanical sensitivity in young (3-month) and aged (24-month) wild-type (TRPA1+/+) and TRPA1-deficient (TRPA1-/-) mice was measured behaviorally for 8-weeks following injection of Complete Freund's Adjuvant (CFA) into the plantar hindpaw. Histological analysis and hindpaw measurements evaluated inflammation. Ex-vivo skin-saphenous nerve preparations quantified C-fiber sensitivity. Results In naïve wild-type mice, aged animals were less sensitive to mechanical stimuli than young. Afferent recordings from TRPA1-/- mice indicate that TRPA1 contributes to the normal mechanical sensitivity in both age groups. Following CFA injection, both young and aged TRPA1+/+ mice exhibited mechanical hypersensitivity. Development of mechanical hypersensitivity was delayed until week 4 in young TRPA1-/- mice, when they exhibited a sharp decrease (9-fold) in mechanical thresholds. In contrast, CFA-injected aged TRPA1-/- mice did not exhibit mechanical hypersensitivity at any time during the entire 8-weeks. Recordings of C-fibers supported these findings and showed that action potential firing increased in both young (25%) and aged (60%) TRPA1+/+ mice 8 weeks after CFA. Interestingly, mechanical firing increased markedly in C-fibers from young TRPA1-/- mice (80%) but not in C-fibers from aged TRPA1-/- mice after CFA. Conclusions These data reveal marked differences in long-term mechanical behavioral sensitivity of aged and young mice, and suggest that TRPA1 may be a key contributor to the transition from acute to chronic inflammatory mechanical pain and nociceptor sensitization selectively in aged mice. PMID:24891324

  1. Progranulin Knockout Accelerates Intervertebral Disc Degeneration in Aging Mice

    PubMed Central

    Zhao, Yun-peng; Tian, Qing-yun; Liu, Ben; Cuellar, Jason; Richbourgh, Brendon; Jia, Tang-hong; Liu, Chuan-ju

    2015-01-01

    Intervertebral disc (IVD) degeneration is a common degenerative disease, yet much is unknown about the mechanisms during its pathogenesis. Herein we investigated whether progranulin (PGRN), a chondroprotective growth factor, is associated with IVD degeneration. PGRN was detectable in both human and murine IVD. The levels of PGRN were upregulated in murine IVD tissue during aging process. Loss of PGRN resulted in an early onset of degenerative changes in the IVD tissue and altered expressions of the degeneration-associated molecules in the mouse IVD tissue. Moreover, PGRN knockout mice exhibited accelerated IVD matrix degeneration, abnormal bone formation and exaggerated bone resorption in vertebra with aging. The acceleration of IVD degeneration observed in PGRN null mice was probably due to the enhanced activation of NF-κB signaling and β-catenin signaling. Taken together, PGRN may play a critical role in homeostasis of IVD, and may serve as a potential molecular target for prevention and treatment of disc degenerative diseases. PMID:25777988

  2. Trpc2-deficient lactating mice exhibit altered brain and behavioral responses to bedding stimuli.

    PubMed

    Hasen, Nina S; Gammie, Stephen C

    2011-03-01

    The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2(-/-) knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female.

  3. Socially isolated mice exhibit a blunted homeostatic sleep response to acute sleep deprivation compared to socially paired mice.

    PubMed

    Kaushal, Navita; Nair, Deepti; Gozal, David; Ramesh, Vijay

    2012-05-15

    Sleep is an important physiological process underlying maintenance of physical, mental and emotional health. Consequently, sleep deprivation (SD) is associated with adverse consequences and increases the risk for anxiety, immune, and cognitive disorders. SD is characterized by increased energy expenditure responses and sleep rebound upon recovery that are regulated by homeostatic processes, which in turn are influenced by stress. Since all previous studies on SD were conducted in a setting of social isolation, the impact of the social contextual setting is unknown. Therefore, we used a relatively stress-free SD paradigm in mice to assess the impact of social isolation on sleep, wakefulness and delta electroencephalogram (EEG) power during non-rapid eye movement (NREM) sleep. Paired or isolated C57BL/6J adult chronically-implanted male mice were exposed to SD for 6h and telemetric polygraphic recordings were conducted, including 18 h recovery. Recovery from SD in the paired group showed a significant decrease in wake and significant increase in NREM sleep and rapid eye movement (REM), and a similar, albeit less robust response occurred in the isolated mice. Delta power during NREM sleep was increased in both groups immediately following SD, but paired mice exhibited significantly higher delta power throughout the dark period. The increase in body temperature and gross motor activity observed during the SD procedure was decreased during the dark period. In both open field and elevated plus maze tests, socially isolated mice showed significantly higher anxiety than paired mice. The homeostatic processes altered by SD are differentially affected in paired and isolated mice, suggesting that the social context of isolation stress may adversely affect the quantity and quality of sleep in mice.

  4. Age-independent and age-related deficits in visuospatial learning, sleep-wake states, thermoregulation and motor activity in PDAPP mice.

    PubMed

    Huitrón-Reséndiz, Salvador; Sánchez-Alavez, Manuel; Gallegos, Roger; Berg, Greta; Crawford, Elena; Giacchino, Jeannie L; Games, Dora; Henriksen, Steven J; Criado, José R

    2002-02-22

    Recent studies demonstrated that mice overexpressing the human mutant beta-amyloid precursor protein (hbetaAPP; PDAPP mice) show age-independent and age-related deficits in spatial learning. We used behavioral and electrophysiological techniques to determine in young and aged PDAPP mice whether deficits in spatial learning also involve alterations in sleep-wake states, thermoregulation and motor activity. Consistent with earlier studies, young PDAPP mice exhibited selective age-independent deficits using spatial, but not random and serial strategies in the circular maze. Aged PDAPP mice exhibited deficits using all search strategies. The core body temperature (Tb) in young and aged PDAPP mice was significantly lower than in age-matched non-transgenic (non-Tg) littermates. During the dark period, the motor activity (LMA) was significantly increased in young PDAPP mice, but not in aged PDAPP mice. During the light period, young PDAPP mice showed a reduction in the generation of rapid-eye-movement (REM) sleep. In contrast, aged PDAPP mice exhibited a reduction in the amount of time spent in W and an increase in SWS during the light period. Aged PDAPP mice also showed an increase in the amount of time spent in W and a reduction in REM sleep during the dark period. Our findings support previous reports indicating deficits in spatial learning in young and aged PDAPP mice. These data also suggest that PDAPP mice exhibit age-independent and age-related deficits in neural mechanisms regulating visuospatial learning, the total amount and the circadian distribution of sleep-wake states, thermoregulation and motor activity.

  5. Transgenic Mice Expressing Dominant Negative Bright Exhibit Defects in B1 B Cells

    PubMed Central

    Nixon, Jamee C.; Ferrell, Scott; Miner, Cathrine; Oldham, Athenia L.; Hochgeschwender, Ute; Webb, Carol F.

    2009-01-01

    The transcription factor Bright up-regulates immunoglobulin heavy chain production from select variable region promoters and requires Bright dimerization, Bruton’s tyrosine kinase (Btk) and the Btk substrate, TFII-I for this activity. Defects in Btk cause X-linked immunodeficiency disease in mice and man. Btk-deficient mice exhibit decreased serum IgM production, B cell developmental blocks, absence of peritoneal B1 cells, and subnormal immune responses against antigens, including phosphorylcholine, which confer protection against Streptococcus pneumoniae. Transgenic mice expressing dominant negative (DN) Bright share similarities with Btk-deficient mice, including decreased serum IgM, poor anti-phosphorylcholine responses, and slightly reduced numbers of mature B cells. Although DN Bright mice developed B1 B cells, these were functionally deficient in immunoglobulin secretion. These data suggest a mechanistic explanation for the abnormal responses to phosphorylcholine observed in Btk-deficient mice, and indicate that Bright functions in a subset of Btk-dependent pathways in vivo, particularly those responses dominated by B1 B cells. PMID:18981111

  6. Mutant mice derived by ICSI of evaporatively dried spermatozoa exhibit expected phenotype.

    PubMed

    Li, Ming-Wen; Baridon, Brian; Trainor, Amanda; Djan, Esi; Koehne, Amanda; Griffey, Stephen M; Biggers, John D; Toner, Mehmet; Lloyd, K C Kent

    2012-04-01

    Apolipoprotein E (Apoe)-deficient knockout mice were used to test the hypothesis that mutant mice preserved as evaporatively dried (ED) spermatozoa, stored at -80 °C for 6 months, and then recovered by ICSI will exhibit the same phenotype as before preservation. The birth rate of mice recovered by ICSI of evaporatively dried spermatozoa was lower than that of fresh spermatozoa (17.5 vs 38.0%). Progeny of mice preserved using evaporatively dried spermatozoa were reproductively sound. From these, the second generation of mice produced by natural mating showed lesions typical of APOE deficiency, including severe hypercholesterolemia, hypertriglyceridemia, markedly increased plasma low-density lipoprotein level, and extensive and severe atherosclerotic lesions in the aorta. We conclude that the expected phenotype caused by an induced genetic mutation can be faithfully recapitulated and sustained in subsequent generations of mice preserved and stored as ED spermatozoa and recovered using ICSI. Because it is simpler, faster, and cheaper than conventional (cryopreservation) and nonconventional (freeze-drying) preservation procedures, evaporative drying is a viable, cost-effective, and efficient method for preserving and storing valuable mutant mouse strains.

  7. Gomafu lncRNA knockout mice exhibit mild hyperactivity with enhanced responsiveness to the psychostimulant methamphetamine

    PubMed Central

    Ip, Joanna Y.; Sone, Masamitsu; Nashiki, Chieko; Pan, Qun; Kitaichi, Kiyoyuki; Yanaka, Kaori; Abe, Takaya; Takao, Keizo; Miyakawa, Tsuyoshi; Blencowe, Benjamin J.; Nakagawa, Shinichi

    2016-01-01

    The long noncoding RNA Gomafu/MIAT/Rncr2 is thought to function in retinal cell specification, stem cell differentiation and the control of alternative splicing. To further investigate physiological functions of Gomafu, we created mouse knockout (KO) model that completely lacks the Gomafu gene. The KO mice did not exhibit any developmental deficits. However, behavioral tests revealed that the KO mice are hyperactive. This hyperactive behavior was enhanced when the KO mice were treated with the psychostimulant methamphetamine, which was associated with an increase in dopamine release in the nucleus accumbens. RNA sequencing analyses identified a small number of genes affected by the deficiency of Gomafu, a subset of which are known to have important neurobiological functions. These observations suggest that Gomafu modifies mouse behavior thorough a mild modulation of gene expression and/or alternative splicing of target genes. PMID:27251103

  8. IL-5-overexpressing mice exhibit eosinophilia and altered wound healing through mechanisms involving prolonged inflammation.

    PubMed

    Leitch, Victoria D; Strudwick, Xanthe L; Matthaei, Klaus I; Dent, Lindsay A; Cowin, Allison J

    2009-02-01

    Leucocytes are essential in healing wounds and are predominantly involved in the inflammatory and granulation stages of wound repair. Eosinophils are granulocytic leucocytes and are specifically regulated by interleukin-5 (IL-5), a cytokine produced by T helper 2 (Th2) cells. To characterize more clearly the role of the IL-5 and eosinophils in the wound healing process, IL-5-overexpressing and IL-5-deficient mice were used as models of eosinophilia and eosinophil depletion, respectively. Our results reveal a significantly altered inflammatory response between IL-5-overexpressing and IL-5 knockout mice post-wounding. Healing was significantly delayed in IL-5-overexpressing mice with wounds gaping wider and exhibiting impaired re-epithelialization. A delay in collagen deposition was observed suggesting a direct effect on matrix synthesis. A significant increase in inflammatory cell infiltration, particularly eosinophils and CD4(+) cells, one of the main cell types which secrete IL-5, was observed in IL-5-overexpressing mice wounds suggesting that one of the main roles of IL-5 in wound repair may be to promote the infiltration of eosinophils into healing wounds. Healing is delayed in IL-5-overexpressing mice and this corresponds to significantly increased levels of eosinophils and CD4(+) cells within the wound site that may contribute to and exacerbate the inflammatory response, resulting in detrimental wound repair.

  9. Aging synaptic mitochondria exhibit dynamic proteomic changes while maintaining bioenergetic function

    PubMed Central

    Stauch, Kelly L.; Purnell, Phillip R.; Fox, Howard S.

    2014-01-01

    Aging correlates with a progressive impairment of mitochondrial homeostasis and is an influential factor for several forms of neurodegeneration. However, the mechanisms underlying age-related alterations in synaptosomal mitochondria, a neuronal mitochondria population highly susceptible to insults and critical for brain function, remain incompletely understood. Therefore this study investigates the synaptic mitochondrial proteomic and bioenergetic alterations that occur with age. The utilization of a state of the art quantitative proteomics approach allowed for the comparison of protein expression levels in synaptic mitochondria isolated from 5 (mature), 12 (old), and 24 (aged) month old mice. During the process of aging we find that dynamic proteomic alterations occur in synaptic mitochondria. Despite direct (mitochondrial DNA deletions) and indirect (increased antioxidant protein levels) signs of mitochondrial damage in the aged mice, there was an overall maintenance of mitochondrial function. Therefore the synaptic mitochondrial proteomic changes that occur with aging correlate with preservation of synaptic mitochondrial function. PMID:24827396

  10. Aging synaptic mitochondria exhibit dynamic proteomic changes while maintaining bioenergetic function.

    PubMed

    Stauch, Kelly L; Purnell, Phillip R; Fox, Howard S

    2014-04-01

    Aging correlates with a progressive impairment of mitochondrial homeostasis and is an influential factor for several forms of neurodegeneration. However, the mechanisms underlying age-related alterations in synaptosomal mitochondria, a neuronal mitochondria population highly susceptible to insults and critical for brain function, remain incompletely understood. Therefore this study investigates the synaptic mitochondrial proteomic and bioenergetic alterations that occur with age. The utilization of a state of the art quantitative proteomics approach allowed for the comparison of protein expression levels in synaptic mitochondria isolated from 5 (mature), 12 (old), and 24 (aged) month old mice. During the process of aging we find that dynamic proteomic alterations occur in synaptic mitochondria. Despite direct (mitochondrial DNA deletions) and indirect (increased antioxidant protein levels) signs of mitochondrial damage in the aged mice, there was an overall maintenance of mitochondrial function. Therefore the synaptic mitochondrial proteomic changes that occur with aging correlate with preservation of synaptic mitochondrial function.

  11. 76 FR 60112 - Culturally Significant Objects Imported for Exhibition Determinations: “Byzantium and Islam: Age...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-28

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF STATE Culturally Significant Objects Imported for Exhibition Determinations: ``Byzantium and Islam: Age of... Islam: Age of Transition (7th-9th Century),'' imported from abroad for temporary exhibition within...

  12. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice

    PubMed Central

    Mirsoian, Annie; Bouchlaka, Myriam N.; Sckisel, Gail D.; Chen, Mingyi; Pai, Chien-Chun Steven; Maverakis, Emanuel; Spencer, Richard G.; Fishbein, Kenneth W.; Siddiqui, Sana; Monjazeb, Arta M.; Martin, Bronwen; Maudsley, Stuart; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L.; Blazar, Bruce R.; Wiltrout, Robert H.; Taub, Dennis D.

    2014-01-01

    Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF+ macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT. PMID:25366964

  13. Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance

    PubMed Central

    Hwang, M; Go, Y; Park, J-H; Shin, S-K; Song, S E; Oh, B-C; Im, S-S; Hwang, I; Jeon, Y H; Lee, I-K; Seino, S; Song, D-K

    2017-01-01

    Background: The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. Methods: To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed. Results: Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression. Conclusions: Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to

  14. Microbiota and bile acid profiles in retinoic acid-primed mice that exhibit accelerated liver regeneration

    PubMed Central

    Liu, Hui-Xin; Hu, Ying; Wan, Yu-Jui Yvonne

    2016-01-01

    Background & Aims All-trans Retinoic acid (RA) regulates hepatic lipid and bile acid homeostasis. Similar to bile acid (BA), RA accelerates partial hepatectomy (PHx)-induced liver regeneration. Because there is a bidirectional regulatory relationship between gut microbiota and BA synthesis, we examined the effect of RA in altering the gut microbial population and BA composition and established their relationship with hepatic biological processes during the active phases of liver regeneration. Methods C57BL/6 mice were treated with RA orally followed by 2/3 PHx. The roles of RA in shifting gut microbiota and BA profiles as well as hepatocyte metabolism and proliferation were studied. Results RA-primed mice exhibited accelerated hepatocyte proliferation revealed by higher numbers of Ki67-positive cells compared to untreated mice. Firmicutes and Bacteroidetes phyla dominated the gut microbial community (>85%) in both control and RA-primed mice after PHx. RA reduced the ratio of Firmicutes to Bacteroidetes, which was associated with a lean phenotype. Consistently, RA-primed mice lacked transient lipid accumulation normally found in regenerating livers. In addition, RA altered BA homeostasis and shifted BA profiles by increasing the ratio of hydrophilic to hydrophobic BAs in regenerating livers. Accordingly, metabolic regulators fibroblast growth factor 21, Sirtuin1, and their downstream targets AMPK and ERK1/2 were more robustly activated in RA-primed than unprimed regenerating livers. Conclusions Priming mice with RA resulted in a lean microbiota composition and hydrophilic BA profiles, which were associated with facilitated metabolism and enhanced cell proliferation. PMID:26701854

  15. CRSBP-1/LYVE-1-null Mice Exhibit Identifiable Morphological and Functional Alterations of Lymphatic Capillary Vessels

    PubMed Central

    Huang, Shuan S.; Liu, I-Hua; Smith, Tracy; Shah, Maulik R.; Johnson, Frank E.; Huang, Jung S.

    2010-01-01

    CRSBP-1, a membrane glycoprotein, can mediate cell-surface retention of secreted growth factors containing CRS motifs such as PDGF-BB. CRSBP-1 has recently been found to be identical to LYVE-1, a specific marker for lymphatic capillary endothelial cells. The in vivo role of CRSBP-1/LYVE-1 is unknown. CRSBP-1-null mice are overtly normal and fertile but exhibit identifiable morphological and functional alterations of lymphatic capillary vessels in certain tissues, marked by the constitutively increased interstitial-lymphatic flow and lack of typical irregularly-shaped lumens. The CRSBP-1 ligands PDGF-BB and HA enhance interstitial-lymphatic flow in wild-type mice but not in CRSBP-1-null animals. PMID:17070806

  16. Fibroblast Growth Factor 21-Null Mice Do Not Exhibit an Impaired Response to Fasting

    PubMed Central

    Antonellis, Patrick Joseph; Hayes, Meghan Patricia; Adams, Andrew Charles

    2016-01-01

    Fibroblast growth factor 21 (FGF21) is a pleotropic metabolic regulator, expression of which is elevated during fasting. To this end, the precise role played by FGF21 in the biology of fasting has been the subject of several recent studies, which have demonstrated contributions to the regulation of both lipid and carbohydrate metabolism. In the present study, we compared wild-type (WT) and FGF21-null (FGF21KO) mice, demonstrating that, despite the significant induction of FGF21 during fasting in the WT animals, our strain of FGF21-null mice exhibits only limited impairments in their adaptation to nutrient deprivation. Specifically, fasted FGF21KO mice display a mild attenuation of gluconeogenic transcriptional induction in the liver accompanied by partially blunted glucose production in response to a pyruvate challenge. Furthermore, FGF21KO mice displayed only minor impairments in lipid metabolism in the fasted state, limited to accumulation of hepatic triglycerides and a reduction in expression of genes associated with fatty acid oxidation. To address the possibility of compensation to germline deletion of FGF21, we further interrogated the role of endogenous FGF21 via acute pharmacological blockade of FGF21 signaling. At the transcriptional level, we show that FGF21 signaling is required for full induction of gluconeogenic and oxidative genes in the liver. However, corroborating our findings in FGF21KO mice, pharmacological blockade of the FGF21 axis did not profoundly disrupt the physiological response to fasting. Taken as a whole, these data demonstrate that, while FGF21 is partially required for appropriate gene expression during the fed to fasted transition, its absence does not significantly impact the downstream physiology of the fasted state. PMID:27445980

  17. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas.

    PubMed

    Imgrund, Silke; Hartmann, Dieter; Farwanah, Hany; Eckhardt, Matthias; Sandhoff, Roger; Degen, Joachim; Gieselmann, Volkmar; Sandhoff, Konrad; Willecke, Klaus

    2009-11-27

    (Dihydro)ceramide synthase 2 (cers2, formerly called lass2) is the most abundantly expressed member of the ceramide synthase gene family, which includes six isoforms in mice. CERS2 activity has been reported to be specific toward very long fatty acid residues (C22-C24). In order to study the biological role of CERS2, we have inactivated its coding region in transgenic mice using gene-trapped embryonic stem cells that express lacZ reporter DNA under control of the cers2 promoter. The resulting mice lack ceramide synthase activity toward C24:1 in the brain as well as the liver and show only very low activity toward C18:0-C22:0 in liver and reduced activity toward C22:0 residues in the brain. In addition, these mice exhibit strongly reduced levels of ceramide species with very long fatty acid residues (>or=C22) in the liver, kidney, and brain. From early adulthood on, myelin stainability is progressively lost, biochemically accompanied by about 50% loss of compacted myelin and 80% loss of myelin basic protein. Starting around 9 months, both the medullary tree and the internal granular layer of the cerebellum show significant signs of degeneration associated with the formation of microcysts. Predominantly in the peripheral nervous system, we observed vesiculation and multifocal detachment of the inner myelin lamellae in about 20% of the axons. Beyond 7 months, the CERS2-deficient mice developed hepatocarcinomas with local destruction of tissue architecture and discrete gaps in renal parenchyma. Our results indicate that CERS2 activity supports different biological functions: maintenance of myelin, stabilization of the cerebellar as well as renal histological architecture, and protection against hepatocarcinomas.

  18. Mice Lacking the kf-1 Gene Exhibit Increased Anxiety- but not Despair-Like Behavior

    PubMed Central

    Tsujimura, Atsushi; Matsuki, Masato; Takao, Keizo; Yamanishi, Kiyofumi; Miyakawa, Tsuyoshi; Hashimoto-Gotoh, Tamotsu

    2008-01-01

    KF-1 was originally identified as a protein encoded by human gene with increased expression in the cerebral cortex of a patient with Alzheimer's disease. In mouse brain, kf-1 mRNA is detected predominantly in the hippocampus and cerebellum, and kf-1 gene expression is elevated also in the frontal cortex of rats after chronic antidepressant treatments. KF-1 mediates E2-dependent ubiquitination and may modulate cellular protein levels as an E3 ubiquitin ligase, though its target proteins are not yet identified. To elucidate the role of kf-1 in the central nervous system, we generated kf-1 knockout mice by gene targeting, using Cre-lox recombination. The resulting kf-1−/− mice were normal and healthy in appearance. Behavioral analyses revealed that kf-1−/− mice showed significantly increased anxiety-like behavior compared with kf-1+/+ littermates in the light/dark transition and elevated plus maze tests; however, no significant differences were observed in exploratory locomotion using the open field test or in behavioral despair using the forced swim and tail suspension tests. These observations suggest that KF-1 suppresses selectively anxiety under physiological conditions probably through modulating protein levels of its unknown target(s). Interestingly, kf-1−/− mice exhibited significantly increased prepulse inhibition, which is usually reduced in human schizophrenic patients. Thus, the kf-1−/− mice provide a novel animal model for elucidating molecular mechanisms of psychiatric diseases such as anxiety/depression, and may be useful for screening novel anxiolytic/antidepressant compounds. PMID:18958194

  19. BDNF +/− Mice Exhibit Deficits in Oligodendrocyte Lineage Cells of the Basal Forebrain

    PubMed Central

    VonDran, Melissa W.; Clinton-Luke, Patricia; Honeywell, Jean Z.; Dreyfus, Cheryl F.

    2009-01-01

    Previous work indicated that BDNF, through the trkB receptor, increases DNA synthesis in oligodendrocyte progenitor cells (OPCs) and differentiation of post-mitotic oligodendrocytes (OLGs) of the basal forebrain (BF). In the present studies, BDNF knockout animals were used to investigate BDNF’s effects on OLG lineage cells (OLCs) in vivo. OLCs of the BF were found to express the trkB receptor, suggesting they are responsive to BDNF. Immunohistochemistry using NG2 and CC1 antibodies was utilized to examine numbers of NG2+ OPCs and CC1+ post-mitotic BF OLGs. In the embryo (E17), BDNF −/− animals display reduced NG2+ cells. This reduction was also observed in BDNF +/− mice at E17 and at postnatal day 1 (P1), P14 and adult, suggesting that BDNF plays a role in OPC development. BDNF +/− mice do not exhibit deficits in numbers of CC1+ OLGs. However, myelin basic protein (MBP), myelin associated glycoprotein (MAG), and proteolipid protein (PLP) are reduced in BDNF +/− mice, suggesting that BDNF plays a role in differentiation. These data indicate that progenitor cells and myelin proteins may be affected in vivo by a decrease in BDNF. PMID:20091777

  20. Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota

    PubMed Central

    Lynch, Susan V.; Goldfarb, Katherine C.; Wild, Yvette K.; Kong, Weidong; De Lisle, Robert C.; Brodie, Eoin L.

    2013-01-01

    The composition of the gastrointestinal microbiome is increasingly recognized as a crucial contributor to immune and metabolic homeostasis—deficiencies in which are characteristic of cystic fibrosis (CF) patients. The murine model (CFTR−/−, CF), has, in previous studies, demonstrated characteristic CF gastrointestinal (GI) manifestations including slowed transit and significant upregulation of genes associated with inflammation. To determine if characteristics of the microbiome are associated with these phenotypes we used a phylogenetic microarray to compare small intestine bacterial communities of wild type and congenic CF mice. Loss of functional CFTR is associated with significant decreases in GI bacterial community richness, evenness and diversity and reduced relative abundance of putative protective species such as Acinetobacter lwoffii and a multitude of Lactobacilliales members. CF mice exhibited significant enrichment of Mycobacteria species and Bacteroides fragilis, previously associated with GI infection and immunomodulation. Antibiotic administration to WT and CF animals resulted in convergence of their microbiome composition and significant increases in community diversity in CF mice. These communities were characterized by enrichment of members of the Lactobacillaceae and Bifidobacteriaceae and reduced abundance of Enterobacteriaceae and Clostridiaceae. These data suggest that Enterobacteria and Clostridia species, long associated with small intestinal overgrowth and inflammatory bowel disease, may suppress both ileal bacterial diversity and the particular species which maintain motility and immune homeostasis in this niche. Thus, these data provide the first indications that GI bacterial colonization is strongly impacted by the loss of functional CFTR and opens up avenues for alternative therapeutic approaches to improve CF disease management. PMID:23060053

  1. Runx3 deficiency results in myeloproliferative disorder in aged mice.

    PubMed

    Wang, Chelsia Qiuxia; Motoda, Lena; Satake, Masanobu; Ito, Yoshiaki; Taniuchi, Ichiro; Tergaonkar, Vinay; Osato, Motomi

    2013-07-25

    The RUNX family genes encode transcription factors that are involved in development and human diseases. RUNX1 is one of the most frequently mutated genes in human hematological malignancies and is a critical factor for the generation and maintenance of hematopoietic stem cells. Another Runx family gene, Runx3, is known to be expressed in hematopoietic cells. However, its involvement in hematopoiesis remains unclear. Here we show the hematopoietic phenotypes in Runx3 conditional knockout (KO) mice (Runx3(fl/fl);Mx1-Cre(+)): whereas young Runx3 KO mice did not exhibit any significant hematopoietic defects, aged Runx3 KO mice developed a myeloproliferative disorder characterized by myeloid-dominant leukocytosis, splenomegaly, and an increase of hematopoietic stem/progenitor cells (HSPCs). Notably, Runx3-deficient cells showed hypersensitivity to granulocyte-colony stimulating factor, suggesting enhanced proliferative and mobilization capability of Runx3-deficient HSPCs when stimulated. These results suggest that, besides Runx1, Runx3 also plays a role in hematopoiesis.

  2. Enhanced Dopamine Transporter Activity in Middle-Aged Gdnf Heterozygous Mice

    PubMed Central

    Littrell, Ofelia M.; Pomerleau, Francois; Huettl, Peter; Surgener, Stewart; McGinty, Jacqueline F.; Middaugh, Lawrence D.; Granholm, Ann-Charlotte; Gerhardt, Greg A.; Boger, Heather A.

    2010-01-01

    Glial cell line-derived neurotrophic factor (GDNF) supports the viability of midbrain dopamine (DA) neurons that degenerate in Parkinson’s disease. Middle aged, 12-month-old, Gdnf heterozygous (Gdnf+/−) mice have diminished spontaneous locomotor activity and enhanced synaptosomal DA uptake compared to wildtype mice. In this study, dopamine transporter (DAT) function in middle-aged, 12-month-old Gdnf+/− mice was more thoroughly investigated using in vivo electrochemistry. Gdnf+/− mice injected with the DAT inhibitor, nomifensine, exhibited significantly more locomotor activity than wildtype mice. In vivo electrochemistry with carbon fiber microelectrodes demonstrated enhanced clearance of DA in the striatum of Gdnf+/− mice, suggesting greater surface expression of DAT than in wildtype littermates. Additionally, 12 month old Gdnf+/− mice expressed greater D2 receptor mRNA and protein in the striatum than wildtype mice. Neurochemical analyses of striatal tissue samples indicated significant reductions in DA and a faster DA metabolic rate in Gdnf+/− mice than in wildtype mice. Altogether, these data support an important role for GDNF in the regulation of uptake, synthesis, and metabolism of DA during aging. PMID:21144620

  3. Lipopolysaccharide-induced lethality and cytokine production in aged mice.

    PubMed Central

    Tateda, K; Matsumoto, T; Miyazaki, S; Yamaguchi, K

    1996-01-01

    This study was designed to define the lipopolysaccharide (LPS) sensitivity of aged mice in terms of lethality and cytokine production and to determine down-regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were 601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight), respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF-alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups of mice. However, the peak values of these cytokines were significantly higher in aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable at 3 h, and sustained high levels were still detected after 12 h in both age groups. Although there were no significant differences in levels of IFN-gamma in sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3- to 12-h study period. Administration of increasing doses of LPS revealed that aged mice had a lower threshold to IL-1alpha production than young mice. In addition, aged mice were approximately 4-fold more sensitive to the lethal toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per kilogram) than young mice. With regard to down-regulating factors, corticosterone amounts were similar at basal levels and no differences in kinetics after the LPS challenge were observed, whereas IL-10 levels in sera were significantly higher in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate that aged mice are more sensitive to the lethal toxicities of LPS and TNF than young mice. We conclude that a relatively activated, or primed, state for LPS

  4. Rhabdomyosarcomas in Aging A/J Mice

    PubMed Central

    Sher, Roger B.; Cox, Gregory A.; Mills, Kevin D.; Sundberg, John P.

    2011-01-01

    Rhabdomyosarcomas (RSCs) are skeletal muscle neoplasms found in humans and domestic mammals. The A/J inbred strain developed a high frequency (between 70–80%) of adult pleomorphic type (APT) RSC at >20 months of age while BALB/cByJ also develop RSC but less frequently. These neoplasms invaded skeletal muscle surrounding either the axial or proximal appendicular skeleton and were characterized by pleomorphic cells with abundant eosinophilic cytoplasm, multiple nuclei, and cross striations. The diagnosis was confirmed by detection of alpha-sarcomeric actin and myogenin in the neoplastic cells using immunocytochemistry. The A/J strain, but not the related BALB/c substrains, is also characterised by a progressive muscular dystrophy homologous to limb-girdle muscular dystrophy type 2B. The association between the development of RSC in similar muscle groups to those most severely affected by the progressive muscular dystrophy suggested that these neoplasms developed from abnormal regeneration of the skeletal muscle exacerbated by the dysferlin mutation. Transcriptome analyses of RSCs revealed marked downregulation of genes in muscular development and function signaling networks. Non-synonymous coding SNPs were found in Myl1, Abra, Sgca, Ttn, and Kcnj12 suggesting these may be important in the pathogenesis of RSC. These studies suggest that A strains of mice can be useful models for dissecting the molecular genetic basis for development, progression, and ultimately for testing novel anticancer therapeutic agents dealing with rhabdomyosarcoma. PMID:21853140

  5. Initial evidence linking synaptic superoxide production with poor short-term memory in aged mice.

    PubMed

    Ali, Sameh S; Young, Jared W; Wallace, Chelsea K; Gresack, Jodi; Jeste, Dilip V; Geyer, Mark A; Dugan, Laura L; Risbrough, Victoria B

    2011-01-12

    Unregulated production of reactive oxygen species (ROS) is a marker of cellular and organismal aging linked to cognitive decline in humans and rodents. The sources of elevated ROS contributing to cognitive decline are unknown. Because NADPH oxidase (Nox) inhibition may prevent memory decline with age, we hypothesized that Nox and not mitochondrial sources of synaptic ROS production are linked to individual variance in cognitive performance in aged mice. Young (8 months) and aged (26 months) mice were tested in the novel object recognition task (NORT). Mitochondrial and Nox ROS production was assayed in isolated synaptosomes using spin trapping electron paramagnetic resonance (EPR) spectroscopy. Aged mice exhibited variance in NORT performance, with some performing similar to young mice while others exhibited poorer short-term memory. EPR studies indicated that Nox rather than mitochondria was the major ROS source at the synapse, and Nox-induced but not mitochondrial-induced ROS levels correlated with NORT performance in aged mice. Our findings support the hypothesis that variance in Nox-specific synaptic ROS production may predict short-term memory deficits with age.

  6. Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice

    PubMed Central

    Praag, Henriette van; Shubert, Tiffany; Zhao, Chunmei; Gage, Fred H.

    2005-01-01

    Aging causes changes in the hippocampus that may lead to cognitive decline in older adults. In young animals, exercise increases hippocampal neurogenesis and improves learning. We investigated whether voluntary wheel running would benefit mice that were sedentary until 19 months of age. Specifically, young and aged mice were housed with or without a running wheel and injected with bromodeoxyuridine or retrovirus to label newborn cells. After 1 month, learning was tested in the Morris water maze. Aged runners showed faster acquisition and better retention of the maze than age-matched controls. The decline in neurogenesis in aged mice was reversed to 50% of young control levels by running. Moreover, fine morphology of new neurons did not differ between young and aged runners, indicating that the initial maturation of newborn neurons was not affected by aging. Thus, voluntary exercise ameliorates some of the deleterious morphological and behavioral consequences of aging. PMID:16177036

  7. 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

  8. Spontaneous development of autoimmune sialadenitis in aging BDF1 mice.

    PubMed Central

    Hayashi, Y.; Kurashima, C.; Utsuyama, M.; Hirokawa, K.

    1988-01-01

    This study reports that spontaneous autoimmune sialadenitis developed in aging female, rather than male, BDF1 mice. The lesions first appeared in 6-month-old female BDF1 mice and were aggravated with advancing age, especially in 24-month-old and 30-month-old senescent mice. In contrast, significant inflammatory changes did not develop in aging male BDF1 mice. The presence of antisalivary duct antibody was found in sera from mice with sialadenitis. The infiltrating cells in the lesions of submandibular salivary glands were mainly composed of T cells, especially Lyt 1+ and L3T4+ cells. Moreover, mild inflammatory lesions were observed in parotid, sublingual salivary glands, pancreas, or kidneys in some mice that developed spontaneously occurring sialadenitis. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:3260751

  9. 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.

  10. Atrial structure, function and arrhythmogenesis in aged and frail mice

    PubMed Central

    Jansen, Hailey J.; Moghtadaei, Motahareh; Mackasey, Martin; Rafferty, Sara A.; Bogachev, Oleg; Sapp, John L.; Howlett, Susan E.; Rose, Robert A.

    2017-01-01

    Atrial fibrillation (AF) is prevalent in aging populations; however not all individuals age at the same rate. Instead, individuals of the same chronological age can vary in health status from fit to frail. Our objective was to determine the impacts of age and frailty on atrial function and arrhythmogenesis in mice using a frailty index (FI). Aged mice were more frail and demonstrated longer lasting AF compared to young mice. Consistent with this, aged mice showed longer P wave duration and PR intervals; however, both parameters showed substantial variability suggesting differences in health status among mice of similar chronological age. In agreement with this, P wave duration and PR interval were highly correlated with FI score. High resolution optical mapping of the atria demonstrated reduced conduction velocity and action potential duration in aged hearts that were also graded by FI score. Furthermore, aged mice had increased interstitial fibrosis along with changes in regulators of extracellular matrix remodelling, which also correlated with frailty. These experiments demonstrate that aging results in changes in atrial structure and function that create a substrate for atrial arrhythmias. Importantly, these changes were heterogeneous due to differences in health status, which could be identified using an FI. PMID:28290548

  11. QRFP-Deficient Mice Are Hypophagic, Lean, Hypoactive and Exhibit Increased Anxiety-Like Behavior

    PubMed Central

    Okamoto, Kitaro; Yamasaki, Miwako; Takao, Keizo; Soya, Shingo; Iwasaki, Monica; Sasaki, Koh; Magoori, Kenta; Sakakibara, Iori; Miyakawa, Tsuyoshi; Mieda, Michihiro; Watanabe, Masahiko; Sakai, Juro; Yanagisawa, Masashi; Sakurai, Takeshi

    2016-01-01

    How the hypothalamus transmits hunger information to other brain regions to govern whole brain function to orchestrate feeding behavior has remained largely unknown. Our present study suggests the importance of a recently found lateral hypothalamic neuropeptide, QRFP, in this signaling. Qrfp-/- mice were hypophagic and lean, and exhibited increased anxiety-like behavior, and were hypoactive in novel circumstances as compared with wild type littermates. They also showed decreased wakefulness time in the early hours of the dark period. Histological studies suggested that QRFP neurons receive rich innervations from neurons in the arcuate nucleus which is a primary region for sensing the body’s metabolic state by detecting levels of leptin, ghrelin and glucose. These observations suggest that QRFP is an important mediator that acts as a downstream mediator of the arcuate nucleus and regulates feeding behavior, mood, wakefulness and activity. PMID:27835635

  12. Alk7 Depleted Mice Exhibit Prolonged Cardiac Repolarization and Are Predisposed to Ventricular Arrhythmia

    PubMed Central

    Ying, Shaozhen; Cao, Hong; Hu, He; Wang, Xin; Tang, Yanhong; Huang, Congxin

    2016-01-01

    We aimed to investigate the role of activin receptor-like kinase (ALK7) in regulating cardiac electrophysiology. Here, we showed that Alk7-/- mice exhibited prolonged QT intervals in telemetry ECG recordings. Furthermore, Langendorff-perfused Alk7-/- hearts had significantly longer action potential duration (APD) and greater incidence of ventricular arrhythmia (AV) induced by burst pacing. Using whole-cell patch clamp, we found that the densities of repolarizing K+ currents Ito and IK1 were profoundly reduced in Alk7-/- ventricular cardiomyocytes. Mechanistically, the expression of Kv4.2 (a major subunit of Ito carrying channel) and KCHIP2 (a key accessory subunit of Ito carrying channel), was markedly decreased in Alk7-/- hearts. These findings suggest that endogenous expression of ALK7 is necessary to maintain repolarizing K+ currents in ventricular cardiomyocytes, and finally prevent action potential prolongation and ventricular arrhythmia. PMID:26882027

  13. Rinderpest and peste des petits ruminants viruses exhibit neurovirulence in mice.

    PubMed

    Galbraith, Sareen E; McQuaid, Stephen; Hamill, Louise; Pullen, L; Barrett, Thomas; Cosby, S Louise

    2002-02-01

    Members of the morbillivirus genus, canine distemper (CDV), phocine distemper virus (PDV), and the cetacean viruses of dolphins and porpoises exhibit high levels of CNS infection in their natural hosts. CNS complications are rare for measles virus (MV) and are not associated with rinderpest virus (RPV) and peste des petits ruminants virus (PPRV) infection. However, it is possible that all morbilliviruses infect the CNS but in some hosts are rapidly cleared by the immune response. In this study, we assessed whether RPV and PPRV have the potential to be neurovirulent. We describe the outcome of infection, of selected mouse strains, with isolates of RPV, PPRV, PDV, porpoise morbillivirus (PMV), dolphin morbillivirus (DMV), and a wild-type strain of MV. In the case of RPV virus, strains with different passage histories have been examined. The results of experiments with these viruses were compared with those using neuroadapted and vaccine strains of MV, which acted as positive and negative controls respectively. Intracerebral inoculation with RPV (Saudi/81) and PPRV (Nigeria75/1) strains produced infection in Balb/C and Cd1, but not C57 suckling mice, whereas the CAM/RB rodent-adapted strain of MV infected all three strains of mice. Weanling mice were only infected by CAM/RB. Intranasal and intraperitoneal inoculation failed to produce infection with any virus strains. We have shown that, both RPV and PPRV, in common with other morbilliviruses are neurovirulent in a permissive system. Transient infection of the CNS of cattle and goats with RPV and PPRV, respectively, remains a possibility, which could provide relevant models for the initial stages of MV infection in humans.

  14. Alx3-deficient mice exhibit folic acid-resistant craniofacial midline and neural tube closure defects.

    PubMed

    Lakhwani, Sita; García-Sanz, Patricia; Vallejo, Mario

    2010-08-15

    Neural tube closure defects are among the most frequent congenital malformations in humans. Supplemental maternal intake of folic acid before and during pregnancy reduces their incidence significantly, but the mechanism underlying this preventive effect is unknown. As a number of genes that cause neural tube closure defects encode transcriptional regulators in mice, one possibility is that folic acid could induce the expression of transcription factors to compensate for the primary genetic defect. We report that folic acid is required in mouse embryos for the specific expression of the homeodomain gene Alx3 in the head mesenchyme, an important tissue for cranial neural tube closure. Alx3-deficient mice exhibit increased failure of cranial neural tube closure and increased cell death in the craniofacial region, two effects that are also observed in wild type embryos developing in the absence of folic acid. Folic acid cannot prevent these defects in Alx3-deficient embryos, indicating that one mechanism of folic acid action is through induced expression of Alx3. Thus, Alx3 emerges as a candidate gene for human neural tube defects and reveals the existence of induced transcription factor gene expression as a previously unknown mechanism by which folic acid prevents neural tube closure defects.

  15. Gait disorder as a predictor of spatial learning and memory impairment in aged mice

    PubMed Central

    Wang, Qing M.; Meng, Zhaoxiang; Yin, Zhenglu

    2017-01-01

    Objective To investigate whether gait dysfunction is a predictor of severe spatial learning and memory impairment in aged mice. Methods A total of 100 12-month-old male mice that had no obvious abnormal motor ability and whose Morris water maze performances were not significantly different from those of two-month-old male mice were selected for the study. The selected aged mice were then divided into abnormal or normal gait groups according to the results from the quantitative gait assessment. Gaits of aged mice were defined as abnormal when the values of quantitative gait parameters were two standard deviations (SD) lower or higher than those of 2-month-old male mice. Gait parameters included stride length, variability of stride length, base of support, cadence, and average speed. After nine months, mice exhibiting severe spatial learning and memory impairment were separated from mice with mild or no cognitive dysfunction. The rate of severe spatial learning and memory impairment in the abnormal and normal gait groups was tested by a chi-square test and the correlation between gait dysfunction and decline in cognitive function was tested using a diagnostic test. Results The 12-month-old aged mice were divided into a normal gait group (n = 75) and an abnormal gait group (n = 25). Nine months later, three mice in the normal gait group and two mice in the abnormal gait group had died. The remaining mice were subjected to the Morris water maze again, and 17 out of 23 mice in the abnormal gait group had developed severe spatial learning and memory impairment, including six with stride length deficits, 15 with coefficient of variation (CV) in stride length, two with base of support (BOS) deficits, five with cadence dysfunction, and six with average speed deficits. In contrast, only 15 out of 72 mice in the normal gait group developed severe spatial learning and memory impairment. The rate of severe spatial learning and memory impairment was significantly higher in

  16. Chronic stress impairs collateral blood flow recovery in aged mice.

    PubMed

    Lassance-Soares, Roberta M; Sood, Subeena; Chakraborty, Nabarun; Jhamnani, Sunny; Aghili, Nima; Nashin, Hajra; Hammamieh, Rasha; Jett, Marti; Epstein, Stephen E; Burnett, Mary Susan

    2014-11-01

    Chronic stress is associated with increased risk of cardiovascular diseases. Aging is also associated with vascular dysfunction. We hypothesize that chronic stress accelerates collateral dysfunction in old mice. Mice were subjected to either chronic social defeat (CSD) or chronic cold stress (CCS). The CSD mice were housed in a box inside an aggressor's cage and exposed to the aggressor. The CCS group was placed in iced water. After chronic stress, mice underwent femoral artery ligation (FAL) and flow recovery was measured. For the CSD group, appearance and use scores of the foot and a behavioral test were performed. CSD impaired collateral flow recovery after FAL. Further, stressed mice had greater ischemic damage, impaired foot function, and altered behavior. The CCS mice also showed impaired collateral flow recovery. Chronic stress causes hind limb collateral dysfunction in old mice, a conclusion reinforced by the fact that two types of stress produced similar changes.

  17. Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice

    PubMed Central

    Grieb, Brian C.; Boyd, Kelli; Mitra, Ramkrishna; Eischen, Christine M.

    2016-01-01

    Alterations of specific genes can modulate aging. Myc, a transcription factor that regulates the expression of many genes involved in critical cellular functions was shown to have a role in controlling longevity. Decreased expression of Myc inhibited many of the deleterious effects of aging and increased lifespan in mice. Without altering Myc expression, reduced levels of Mtbp, a recently identified regulator of Myc, limit Myc transcriptional activity and proliferation, while increased levels promote Myc-mediated effects. To determine the contribution of Mtbp to the effects of Myc on aging, we studied a large cohort of Mtbp heterozygous mice and littermate matched wild-type controls. Mtbp haploinsufficiency significantly increased longevity and maximal survival in mice. Reduced levels of Mtbp did not alter locomotor activity, litter size, or body size, but Mtbp heterozygous mice did exhibit elevated markers of metabolism, particularly in the liver. Mtbp+/− mice also had a significant delay in spontaneous cancer development, which was most prominent in the hematopoietic system, and an altered tumor spectrum compared to Mtbp+/+ mice. Therefore, the data suggest Mtbp is a regulator of longevity in mice that mimics some, but not all, of the properties of Myc in aging. PMID:27803394

  18. Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of Locus coeruleus dendrites

    PubMed Central

    Hashemi, Ezzat; Sahbaie, Peyman; Davies, M. Frances; Clark, J. David; DeLorey, Timothy M.

    2007-01-01

    Gabrb3 gene deficient (gabrb3-/-) mice, control littermates (gabrb3+/+) and their progenitor strains, C57Bl/6J and 129/SvJ were assessed for changes in the morphology of the main noradrenergic nuclei, the locus coeruleus (LC) and LC-associated behaviors including anxiety and muscle tone. While the area defined by the cell bodies of the LC was found not to differ between gabrb3-/- mice and controls, the pericoerulear dendritic zone of the LC was found to be significantly enlarged in gabrb3-/- mice. Relative to controls, gabrb3-/- mice were also found to be hypotonic, as was indicated by poor performance on the wire hanging task. Gabrb3-/- mice also exhibited a significant increase in stretch-attend posturing, a form of risk assessment behavior associated with anxiety. However, in the plus maze, a commonly used behavioral test for assessing anxiety, no significant difference was observed between gabrb3-/- and control mice. Lastly, relative to controls, gabrb3-/- mice exhibited significantly less marble burying behavior, a method commonly used to assess obsessive-compulsive behavior. However, the poor marble burying performance of the gabrb3-/- mice could be associated with the hypotonic condition exhibited by these mice. In conclusion, the results of this study indicate that the gabrb3 gene contributes to LC noradrenergic dendrite development with the disruption of this gene in mice resulting in an enlarged plexus of LC dendrites with a concurrent reduction in muscle tone and marble burying behavior, an increase in risk assessment behavior but no change in the plus maze parameters that are commonly used for assessing anxiety. Section: Disease-related Neuroscience PMID:17156762

  19. Hhip haploinsufficiency sensitizes mice to age-related emphysema.

    PubMed

    Lao, Taotao; Jiang, Zhiqiang; Yun, Jeong; Qiu, Weiliang; Guo, Feng; Huang, Chunfang; Mancini, John Dominic; Gupta, Kushagra; Laucho-Contreras, Maria E; Naing, Zun Zar Chi; Zhang, Li; Perrella, Mark A; Owen, Caroline A; Silverman, Edwin K; Zhou, Xiaobo

    2016-08-09

    Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip(+/-)), we observed increased lung compliance and spontaneous emphysema in Hhip(+/-) mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip(+/-) vs. Hhip(+/+) mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip(+/-) mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip(+/-) mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip(+/-) mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.

  20. Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice.

    PubMed

    Arendash, Gary W; Mori, Takashi; Cao, Chuanhai; Mamcarz, Malgorzata; Runfeldt, Melissa; Dickson, Alexander; Rezai-Zadeh, Kavon; Tane, Jun; Citron, Bruce A; Lin, Xiaoyang; Echeverria, Valentina; Potter, Huntington

    2009-01-01

    We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (Abeta) levels due to suppression of both beta-secretase (BACE1) and presenilin 1 (PS1)/gamma-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Abeta deposition in hippocampus (decrease 40%) and entorhinal cortex (decrease 46%), as well as correlated decreases in brain soluble Abeta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFkappaB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Abeta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.

  1. Respiratory and sniffing behaviors throughout adulthood and aging in mice

    PubMed Central

    Wesson, Daniel W.; Varga-Wesson, Adrienn G.; Borkowski, Anne H.; Wilson, Donald A.

    2011-01-01

    Orienting responses are physiological and active behavioral reactions evoked by novel stimulus perception and are critical for survival. We explored whether odor orienting responses are impacted throughout both adulthood and normal and pathological aging in mice. Novel odor investigation (including duration and bout numbers) and its subsequent habituation as assayed in the odor habituation task were preserved in adult C57BL/6J mice up to 12mo of age with <6% variability between age groups in investigation time. Separately, using whole-body plethysmography we found that both spontaneous respiration and odor-evoked sniffing behaviors were strikingly preserved in wildtype (WT) mice up to 26mo of age. In contrast, mice accumulating amyloid-β protein in the brain by means of overexpressing mutations in the human amyloid precursor protein gene (APP) showed preserved spontaneous respiration up to 12mo, but starting at 14mo showed significant differences from WT. Similar to WTs, odor-evoked sniffing was not impacted in APP mice up to 26mo. These results show that odor-orienting responses are minimally impacted throughout aging in mice, and suggest that the olfactomotor network is mostly spared of insults due to aging. PMID:21524667

  2. Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition

    PubMed Central

    Naruse, Mie; Ono, Ryuichi; Irie, Masahito; Nakamura, Kenji; Furuse, Tamio; Hino, Toshiaki; Oda, Kanako; Kashimura, Misho; Yamada, Ikuko; Wakana, Shigeharu; Yokoyama, Minesuke; Ishino, Fumitoshi; Kaneko-Ishino, Tomoko

    2014-01-01

    Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly acquired genes from LTR retrotransposons in eutherian mammals. Interestingly, Sirh7/Ldoc1 knockout (KO) mice exhibited abnormal placental cell differentiation/maturation, leading to an overproduction of placental progesterone (P4) and placental lactogen 1 (PL1) from trophoblast giant cells (TGCs). The placenta is an organ that is essential for mammalian viviparity and plays a major endocrinological role during pregnancy in addition to providing nutrients and oxygen to the fetus. P4 is an essential hormone in the preparation and maintenance of pregnancy and the determination of the timing of parturition in mammals; however, the biological significance of placental P4 in rodents is not properly recognized. Here, we demonstrate that mouse placentas do produce P4 in mid-gestation, coincident with a temporal reduction in ovarian P4, suggesting that it plays a role in the protection of the conceptuses specifically in this period. Pregnant Sirh7/Ldoc1 knockout females also displayed delayed parturition associated with a low pup weaning rate. All these results suggest that Sirh7/Ldoc1 has undergone positive selection during eutherian evolution as a eutherian-specific acquired gene because it impacts reproductive fitness via the regulation of placental endocrine function. PMID:25468940

  3. Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition.

    PubMed

    Naruse, Mie; Ono, Ryuichi; Irie, Masahito; Nakamura, Kenji; Furuse, Tamio; Hino, Toshiaki; Oda, Kanako; Kashimura, Misho; Yamada, Ikuko; Wakana, Shigeharu; Yokoyama, Minesuke; Ishino, Fumitoshi; Kaneko-Ishino, Tomoko

    2014-12-01

    Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly acquired genes from LTR retrotransposons in eutherian mammals. Interestingly, Sirh7/Ldoc1 knockout (KO) mice exhibited abnormal placental cell differentiation/maturation, leading to an overproduction of placental progesterone (P4) and placental lactogen 1 (PL1) from trophoblast giant cells (TGCs). The placenta is an organ that is essential for mammalian viviparity and plays a major endocrinological role during pregnancy in addition to providing nutrients and oxygen to the fetus. P4 is an essential hormone in the preparation and maintenance of pregnancy and the determination of the timing of parturition in mammals; however, the biological significance of placental P4 in rodents is not properly recognized. Here, we demonstrate that mouse placentas do produce P4 in mid-gestation, coincident with a temporal reduction in ovarian P4, suggesting that it plays a role in the protection of the conceptuses specifically in this period. Pregnant Sirh7/Ldoc1 knockout females also displayed delayed parturition associated with a low pup weaning rate. All these results suggest that Sirh7/Ldoc1 has undergone positive selection during eutherian evolution as a eutherian-specific acquired gene because it impacts reproductive fitness via the regulation of placental endocrine function.

  4. Diet‐induced obese mice exhibit altered immune responses to acute lung injury induced by Escherichia coli

    PubMed Central

    Wan, Taomei; Yuan, Guiqiang; Ren, Yi; Wang, Zhengyi; Jia, Yiping; Cui, Hengmin; Peng, Xi; Fang, Jing; Deng, Junliang; Yu, Shumin; Hu, Yanchun; Shen, Liuhong; Ma, Xiaoping; Wang, Ya; Ren, Zhihua

    2016-01-01

    Objective Obesity has been associated with impaired immunity and increased susceptibility to bacterial infection. It also exerts protective effects against mortality secondary to acute lung injury. The effects of obesity on immune responses to acute lung injury induced by Escherichia coli were investigated to determine if the above‐mentioned differences in its effects were related to infection severity. Methods Diet‐induced obesity (DIO) and lean control mice received intranasal instillations of 109 or 1010 CFUs of E. coli. The immune responses were examined at 0 h (uninfected), 24 h, and 96 h postinfection. Results Following infection, the DIO mice exhibited higher leukocyte, interleukin (IL)−10, IL‐6, and tumor necrosis factor‐α levels and more severe lung injury than the lean mice. Following inoculation with 1010 CFUs of E. coli, the DIO mice exhibited higher mortality and more severe inflammation‐induced injury than the lean mice, but no differences in E. coli counts were noted between the two groups. However, inoculated with 109 CFUs of E. coli, the DIO mice exhibited smaller E. coli burdens at 24 h and 96 h after infection, as well as lower concentrations of IL‐10 and tumor necrosis factor‐α and less severe lung injury at 96 h after infection. Conclusions The results support the emerging view that obesity may be beneficial in the setting of milder infection but detrimental in the setting of more severe infection. PMID:27558300

  5. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia.

    PubMed

    Miyakawa, Tsuyoshi; Leiter, Lorene M; Gerber, David J; Gainetdinov, Raul R; Sotnikova, Tatyana D; Zeng, Hongkui; Caron, Marc G; Tonegawa, Susumu

    2003-07-22

    Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.

  6. Motor Performance is Impaired Following Vestibular Stimulation in Ageing Mice

    PubMed Central

    Tung, Victoria W. K.; Burton, Thomas J.; Quail, Stephanie L.; Mathews, Miranda A.; Camp, Aaron J.

    2016-01-01

    Balance and maintaining postural equilibrium are important during stationary and dynamic movements to prevent falls, particularly in older adults. While our sense of balance is influenced by vestibular, proprioceptive, and visual information, this study focuses primarily on the vestibular component and its age-related effects on balance. C57Bl/6J mice of ages 1, 5–6, 8–9 and 27–28 months were tested using a combination of standard (such as grip strength and rotarod) and newly-developed behavioral tests (including balance beam and walking trajectory tests with a vestibular stimulus). In the current study, we confirm a decline in fore-limb grip strength and gross motor coordination as age increases. We also show that a vestibular stimulus of low frequency (2–3 Hz) and duration can lead to age-dependent changes in balance beam performance, which was evident by increases in latency to begin walking on the beam as well as the number of times hind-feet slip (FS) from the beam. Furthermore, aged mice (27–28 months) that received continuous access to a running wheel for 4 weeks did not improve when retested. Mice of ages 1, 10, 13 and 27–28 months were also tested for changes in walking trajectory as a result of the vestibular stimulus. While no linear relationship was observed between the changes in trajectory and age, 1-month-old mice were considerably less affected than mice of ages 10, 13 and 27–28 months. Conclusion: this study confirms there are age-related declines in grip strength and gross motor coordination. We also demonstrate age-dependent changes to finer motor abilities as a result of a low frequency and duration vestibular stimulus. These changes showed that while the ability to perform the balance beam task remained intact across all ages tested, behavioral changes in task performance were observed. PMID:26869921

  7. High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin)-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses.

    PubMed

    Clark, Erica S; Flannery, Brenna M; Gardner, Elizabeth M; Pestka, James J

    2015-10-19

    Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.

  8. Astaxanthin affects oxidative stress and hyposalivation in aging mice

    PubMed Central

    Kuraji, Manatsu; Matsuno, Tomonori; Satoh, Tazuko

    2016-01-01

    Oral dryness, a serious problem for the aging Japanese society, is induced by aging-related hyposalivation and causes dysphagia, dysgeusia, inadaptation of dentures, and growth of oral Candida albicans. Oxidative stress clearly plays a role in decreasing saliva secretion and treatment with antioxidants such astaxanthin supplements may be beneficial. Therefore, we evaluated the effects of astaxanthin on the oral saliva secretory function of aging mice. The saliva flow increased in astaxanthin-treated mice 72 weeks after administration while that of the control decreased by half. The plasma d-ROMs values of the control but not astaxanthin-treated group measured before and 72 weeks after treatment increased. The diacron-reactive oxygen metabolites (d-ROMs) value of astaxanthin-treated mice 72 weeks after treatment was significantly lower than that of the control group was. The plasma biological antioxidative potential (BAP) values of the control but not astaxanthin-treated mice before and 72 weeks after treatment decreased. Moreover, the BAP value of the astaxanthin-treated group 72 weeks after treatment was significantly higher than that of the control was. Furthermore, the submandibular glands of astaxanthin-treated mice had fewer inflammatory cells than the control did. Specifically, immunofluorescence revealed a significantly large aquaporin-5 positive cells in astaxanthin-treated mice. Our results suggest that astaxanthin treatment may prevent age-related decreased saliva secretion. PMID:27698533

  9. Altered left ventricular performance in aging physically active mice with an ankle sprain injury.

    PubMed

    Turner, Michael J; Guderian, Sophie; Wikstrom, Erik A; Huot, Joshua R; Peck, Bailey D; Arthur, Susan T; Marino, Joseph S; Hubbard-Turner, Tricia

    2016-02-01

    We assessed the impact of differing physical activity levels throughout the lifespan, using a musculoskeletal injury model, on the age-related changes in left ventricular (LV) parameters in active mice. Forty male mice (CBA/J) were randomly placed into one of three running wheel groups (transected CFL group, transected ATFL/CFL group, SHAM group) or a SHAM Sedentary group (SHAMSED). Before surgery and every 6 weeks after surgery, LV parameters were measured under 2.5 % isoflurane inhalation. Group effects for daily distance run was significantly greater for the SHAM and lesser for the ATLF/CFL mice (p = 0.013) with distance run decreasing with age for all mice (p < 0.0001). Beginning at 6 months of age, interaction (group × age) was noted with LV posterior wall thickness-to-radius ratios (h/r) where h/r increased with age in the ATFL/CFL and SHAMSED mice while the SHAM and CFL mice exhibited decreased h/r with age (p = 0.0002). Passive filling velocity (E wave) was significantly greater in the SHAM mice and lowest for the ATFL/CFL and SHAMSED mice (p < 0.0001) beginning at 9 months of age. Active filling velocity (A wave) was not different between groups (p = 0.10). Passive-to-active filling velocity ratio (E/A ratio) was different between groups (p < 0.0001), with higher ratios for the SHAM mice and lower ratios for the ATFL/CFL and SHAMSED mice in response to physical activity beginning at 9 months of age. Passive-to-active filling velocity ratio decreased with age (p < 0.0001). Regular physical activity throughout the lifespan improved LV structure, passive filling velocity, and E/A ratio by 6 to 9 months of age and attenuated any negative alterations throughout the second half of life. The diastolic filling differences were found to be significantly related to the amount of activity performed by 9 months and at the end of the lifespan.

  10. Cerebral lipid deposition in aged apolipoprotein-E-deficient mice.

    PubMed Central

    Walker, L. C.; Parker, C. A.; Lipinski, W. J.; Callahan, M. J.; Carroll, R. T.; Gandy, S. E.; Smith, J. D.; Jucker, M.; Bisgaier, C. L.

    1997-01-01

    To assess the influence of age and diet on cerebral pathology in mice lacking apolipoprotein E (apoE), four male apoE knockout mice (epsilon -/-), and five male wild-type (epsilon +/+) littermate controls were placed on a high-fat/high-cholesterol diet for 7 weeks beginning at 17 months of age. All four aged knockout mice developed xanthomatous lesions in the brain consisting mostly of crystalline cholesterol clefts, lipid globules, and foam cells. Smaller xanthomas were confined mainly to the choroid plexus and ventral fornix in the roof of the third ventricle, occasionally extending subpially along the choroidal fissure and into the adjacent parenchyma. More advanced xanthomas disrupted adjoining neural tissue in the fornix, hippocampus, and dorsal diencephalon; in one case, over 60% of one telencephalic hemisphere, including nearly the entire neocortex, was obliterated by the lesion. No xanthomas were observed in aged wild-type controls fed the high-fat/high-cholesterol diet. Brains from 42 additional animals, fed only conventional chow, were examined; 3 of 15 aged (15- to 23-month-old) apoE knockout mice developed small choroidal xanthomas. In contrast, no lesions were observed in five young (2- to 4-month-old) apoE knockout mice or in any wild-type controls between the ages of 2 and 23 months. Our findings indicate that disorders of lipid metabolism can induce significant pathological changes in the central nervous system of aged apoE knockout mice, particularly those on a high-fat/high-cholesterol diet. It may be fruitful to seek potential interactions between genetic factors and diet in modulating the risk of Alzheimer's disease and other neurodegenerative disorders in aged humans. Images Figure 1 Figure 2 PMID:9358763

  11. Sirt1 is involved in decreased bone formation in aged apolipoprotein E-deficient mice

    PubMed Central

    Hong, Wei; Xu, Xiao-ya; Qiu, Zhao-hui; Gao, Jian-jun; Wei, Zhan-ying; Zhen, Li; Zhang, Xiao-li; Ye, Zhi-bing

    2015-01-01

    Aim: Apolipoprotein E (ApoE) plays an important role in the transport and metabolism of lipids. Recent studies show that bone mass is increased in young apoE−/− mice. In this study we investigated the bone phenotype and metabolism in aged apoE−/− mice. Methods: Femurs and tibias were collected from 18- and 72-week-old apoE−/− mice and their age-matched wild-type (WT) littermates, and examined using micro-CT and histological analysis. Serum levels of total cholesterol, oxidized low-density lipoprotein (ox-LDL) and bone turnover markers were measured. Cultured bone mesenchymal stem cells (BMSCs) from tibias and femurs of 18-week-old apoE−/− mice were used in experiments in vitro. The expression levels of Sirt1 and Runx2 in bone tissue and BMSCs were measured using RT-PCR and Western blot analysis. Results: Compared with age-matched WT littermates, young apoE−/− mice exhibited high bone mass with increased bone formation, accompanied by higher serum levels of bone turnover markers OCN and TRAP5b, and higher expression levels of Sirt1, Runx2, ALP and OCN in bone tissue. In contrast, aged apoE−/− mice showed reduced bone formation and lower bone mass relative to age-matched WT mice, accompanied by lower serum OCN levels, and markedly reduced expression levels of Sirt1, Runx2, ALP and OCN in bone tissue. After BMSCs were exposed to ox-LDL (20 μg/mL), the expression of Sirt1 and Runx2 proteins was significantly increased at 12 h, and then decreased at 72 h. Treatment with the Sirt1 inhibitor EX527 (10 μmol/L) suppressed the expression of Runx2, ALP and OCN in BMSCs. Conclusion: In contrast to young apoE−/− mice, aged apoE−/− mice showe lower bone mass than age-matched WT mice. Long-lasting exposure to ox-LDL decreases the expression of Sirt1 and Runx2 in BMSCs, which may explain the decreased bone formation in aged apoE−/− mice. PMID:26592520

  12. Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice.

    PubMed

    Bajwa, Preety; Nielsen, Sarah; Lombard, Janine M; Rassam, Loui; Nahar, Pravin; Rueda, Bo R; Wilkinson, J Erby; Miller, Richard A; Tanwar, Pradeep S

    2017-01-31

    During aging, uncontrolled epithelial cell proliferation in the uterus results in endometrial hyperplasia and/or cancer development. The mTOR signaling pathway is one of the major regulators of aging as suppression of this pathway prolongs lifespan in model organisms. Genetic alterations in this pathway via mutations and/or amplifications are often encountered in endometrial cancers. However, the exact contribution of mTOR signaling and uterine aging to endometrial pathologies is currently unclear. This study examined the role of mTOR signaling in uterine aging and its implications in the development of endometrial hyperplasia. The hyperplastic endometrium of both postmenopausal women and aged mice exhibited elevated mTOR activity as seen with increased expression of the pS6 protein. Analysis of uteri from Pten heterozygous and Pten overexpressing mice further confirmed that over-activation of mTOR signaling leads to endometrial hyperplasia. Pharmacological inhibition of mTOR signaling using rapamycin treatment suppressed endometrial hyperplasia in aged mice. Furthermore, treatment with mTOR inhibitors reduced colony size and proliferation of a PTEN negative endometrial cancer cell line in 3D culture. Collectively, this study suggests that hyperactivation of the mTOR pathway is involved in the development of endometrial hyperplasia in aged women and mice.

  13. ApoE-/-Fas-/- C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis, and osteopenia.

    PubMed

    Feng, Xuebing; Li, Hongyun; Rumbin, Alexis A; Wang, Xuping; La Cava, Antonio; Brechtelsbauer, Katherine; Castellani, Lawrence W; Witztum, Joseph L; Lusis, Aldons J; Tsao, Betty P

    2007-04-01

    To establish a mouse model of accelerated atherosclerosis in lupus, we generated apolipoprotein E-deficient (apoE(-/-)) and Fas(lpr/lpr) (Fas(-/-)) C57BL/6 mice. On a normal chow diet, 5 month old apoE(-/-)Fas(-/-) mice had enlarged glomerular tuft areas, severe proteinuria, increased circulating autoantibody levels, and increased apoptotic cells in renal and vascular lesions compared with either single knockout mice. Also, double knockout mice developed increased atherosclerotic lesions but decreased serum levels of total and non-HDL cholesterol compared with apoE(-/-)Fas(+/+) littermates. Moreover, female apoE(-/-)Fas(-/-) mice had lower vertebral bone mineral density (BMD) and bone volume density (BV/TV) than age-matched female apoE(-/-)Fas(+/+) mice. Compared with apoE(-/-)Fas(+/+) and apoE(+/+)Fas(-/-) mice, apoE(-/-)Fas(-/-) mice had decreased circulating oxidized phospholipid (OxPL) content on apoB-100 containing lipoprotein particles and increased serum IgG antibodies to OxPL, which were significantly correlated with aortic lesion areas (r = 0.58), glomerular tuft areas (r = 0.87), BMD (r = -0.57), and BV/TV (r = -0.72). These results suggest that the apoE(-/-)Fas(-/-) mouse model might be used to study atherosclerosis and osteopenia in lupus. Correlations of IgG anti-OxPL with lupus-like disease, atherosclerosis, and bone loss suggested a shared pathway of these disease processes.

  14. Restoration of Retarded Influenza Virus-specific Immunoglobulin Class Switch in Aged Mice

    PubMed Central

    Zhang, Yongxin; Wang, Ying; Zhang, Monica; Liu, Lin; Mbawuike, Innocent N

    2016-01-01

    Objective The declined immune response to infection causes significant higher morbidity and mortality in aging in spite of the coexisted hyperimmunoglobulinemia (HIG). This study is to reveal the cellular basis of HIG and mechanism of weakened HA-specific IgG response in aged mice and to test cell therapy in the treatment of age-related IgG antibody production deficiency with immunocyte adoptive transfer. Methods BALB/c mice was immunized with Influenza A/Taiwan vaccine and challenged with the same strain of virus. ELISA was used to assess the levels of total immunoglobulins and antigen specific antibody response. The flow cytometry and ELISPOT were used to evaluate the frequencies of total immunoglobulin- and specific antibody-producing and secreting B lymphocytes. In vitro expanded mononuclear cells, CD4+ T lymphocytes and CD20+ B lymphocytes from old and young mice were adoptively transferred into influenza virus-challenged aged mice, and HA-specific IgG responses were observed. Results It is found that old mice exhibited higher levels of total serum IgG, IgM and IgA, higher frequencies of IgG+, IgM+ and IgA+ cells, and greater antigen-specific IgM and IgA responses to influenza infection, in comparison to young mice. However, influenza antigen- specific IgG and its subclass responses in old mice were significantly lower. Conclusion The retarded specific IgG response could be attributed to an insufficiency of immunoglobulin class switch in aging. Correlation analysis indicated that HIG and deficient specific IgG production in aged mice could be independent to each other in their pathogenesis. Correction of deficient specific IgG production by adoptive transfer of in vitro expanded and unexpanded CD4+ cells from immunized young mice suggests the CD4+ cell dysfunction contributes to the insufficiency of immunoglobulin class switch in aged mice. The transfusion of in vitro expanded lymphocytes could be a potential effective therapy for the age

  15. Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders

    PubMed Central

    Sakai, Kaori; Shoji, Hirotaka; Kohno, Takao; Miyakawa, Tsuyoshi; Hattori, Mitsuharu

    2016-01-01

    The secreted glycoprotein Reelin is believed to play critical roles in the pathogenesis of several neuropsychiatric disorders. The highly basic C-terminal region (CTR) of Reelin is necessary for efficient activation of its downstream signaling, and the brain structure of knock-in mice that lack the CTR (ΔC-KI mice) is impaired. Here, we performed a comprehensive behavioral test battery on ΔC-KI mice, in order to evaluate the effects of partial loss-of-function of Reelin on brain functions. The ΔC-KI mice were hyperactive and exhibited reduced anxiety-like and social behaviors. The working memory in ΔC-KI mice was impaired in a T-maze test. There was little difference in spatial reference memory, depression-like behavior, prepulse inhibition, or fear memory between ΔC-KI and wild-type mice. These results suggest that CTR-dependent Reelin functions are required for some specific normal brain functions and that ΔC-KI mice recapitulate some aspects of neuropsychiatric disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder. PMID:27346785

  16. Disruption of Protein Kinase A in Mice Enhances Healthy Aging

    PubMed Central

    Enns, Linda C.; Morton, John F.; Treuting, Piper R.; Emond, Mary J.; Wolf, Norman S.; McKnight, G. S.; Rabinovitch, Peter S.; Ladiges, Warren C.

    2009-01-01

    Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIβ, a regulatory subunit of PKA expressed in brain and adipose tissue, results in mice that are lean and insulin sensitive. It was therefore hypothesized that RIIB null (RIIβ−/−) mice would express anti-aging phenotypes. We conducted lifespan studies using 40 mutant and 40 wild type (WT) littermates of equal gender numbers and found that both the median and maximum lifespans were significantly increased in mutant males compared to WT littermates. The median lifespan was increased from 884 days to 1005 days (p = 0.006 as determined by the log rank test) and the 80% lifespan (defined here as 80% deaths) was increased from 941 days to 1073 days (p = 0.004 as determined by the Wang-Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders became increasingly obese with age, while mutant mice maintained their lean phenotype into old age. Adiposity was found to correlate with lifespan for males only. 50% of male mice between 30 and 35 g, corresponding to about 5% body fat, for either genotype lived over 1000 days. No male mouse outside of this weight range achieved this lifespan. During their last month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively), but RIIβ−/− male mice maintained their lean body mass to end of life. This attenuation of decline was not seen in female mutant mice. Old male mutant mice were insulin sensitive throughout their life. Both genders showed modestly lower blood glucose levels in old mutants compared to WT. Male mutants were also resistant to age-induced fatty liver. Pathological assessment of tissues from end of life male mutant mice showed a decrease in tumor incidence, decreased severity of renal lesions, and a trend towards a decrease in age

  17. Soluble Epoxide Hydrolase Null Mice Exhibit Female and Male Differences In Regulation of Vascular Homeostasis

    PubMed Central

    Vanella, Luca; Canestraro, Martina; Lee, Craig R.; Cao, Jian; Zeldin, Darryl C.; Schwartzman, Michal L.; Abraham, Nader G.

    2015-01-01

    Increased CYP epoxygenase activity and consequently up regulation of epoxyeicosatrienoic acids (EETs) levels provides protection against metabolic syndrome and cardiovascular diseases. Conversion of arachidonic acid epoxides to diols by soluble epoxide hydrolase (sEH) diminishes the beneficial cardiovascular properties of these epoxyeicosanoids. We therefore examined the possible biochemical consequences of sEH deletion on vascular responses in male and female mice. Through the use of the sEH KO mouse, we provide evidence of differences in the compensatory response in the balance between nitric oxide (NO), carbon monoxide (CO), EETs and the vasoconstrictor 20-HETE in male and female KO mice. Serum levels of adiponectin, TNFα, IL-1b and MCP1 and protein expression in vascular tissue of p-AMPK, p-AKT and p-eNOS were measured. Deletion of sEH caused a significant (p<0,05) decrease in body weight, and an increase in adiponectin, pAMPK and pAKT levels in female KO mice compared to male KO mice. Gene deletion resulted in a higher production of renal EETs in female KO compared to male KO mice and, concomitantly, we observed an increase in renal 20-HETEs levels and superoxide anion production only in male KO mice. sEH deletion increased p-AKT and p-eNOS protein expression but decreased p-AMPK levels in female KO mice. Increased levels of p-eNOS at Thr-495 were observed only in KO male mice. While p-eNOS at 1177 were not significantly different between male and female. Nitric oxide production was unaltered in male KO mice. These results provide evidence of gender differences in the preservation of vascular homeostasis in response to sEH deletion which involves regulation of phosphorylation of eNOS at the 495 site. PMID:25908301

  18. Running reduces stress and enhances cell genesis in aged mice.

    PubMed

    Kannangara, Timal S; Lucero, Melanie J; Gil-Mohapel, Joana; Drapala, Robert J; Simpson, Jessica M; Christie, Brian R; van Praag, Henriette

    2011-12-01

    Cell proliferation and neurogenesis are diminished in the aging mouse dentate gyrus. However, it is not known whether isolated or social living affects cell genesis and stress levels in old animals. To address this question, aged (17-18 months old) female C57Bl/6 mice were single or group housed, under sedentary or running conditions. We demonstrate that both individual and socially housed aged C57Bl/6 mice have comparable basal cell proliferation levels and demonstrate increased running-induced cell genesis. To assess stress levels in young and aged mice, corticosterone (CORT) was measured at the onset of the active/dark cycle and 4h later. In young mice, no differences in CORT levels were observed as a result of physical activity or housing conditions. However, a significant increase in stress in socially housed, aged sedentary animals was observed at the onset of the dark cycle; CORT returned to basal levels 4h later. Together, these results indicate that voluntary exercise reduces stress in group housed aged animals and enhances hippocampal cell proliferation.

  19. Modeling early-onset post-ischemic seizures in aging mice.

    PubMed

    Wu, Chiping; Wang, Justin; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2015-09-01

    Stroke is the leading cause of seizures and epilepsy in the aged population, with post-stroke seizures being a poor prognostic factor. The pathological processes underlying post-stroke seizures are not well understood and studies of these seizures in aging/aged animals remain scarce. Therefore, our primary objective was to model post-stroke seizures in aging mice (C57 black strain, 16-20 months-old), with a focus on early-onset, convulsive seizures that occur within 24-hours of brain ischemia. We utilized a middle cerebral artery occlusion model and examined seizure activity and brain injury using combined behavioral and electroencephalographic monitoring and histological assessments. Aging mice exhibited vigorous convulsive seizures within hours of the middle cerebral artery occlusion. These seizures manifested with jumping, rapid running, barrel-rolling and/or falling all in the absence of hippocampal-cortical electrographic discharges. Seizure development was closely associated with severe brain injury and acute mortality. Anticonvulsive treatments after seizure occurrence offered temporary seizure control but failed to improve animal survival. A separate cohort of adult mice (6-8 months-old) exhibited analogous early-onset convulsive seizures following the middle cerebral artery occlusion but had better survival outcomes following anticonvulsive treatment. Collectively, our data suggest that early-onset convulsive seizures are a result of severe brain ischemia in aging animals.

  20. Transmitochondrial mito-miceΔ and mtDNA mutator mice, but not aged mice, share the same spectrum of musculoskeletal disorders.

    PubMed

    Mito, Takayuki; Ishizaki, Hikari; Suzuki, Michiko; Morishima, Hitomi; Ota, Azusa; Ishikawa, Kaori; Nakada, Kazuto; Maeno, Akiteru; Shiroishi, Toshihiko; Hayashi, Jun-Ichi

    2015-01-24

    The spectra of phenotypes associated with aging and mitochondrial diseases sometimes appear to overlap with each other. We used aged mice and a mouse model of mitochondrial diseases (transmitochondrial mito-miceΔ with deleted mtDNA) to study whether premature aging phenotypes observed in mtDNA mutator mice are associated with aging or mitochondrial diseases. Here, we provide convincing evidence that all the mice examined had musculoskeletal disorders of osteoporosis and muscle atrophy, which correspond to phenotypes prevalently observed in the elderly. However, precise investigation of musculoskeletal disorders revealed that the spectra of osteoporosis and muscle atrophy phenotypes in mtDNA mutator mice were very close to those in mito-miceΔ, but different from those of aged mice. Therefore, mtDNA mutator mice and mito-miceΔ, but not aged mice, share the spectra of musculoskeletal disorders.

  1. Increased human AP endonuclease 1 level confers protection against the paternal age effect in mice

    PubMed Central

    Sanchez, Jamila R.; Reddick, Traci L.; Perez, Marissa; Centonze, Victoria E.; Mitra, Sankar; Izumi, Tadahide; McMahan, C. Alex; Walter, Christi A.

    2015-01-01

    Increased paternal age is associated with a greater risk of producing children with genetic disorders originating from de novo germline mutations. Mice mimic the human condition by displaying an age-associated increase in spontaneous mutant frequency in spermatogenic cells. The observed increase in mutant frequency appears to be associated with a decrease in the DNA repair protein, AP endonuclease1 (APEX1) and Apex1 heterozygous mice display an accelerated paternal age effect as young adults. In this study, we directly tested if APEX1 over-expression in cell lines and transgenic mice could prevent increases in mutagenesis. Cell lines with ectopic expression of APEX1 had increased APEX1 activity and lower spontaneous and induced mutations in the lacI reporter gene relative to the control. Spermatogenic cells obtained from mice transgenic for human APEX1 displayed increased APEX1 activity, were protected from the age-dependent increase in spontaneous germline mutagenesis, and exhibited increased apoptosis in the spermatogonial cell population. These results directly indicate that increases in APEX1 level confer protection against the murine paternal age effect, thus highlighting the role of APEX1 in preserving reproductive health with increasing age and in protection against genotoxin-induced mutagenesis in somatic cells. PMID:26201249

  2. 5-lipoxygenase knockout mice exhibit a resistance to acute pancreatitis induced by cerulein

    PubMed Central

    Cuzzocrea, Salvatore; Rossi, Antonietta; Serraino, Ivana; Di Paola, Rosanna; Dugo, Laura; Genovese, Tiziana; Britti, Domenico; Sciarra, Giuseppe; De Sarro, Angelina; Caputi, Achille P; Sautebin, Lidia

    2003-01-01

    Here we compare the degree of pancreatitis caused by cerulein in mice lacking 5-lipoxygenase (5-LO) and in the corresponding wild-type mice. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for intracellular adhesion molecule-1 (ICAM-1), P-selectin and E-selectin in the pancreas and lung of cerulein-treated mice. In contrast, the degree of (1) pancreatic inflammation and tissue injury (histological score), (2) up-regulation/expression of P-selectin, E-selectin and ICAM-1, and (3) neutrophil infiltration was markedly reduced in pancreatic and lung tissue obtained from cerulein-treated 5-LO-deficient mice. These findings support the view that 5-LO plays an important, pro-inflammatory role in the acute pancreatitis caused by cerulein in mice. PMID:12941149

  3. Portal veins of mice infected with Schistosoma mansoni exhibit an increased reactivity to 5-hydroxytryptamine.

    PubMed

    Silva, C L; Morel, N; Noël, F

    1998-01-01

    In chronic severe infection with Schistosoma mansoni, portal hypertension and related vascular alterations usually develop as a consequence of granulomatous response to eggs. In order to investigate a putative direct effect of worms on the reactivity of their host portal vein, mice infected only with male worms were used in the present study. An higher reactivity to 5-hydroxytryptamine (5-HT) characterized by an increase in the maximal contraction and sensitivity was observed in portal vein from infected mice compared to healthy mice. Blockade of NO-synthase with l-NAME induced a small increase in 5-HT potency in portal vein from non-infected mice without changing the amplitude of the contractions, whereas it did not alter the reactivity of veins from infected mice. The present results show that unisexual infection of mice with male S. mansoni increased the reactivity of the portal vein to 5-HT which seems to be partially related to an alteration in the nitric oxide release by endothelium.

  4. Lycopersicon esculentum Extract Enhances Cognitive Function and Hippocampal Neurogenesis in Aged Mice

    PubMed Central

    Bae, Jung-Soo; Han, Mira; Shin, Hee Soon; Shon, Dong-Hwa; Lee, Soon-Tae; Shin, Chang-Yup; Lee, Yuri; Lee, Dong Hun; Chung, Jin Ho

    2016-01-01

    A decrease in adult neurogenesis is associated with the aging process, and this decrease is closely related to memory impairment. Tomato (Lycopersicon esculentum) is a fruit with diverse bioactive nutrients that is consumed worldwide. In this study, we investigated the cognition-enhancing effect of tomato ethanolic extracts (TEE) in aged mice. Six weeks of oral TEE administration in 12-month-old aged mice significantly increased their exploration time of novel objects when compared to vehicle-treated mice. The TEE supplement increased doublecortin (DCX)-positive cells and postsynaptic density-95 (PSD95) expression in mice hippocampus. Moreover, we found an increased expression of brain-derived neurotrophic factor (BDNF) and subsequently-activated extracellular-signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling pathway in the TEE-supplemented mice hippocampus. In conclusion, the oral administration of TEE exhibits a cognition-enhancing effect, and the putative underlying mechanism is the induction of BDNF signaling-mediated proliferation and synapse formation in the hippocampus. These findings indicate that TEE could be a candidate for treatment of age-related memory impairment and neurodegenerative disorders. PMID:27792185

  5. Lycopersicon esculentum Extract Enhances Cognitive Function and Hippocampal Neurogenesis in Aged Mice.

    PubMed

    Bae, Jung-Soo; Han, Mira; Shin, Hee Soon; Shon, Dong-Hwa; Lee, Soon-Tae; Shin, Chang-Yup; Lee, Yuri; Lee, Dong Hun; Chung, Jin Ho

    2016-10-26

    A decrease in adult neurogenesis is associated with the aging process, and this decrease is closely related to memory impairment. Tomato (Lycopersicon esculentum) is a fruit with diverse bioactive nutrients that is consumed worldwide. In this study, we investigated the cognition-enhancing effect of tomato ethanolic extracts (TEE) in aged mice. Six weeks of oral TEE administration in 12-month-old aged mice significantly increased their exploration time of novel objects when compared to vehicle-treated mice. The TEE supplement increased doublecortin (DCX)-positive cells and postsynaptic density-95 (PSD95) expression in mice hippocampus. Moreover, we found an increased expression of brain-derived neurotrophic factor (BDNF) and subsequently-activated extracellular-signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling pathway in the TEE-supplemented mice hippocampus. In conclusion, the oral administration of TEE exhibits a cognition-enhancing effect, and the putative underlying mechanism is the induction of BDNF signaling-mediated proliferation and synapse formation in the hippocampus. These findings indicate that TEE could be a candidate for treatment of age-related memory impairment and neurodegenerative disorders.

  6. Modulation of cutaneous wound healing by ozone: differences between young and aged mice.

    PubMed

    Lim, Yunsook; Phung, Anh D; Corbacho, Ana M; Aung, Hnin Hnin; Maioli, Emanuela; Reznick, Abraham Z; Cross, Carroll E; Davis, Paul A; Valacchi, Giuseppe

    2006-01-05

    Cutaneous tissues are frequently exposed to prooxidative environments, including UV radiation and air pollutants. Among the latter, ozone (O(3)) is of particular concern because of its high and dominating presence in photochemical smog. It is well known that O(3) depletes small molecular weight antioxidants, oxidizes proteins, induces lipid peroxidation and activates cellular responses in various tissues. Using an in vivo model (SKH-1 hairless mice), the interaction between O(3) exposure (0.5ppmx6h/day) and age was examined in relation to cutaneous wound healing. Compared to younger (8 weeks) mice, older (18 months) mice exposed to O(3) (day 0 to day 9 after wounding) exhibited delayed wound closure, increased lipid peroxidation (measured as 4-HNE protein adducts) and protein oxidation (measured as carbonyls concentration) and decreased levels of P-IkappaBalpha and TGFbeta protein. These findings support the hypothesis that oxidant pollutant exposure and age interact so as to disrupt normal wound healing processes.

  7. Accelerated retinal aging in PACAP knock-out mice.

    PubMed

    Kovács-Valasek, Andrea; Szabadfi, Krisztina; Dénes, Viktória; Szalontai, Bálint; Tamás, Andrea; Kiss, Péter; Szabó, Aliz; Setalo, Gyorgy; Reglődi, Dóra; Gábriel, Robert

    2017-02-13

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophic and neuroprotective peptide. PACAP and its receptors are widely distributed in the retina. A number of reports provided evidence that PACAP is neuroprotective in retinal degenerations. The current study compared retina cell type-specific differences in young (3-4months) and aged adults (14-16months), of wild-type (WT) mice and knock-out (KO) mice lacking endogenous PACAP production during the course of aging. Histological, immunocytochemical and Western blot examinations were performed. The staining for standard neurochemical markers (tyrosine hydroxylase for dopaminergic cells, calbindin 28 kDa for horizontal cells, protein kinase Cα for rod bipolar cells) of young adult PACAP KO retinas showed no substantial alterations compared to young adult WT retinas, except for the specific PACAP receptor (PAC1-R) staining. We could not detect PAC1-R immunoreactivity in bipolar and horizontal cells in young adult PACAP KO animals. Some other age-related changes were observed only in the PACAP KO mice only. These alterations included horizontal and rod bipolar cell dendritic sprouting into the photoreceptor layer and decreased ganglion cell number. Also, Müller glial cells showed elevated GFAP expression compared to the aging WT retinas. Furthermore, Western blot analyses revealed significant differences between the phosphorylation state of ERK1/2 and JNK in KO mice, indicating alterations in the MAPK signaling pathway. These results support the conclusion that endogenous PACAP contributes to protection against aging of the nervous system.

  8. Secreted Protein Acidic and Rich in Cysteine (SPARC)-Null Mice Exhibit More Uniform Outflow

    PubMed Central

    Swaminathan, Swarup S.; Oh, Dong-Jin; Kang, Min Hyung; Ren, Ruiyi; Jin, Rui; Gong, Haiyan; Rhee, Douglas J.

    2013-01-01

    Purpose. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein known to regulate extracellular matrix (ECM) in many tissues and is highly expressed in trabecular meshwork (TM). SPARC-null mice have a 15% to 20% decrease in intraocular pressure (IOP) compared to wild-type (WT) mice. We hypothesized that mouse aqueous outflow is segmental, and that transgenic deletion of SPARC causes a more uniform pattern that correlates with IOP and TM morphology. Methods. Eyes of C57BL6-SV129 WT and SPARC-null mice were injected with fluorescent microbeads, which were also passively exposed to freshly enucleated eyes. Confocal and electron microscopy were performed. Percentage effective filtration length (PEFL) was calculated as PEFL = FL/TL × 100%, where TL = total length and FL = filtration length. IOP was measured by rebound tonometry. Results. Passive microbead affinity for WT and SPARC-null ECM did not differ. Segmental flow was observed in the mouse eye. SPARC-null mice had a 23% decrease in IOP. PEFL increased in SPARC-null (70.61 ± 11.36%) versus WT mice (54.68 ± 9.95%, P < 0.005; n = 11 pairs), and PEFL and IOP were negatively correlated (R2 = 0.72, n = 10 pairs). Morphologically, TM of high-tracer regions had increased separation between beams compared to low-tracer regions. Collagen fibril diameter decreased in SPARC-null (28.272 nm) versus WT tissue (34.961 nm, P < 0.0005; n = 3 pairs). Conclusions. Aqueous outflow in mice is segmental. SPARC-null mice demonstrated a more uniform outflow pattern and decreased collagen fibril diameter. Areas of high flow had less compact juxtacanalicular connective tissue ECM, and IOP was inversely correlated with PEFL. Our data show a correlation between morphology, aqueous outflow, and IOP, indicating a modulatory role of SPARC in IOP regulation. PMID:23422826

  9. Mice Deficient for Prion Protein Exhibit Normal Neuronal Excitability and Synaptic Transmission in the Hippocampus

    NASA Astrophysics Data System (ADS)

    Lledo, Pierre-Marie; Tremblay, Patrick; Dearmond, Stephen J.; Prusiner, Stanley B.; Nicoll, Roger A.

    1996-03-01

    We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus.

  10. Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype.

    PubMed

    Guiard, Bruno P; David, Denis J P; Deltheil, Thierry; Chenu, Franck; Le Maître, Erwan; Renoir, Thibault; Leroux-Nicollet, Isabelle; Sokoloff, Pierre; Lanfumey, Laurence; Hamon, Michel; Andrews, Anne M; Hen, René; Gardier, Alain M

    2008-02-01

    Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.

  11. C57BL/6J MICE EXHIBIT REDUCED DOPAMINE D3 RECEPTOR-MEDIATED LOCOMOTOR-INHIBITORY FUNCTION RELATIVE TO DBA/2J MICE

    PubMed Central

    McNAMARA, R. K.; LEVANT, B.; TAYLOR, B.; AHLBRAND, R.; LIU, Y.; SULLIVAN, J. R.; STANFORD, K.; RICHTAND, N. M.

    2007-01-01

    Previous reports have identified greater sensitivity to the locomotor-stimulating, sensitizing, and reinforcing effects of amphetamine in inbred C57BL/6J mice relative to inbred DBA/2J mice. The dopamine D3 receptor (D3R) plays an inhibitory role in the regulation of rodent locomotor activity, and exerts inhibitory opposition to D1 receptor (D1R)-mediated signaling. Based on these observations, we investigated D3R expression and D3R-mediated locomotor-inhibitory function, as well as D1R binding and D1R-mediated locomotor-stimulating function, in C57BL/6J and DBA/2J mice. C57BL/6J mice exhibited lower D3R binding density (−32%) in the ventral striatum (nucleus accumbens/islands of Calleja), lower D3R mRNA expression (−26%) in the substantia nigra/ventral tegmentum, and greater D3R mRNA expression (+40%) in the hippocampus, relative to DBA/2J mice. There were no strain differences in DR3 mRNA expression in the ventral striatum or prefrontal cortex, nor were there differences in D1R binding in the ventral striatum. Behaviorally, C57BL/6J mice were less sensitive to the locomotor-inhibitory effect of the D3R agonist PD128907 (10 μg/kg), and more sensitive to the locomotor-stimulating effects of novelty, amphetamine (1 mg/kg), and the D1R-like agonist ±-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8,-diol hydrochloride (SKF38393) (5–20 mg/kg) than DBA/2J mice. While the selective D3R antagonist N-(4-[4-{2,3-dichlorphenyl}-1 piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904) (0.01–1.0 mg/kg) augmented novelty-, amphetamine-, and SKF38393-induced locomotor activity in DBA/2J mice, it reduced novelty-induced locomotor activity in C57BL/6J mice. Collectively, these results demonstrate that C57BL/6J mice exhibit less D3R-mediated inhibitory function relative to DBA/2J mice, and suggest that reduced D3R-mediated inhibitory function may contribute to heightened sensitivity to the locomotor-stimulating effects of amphetamine in the C57BL/6J mouse strain

  12. Age-related deterioration of rod vision in mice.

    PubMed

    Kolesnikov, Alexander V; Fan, Jie; Crouch, Rosalie K; Kefalov, Vladimir J

    2010-08-18

    Even in healthy individuals, aging leads to deterioration in visual acuity, contrast sensitivity, visual field, and dark adaptation. Little is known about the neural mechanisms that drive the age-related changes of the retina and, more specifically, photoreceptors. According to one hypothesis, the age-related deterioration in rod function is due to the limited availability of 11-cis-retinal for rod pigment formation. To determine how aging affects rod photoreceptors and to test the retinoid-deficiency hypothesis, we compared the morphological and functional properties of rods of adult and aged B6D2F1/J mice. We found that the number of rods and the length of their outer segments were significantly reduced in 2.5-year-old mice compared with 4-month-old animals. Aging also resulted in a twofold reduction in the total level of opsin in the retina. Behavioral tests revealed that scotopic visual acuity and contrast sensitivity were decreased by twofold in aged mice, and rod ERG recordings demonstrated reduced amplitudes of both a- and b-waves. Sensitivity of aged rods determined from single-cell recordings was also decreased by 1.5-fold, corresponding to not more than 1% free opsin in these photoreceptors, and kinetic parameters of dim flash response were not altered. Notably, the rate of rod dark adaptation was unaffected by age. Thus, our results argue against age-related deficiency of 11-cis-retinal in the B6D2F1/J mouse rod visual cycle. Surprisingly, the level of cellular dark noise was increased in aged rods, providing an alternative mechanism for their desensitization.

  13. Towards the modelling of ageing and atherosclerosis effects in ApoE(-/-) mice aortic tissue.

    PubMed

    Waffenschmidt, Tobias; Cilla, Myriam; Sáez, Pablo; Pérez, Marta M; Martínez, Miguel A; Menzel, Andreas; Peña, Estefanía

    2016-08-16

    The goal of this work consists in a quantitative analysis and constitutive modelling of ageing processes associated to plaque formation in mice arteries. Reliable information on the characteristic evolution of pressure-stretch curves due to the ageing effects is extracted from previous inflation test experiments. Furthermore, characteristic age-dependent material parameters are identified on the basis of a continuum-mechanics-based parameter optimisation technique. The results indicate that the aorta-stiffness of the healthy control mice remains basically constant irrespective of the diet-time and age. In contrast, significant differences exist within the material response and in consequence within the material parameters between the ApoE(-/-) and the control mice as well as for the different locations over the aorta which is underlined by our experimental observations. With regard to the temporal evolution of the material parameters, we observe that the material parameters for the ApoE(-/-) mice aortas exhibit a saturation-type increase with respect to age.

  14. Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy.

    PubMed

    Osaki, Yoshinori; Nakagawa, Yoshimi; Miyahara, Shoko; Iwasaki, Hitoshi; Ishii, Akiko; Matsuzaka, Takashi; Kobayashi, Kazuto; Yatoh, Shigeru; Takahashi, Akimitsu; Yahagi, Naoya; Suzuki, Hiroaki; Sone, Hirohito; Ohashi, Ken; Ishibashi, Shun; Yamada, Nobuhiro; Shimano, Hitoshi

    2015-10-23

    HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs.

  15. Senescence-accelerated Mice (SAMs) as a Model for Brain Aging and Immunosenescence

    PubMed Central

    Shimada, Atsuyoshi; Hasegawa-Ishii, Sanae

    2011-01-01

    The Senescence-Accelerated Mouse (SAM) represents a group of inbred mouse strains developed as a model for the study of human aging and age-related diseases. Senescence-prone (SAMP) strains exhibit an early onset of age-related decline in the peripheral immunity such as thymic involution, loss of CD4+ T cells, impaired helper T cell function, decreased antibody-forming capacity, dysfunction of antigen-presenting cells, decreased natural killer activity, increased auto-antibodies, and susceptibility to virus infection. Senescence-prone SAMP10 mice undergo age-related changes in the brain such as brain atrophy, shrinkage and loss of cortical neurons, retraction of cortical neuronal dendrites, loss of dendritic spines, loss of synapses, impaired learning and memory, depressive behavior, accumulation of neuronal DNA damage, neuronal ubiquitinated inclusions, reduced hippocampal cholinergic receptors, decreased neurotrophic factors, decreased hippocampal zinc and zinc transporters, increased sphyngomyelinase, and elevated oxidative-nitrative stress. Recent data indicating increased pro-inflammatory cytokines in the brain of SAMP10 mice are directing investigators toward an integration of immune and neural abnormalities to enhance understanding of the principles of brain aging. We highlight how mouse brain cells adopt cytokine-mediated responses and how SAMP10 mice are defective in these responses. SAMP10 model would be useful to study how age-related disturbances in peripheral immunity have an impact on dysregulation of brain tissue homeostasis, resulting in age-related neurodegeneration. PMID:22396891

  16. Transgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice

    PubMed Central

    Feng, Mingxiao; Field, Kevin; Chatzistamou, Ioulia; Shim, Minsub

    2016-01-01

    Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders. PMID:27750221

  17. Mice lacking integrin β3 expression exhibit altered response to chronic stress

    PubMed Central

    Varney, Seth; Polston, Keith F.; Jessen, Tammy; Carneiro, Ana M.D.

    2015-01-01

    Recent studies indicate multiple roles for integrin αvβ3 in adult neurons, including response to pharmacological agents such as cocaine and selective serotonin reuptake inhibitors. In this study, we examined the role of the integrin β3 gene (Itgb3) in the response to environmental stimuli by subjecting Itgb3+/+ and Itgb3−/− mice to unpredictable chronic mild stressors. We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test. In this test, chronic stress elicited significant decreases in stereotypic behavior and horizontal locomotor activity, including increases in anxiety behaviors. Mild chronic stress led to reductions in dopamine turnover in midbrains of Itgb3+/+, but not Itgb3−/− mice, suggesting a disruption of stress-dependent regulation of DA homeostasis. Chronic stress elicited altered synaptic expression of syntaxin and synaptophysin in midbrains of Itgb3−/− mice, when compared to Itgb3+/+. Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain. Moreover, loss of integrin β3 expression modifies this correlation network. Together, these findings demonstrate that Itgb3−/− mice display a pattern of changes indicating disrupted regulation of midbrain synaptic systems involved in conferring resilience to mild stressors. PMID:26634222

  18. 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.

  19. Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice.

    PubMed

    McLaughlin, Precious J; Bakall, Benjamin; Choi, Jiwon; Liu, Zhonglin; Sasaki, Takako; Davis, Elaine C; Marmorstein, Alan D; Marmorstein, Lihua Y

    2007-12-15

    A mutation in the EFEMP1 gene causes Malattia Leventinese, an inherited macular degenerative disease with strong similarities to age-related macular degeneration. EFEMP1 encodes fibulin-3, an extracellular matrix protein of unknown function. To investigate its biological role, the murine Efemp1 gene was inactivated through targeted disruption. Efemp1(-/-) mice exhibited reduced reproductivity, and displayed an early onset of aging-associated phenotypes including reduced lifespan, decreased body mass, lordokyphosis, reduced hair growth, and generalized fat, muscle and organ atrophy. However, these mice appeared to have normal wound healing ability. Efemp1(-/-) mice on a C57BL/6 genetic background developed multiple large hernias including inguinal hernias, pelvic prolapse and protrusions of the xiphoid process. In contrast, Efemp1(-/-) mice on a BALB/c background rarely had any forms of hernias, indicating the presence of modifiers for fibulin-3's function in different mouse strains. Histological analysis revealed a marked reduction of elastic fibers in fascia, a thin layer of connective tissue maintaining and protecting structures throughout the body. No apparent macular degeneration associated defects were found in Efemp1(-/-) mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in EFEMP1 causes macular degeneration. These data demonstrate that fibulin-3 plays an important role in maintaining the integrity of fascia connective tissues and regulates aging.

  20. 76 FR 51458 - Culturally Significant Objects Imported for Exhibition Determinations: “Wonder of the Age: Master...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-18

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF STATE Culturally Significant Objects Imported for Exhibition Determinations: ``Wonder of the Age: Master Painters... Age: Master Painters of India, 1100-1900,'' imported from abroad for temporary exhibition within...

  1. 76 FR 56492 - Culturally Significant Objects Imported for Exhibition Determinations: “Antico: The Golden Age of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-13

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF STATE Culturally Significant Objects Imported for Exhibition Determinations: ``Antico: The Golden Age of..., 2003), I hereby determine that the objects to be included in the exhibition ``Antico: The Golden Age...

  2. Kidney EPO expression during chronic hypoxia in aged mice.

    PubMed

    Benderro, Girriso F; LaManna, Joseph C

    2013-01-01

    In order to maintain normal cellular function, mammalian tissue oxygen concentrations must be tightly regulated within a narrow physiological range. The hormone erythropoietin (EPO) is essential for maintenance of tissue oxygen supply by stimulating red blood cell production and promoting their survival. In this study we compared the effects of 290 Torr atmospheric pressure on the kidney EPO protein levels in young (4-month-old) and aged (24-month-old) C57BL/6 mice. The mice were sacrificed after being anesthetized, and kidney samples were collected and processed by Western blot analysis. Relatively low basal expression of EPO during normoxia in young mice showed significant upregulation in hypoxia and stayed upregulated throughout the hypoxic period (threefold compared to normoxic control), showing a slight decline toward the third week. Whereas, a relatively higher normoxic basal EPO protein level in aged mice did not show significant increase until seventh day of hypoxia, but showed significant upregulation in prolonged hypoxia. Hence, we confirmed that there is a progressively increased accumulation of EPO during chronic hypoxia in young and aged mouse kidney, and the EPO upregulation during hypoxia showed a similarity with the pattern of increase in hematocrit, which we have reported previously.

  3. Escherichia coli Braun Lipoprotein (BLP) exhibits endotoxemia – like pathology in Swiss albino mice

    PubMed Central

    Lakshmikanth, Chikkamenahalli Lakshminarayana; Jacob, Shancy Petsel; Kudva, Avinash Kundadka; Latchoumycandane, Calivarathan; Yashaswini, Puttaraju Srikanta Murthy; Sumanth, Mosale Seetharam; Goncalves-de-Albuquerque, Cassiano F.; Silva, Adriana R.; Singh, Sridevi Annapurna; Castro-Faria-Neto, Hugo C.; Prabhu, Sandeep Kumble; McIntyre, Thomas M.; Marathe, Gopal Kedihithlu

    2016-01-01

    The endotoxin lipopolysaccharide (LPS) promotes sepsis, but bacterial peptides also promote inflammation leading to sepsis. We found, intraperitoneal administration of live or heat inactivated E. coli JE5505 lacking the abundant outer membrane protein, Braun lipoprotein (BLP), was less toxic than E. coli DH5α possessing BLP in Swiss albino mice. Injection of BLP free of LPS purified from E. coli DH5α induced massive infiltration of leukocytes in lungs and liver. BLP activated human polymorphonuclear cells (PMNs) ex vivo to adhere to denatured collagen in serum and polymyxin B independent fashion, a property distinct from LPS. Both LPS and BLP stimulated the synthesis of platelet activating factor (PAF), a potent lipid mediator, in human PMNs. In mouse macrophage cell line, RAW264.7, while both BLP and LPS similarly upregulated TNF-α and IL-1β mRNA; BLP was more potent in inducing cyclooxygenase-2 (COX-2) mRNA and protein expression. Peritoneal macrophages from TLR2−/− mice significantly reduced the production of TNF-α in response to BLP in contrast to macrophages from wild type mice. We conclude, BLP acting through TLR2, is a potent inducer of inflammation with a response profile both common and distinct from LPS. Hence, BLP mediated pathway may also be considered as an effective target against sepsis. PMID:27698491

  4. Transgenic Mice Overexpressing Renin Exhibit Glucose Intolerance and Diet-Genotype Interactions

    PubMed Central

    Fletcher, Sarah J.; Kalupahana, Nishan S.; Soltani-Bejnood, Morvarid; Kim, Jung Han; Saxton, Arnold M.; Wasserman, David H.; De Taeye, Bart; Voy, Brynn H.; Quignard-Boulange, Annie; Moustaid-Moussa, Naima

    2013-01-01

    Numerous animal and clinical investigations have pointed to a potential role of the renin-angiotensin system (RAS) in the development of insulin resistance and diabetes in conditions of expanded fat mass. However, the mechanisms underlying this association remain unclear. We used a transgenic mouse model overexpressing renin in the liver (RenTgMK) to examine the effects of chronic activation of RAS on adiposity and insulin sensitivity. Hepatic overexpression of renin resulted in constitutively elevated plasma angiotensin II (four- to six-fold increase vs. wild-type, WT). Surprisingly, RenTgMK mice developed glucose intolerance despite low levels of adiposity and insulinemia. The transgenics also had lower plasma triglyceride levels. Glucose intolerance in transgenic mice fed a low-fat diet was comparable to that observed in high-fat fed WT mice. These studies demonstrate that overexpression of renin and associated hyperangiotensinemia impair glucose tolerance in a diet-dependent manner and further support a consistent role of RAS in the pathogenesis of diabetes and insulin resistance, independent of changes in fat mass. PMID:23308073

  5. Lung remodeling in aging surfactant protein D deficient mice.

    PubMed

    Schneider, Jan Philipp; Arkenau, Martina; Knudsen, Lars; Wedekind, Dirk; Ochs, Matthias

    2017-02-07

    Pulmonary surfactant, a mixture of lipids and proteins at the air-liquid interface of alveoli, prevents the lungs from collapsing due to surface tension. One constituent is surfactant-associated protein-D (SP-D), a protein involved in surfactant homeostasis and innate immunity. Mice deficient in SP-D (SP-D (-/-)) has been described as developing a characteristic phenotype which affects the surfactant system (including changes in the intra-cellular and intra-alveolar surfactant pool, alveolar epithelial type II cells and alveolar macrophages), lung architecture and its inflammatory state (development of an emphysema-like pathology, inflammatory cell infiltration). Furthermore, it has been described that these mice develop sub-pleural fibrosis and a thickening of alveolar septal walls. The aim of the present study was to systematically investigate the long term progression of this phenotype with special focus on parenchymal remodeling, whether there are progressive emphysematous changes and whether there is progressive septal wall thickening which might indicate the development of pulmonary fibrosis. By means of design-based stereology and light microscopy, lungs of wild type (wt) and SP-D (-/-) mice of four age groups (3, 6, 12 and ∼18 months) were investigated. The data do not suggest a relevant spontaneous pro-fibrotic remodeling or a destructive process in the aging SP-D (-/-) mice. We demonstrated neither a significant destructive emphysema nor significant thickening of alveolar septal walls, but the data suggest an increase in the number weighted mean alveolar volume in aging SP-D (-/-) mice without loss of alveoli or alveolar epithelial surface area per lung. This increase may reflect over-distension due to altered mechanical properties of alveoli. In the light of our findings and data from the literature, the question arises as to whether a lack of SP-D promotes structural changes in the lung which have been described as being associated with aging lungs

  6. Taurine improves learning and retention in aged mice.

    PubMed

    El Idrissi, Abdeslem

    2008-05-02

    Aging of the brain is characterized by several neurochemical modifications involving structural proteins, neurotransmitters, neuropeptides and related receptors. Alterations of neurochemical indices of synaptic function have been considered as indicators of age-related impairment of central functions, such as locomotion, memory and sensory performances. Several studies demonstrated that GABA receptors, glutamic acid decarboxylase (GAD65&67), and different subpopulations of GABAergic neurons are markedly decreased in experimental animal brains during aging. Thus, the age-related decline in cognitive functions could be attributable, at least in part, to decrements in GABA inhibitory neurotransmission. In this study, using a passive avoidance test, we show that chronic supplementation of taurine to aged mice significantly ameliorates the age-dependent decline in memory acquisition and retention. We have previously shown that taurine supplementation caused changes in the GABAergic system. These changes include increased levels of the neurotransmitters GABA and glutamate, increased expression of glutamic acid decarboxylase and the neuropeptide somatostatin and increase in the number of somatostatin-positive neurons. These specific alterations of the inhibitory system caused by taurine treatment oppose those naturally occurring in aging, and suggest a protective role of taurine against the normal aging process. Increased understanding of age-related neurochemical changes in the GABAergic system will be important in elucidating the underpinnings of the functional changes of aging. Taurine might help forestall the age-related decline in cognitive functions through alterations of the GABAergic system.

  7. Quercetin exhibits adjuvant activity by enhancing Th2 immune response in ovalbumin immunized mice.

    PubMed

    Singh, Divya; Tanwar, Himanshi; Jayashankar, Bindhya; Sharma, Jyoti; Murthy, Swetha; Chanda, Sudipta; Singh, Shashi Bala; Ganju, Lilly

    2017-04-02

    Quercetin, one of the most abundant of plant flavonoids, has been studied with a great deal of attention over the last several decades mainly for its properties in inflammation and allergy. In this study, we are reporting for the first time the in vivo immunostimulatory activity of quercetin in ovalbumin immunized Balb/c mice. Administration of quercetin (50mg/kg body weight) along with ovalbumin antigen showed increased ovalbumin specific serum IgG antibody titres in comparison to the control group (p<0.05). Quercetin administration not only showed predominance of Th2 immune response by increasing the IgG1 antibody titres, but also increased the infiltration of CD11c(+) dendritic cells in the mouse peritoneum and also increased LPS activated IL-1β and nitric oxide (NO) production by peritoneal macrophages. Expression of Tbx21, GATA-3 and Oct-2 proteins also enhanced in splenocytes of quercetin administered mice. Quercetin also did not cause any hemolysis in human RBCs. Overall, our findings strongly demonstrate the novel in vivo immunostimulatory and adjuvant potentials of quercetin.

  8. Ca2+ dynamics in oocytes from naturally-aged mice

    PubMed Central

    Haverfield, Jenna; Nakagawa, Shoma; Love, Daniel; Tsichlaki, Elina; Nomikos, Michail; Lai, F. Anthony; Swann, Karl; FitzHarris, Greg

    2016-01-01

    The ability of human metaphase-II arrested eggs to activate following fertilisation declines with advancing maternal age. Egg activation is triggered by repetitive increases in intracellular Ca2+ concentration ([Ca2+]i) in the ooplasm as a result of sperm-egg fusion. We therefore hypothesised that eggs from older females feature a reduced ability to mount appropriate Ca2+ responses at fertilisation. To test this hypothesis we performed the first examination of Ca2+ dynamics in eggs from young and naturally-aged mice. Strikingly, we find that Ca2+ stores and resting [Ca2+]i are unchanged with age. Although eggs from aged mice feature a reduced ability to replenish intracellular Ca2+ stores following depletion, this difference had no effect on the duration, number, or amplitude of Ca2+ oscillations following intracytoplasmic sperm injection or expression of phospholipase C zeta. In contrast, we describe a substantial reduction in the frequency and duration of oscillations in aged eggs upon parthenogenetic activation with SrCl2. We conclude that the ability to mount and respond to an appropriate Ca2+ signal at fertilisation is largely unchanged by advancing maternal age, but subtle changes in Ca2+ handling occur that may have more substantial impacts upon commonly used means of parthenogenetic activation. PMID:26785810

  9. Effects of Sleep Deprivation and Aging on Long-Term and Remote Memory in Mice

    ERIC Educational Resources Information Center

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora; Abel, Ted

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a…

  10. Running for REST: Physical activity attenuates neuroinflammation in the hippocampus of aged mice.

    PubMed

    Dallagnol, Karine Mathilde Campestrini; Remor, Aline Pertile; da Silva, Rodrigo Augusto; Prediger, Rui Daniel; Latini, Alexandra; Aguiar, Aderbal Silva

    2017-03-01

    Exercise improves mental health and synaptic function in the aged brain. However, the molecular mechanisms involved in exercise-induced healthy brain aging are not well understood. Evidence supports the role of neurogenesis and neurotrophins in exercise-induced neuroplasticity. The gene silencing transcription factor neuronal RE1-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) and an anti-inflammatory role of exercise are also candidate mechanisms. We evaluate the effect of 8weeks of physical activity on running wheels (RW) on motor and depressive-like behavior and hippocampal gene expression of brain-derived neurotrophic factor (BDNF), REST, and interleukins IL-1β and IL-10 of adult and aged C57BL/6 mice. The aged animals exhibited impaired motor function and a depressive-like behavior: decreased mobility in the RW and open field and severe immobility in the tail suspension test. The gene expression of REST, IL-1β, and IL-10 was increased in the hippocampus of aged mice. Physical activity was anxiolytic and antidepressant and improved motor behavior in aged animals. Physical activity also boosted BDNF and REST expression and decreased IL-1β and IL-10 expression in the hippocampus of aged animals. These results support the beneficial role of REST in the aged brain, which can be further enhanced by regular physical activity.

  11. Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

    PubMed

    Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

    2017-02-21

    Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

  12. Red ginseng delays age-related hearing and vestibular dysfunction in C57BL/6 mice.

    PubMed

    Tian, Chunjie; Kim, Yeon Ju; Lim, Hye Jin; Kim, Young Sun; Park, Hun Yi; Choung, Yun-Hoon

    2014-09-01

    Since Korean red ginseng (KRG) has been proven to protect against gentamicin-induced vestibular and hearing dysfunction, the effects of KRG on age-related inner ear disorder in C57BL/6 mice were investigated. While age-related hearing loss was detected at the age of 6months (32kHz) and 9months (16kHz) in the control group, it was significantly delayed (p<0.05) in the 150mg/kg KRG-treated group. Vestibular dysfunction was observed in the tail-hanging and swimming tests, with significantly different severity scores and swimming times detected between the control and 150mg/kg KRG-treated group at the age of 12months (p<0.05). Mice treated with 500mg/kg KRG exhibited irritability and aggravated inner ear dysfunction. Histological observation supported the findings of hearing and vestibular function defects. In conclusion, C57BL/6 mice showed early-onset hearing loss and progressive vestibular dysfunction with aging, which were delayed by treatment with 150mg/kg KRG. However, 500mg/kg KRG treatment may induce aggressive behavior.

  13. Age-Related Changes in Cochlear Gene Expression In Normal and Shaker 2 Mice

    PubMed Central

    Gong, Tzy-Wen L.; Karolyi, I. Jill; MacDonald, James; Beyer, Lisa; Raphael, Yehoash; Kohrman, David C.; Camper, Sally A.

    2006-01-01

    The vertebrate cochlea is a complex organ optimized for sound transduction. Auditory hair cells, with their precisely arranged stereocilia bundles, transduce sound waves to electrical signals that are transmitted to the brain. Mutations in the unconventional myosin XV cause deafness in both human DFNB3 families and in shaker 2 (sh2) mice as a result of defects in stereocilia. In these mutant mice, hair cells have relatively normal spatial organization of stereocilia bundles but lack the graded, stair-step organization. We used sh2 mice as an experimental model to investigate the molecular consequences of the sh2 mutation in the Myo15 gene. Gene expression profiling with Affymetrix GeneChips in deaf homozygous (sh2/sh2) mice at 3 weeks and 3 months of age, and in age-matched, normal-hearing heterozygotes (+/sh2) identified only a few genes whose expression was affected by genotype, but a large number with age-associated changes in expression in both normal mice and sh2/sh2 homozygotes. Microarray data analyzed using Robust Multiarray Average identified Aim1, Dbi, and Tm4sf3 as genes with increased expression in sh2/sh2 homozygotes. These increases were confirmed by quantitative reverse transcription-polymerase chain reaction. Genes exhibiting altered expression with age encoded collagens and proteins involved in collagen maturation, extracellular matrix, and bone mineralization. These results identified potential cellular pathways associated with myosin XV defects, and age-associated molecular events that are likely to be involved in maturation of the cochlea and auditory function. PMID:16794912

  14. Pcsk6 mutant mice exhibit progressive loss of ovarian function, altered gene expression, and formation of ovarian pathology.

    PubMed

    Mujoomdar, Michelle L; Hogan, Laura M; Parlow, Albert F; Nachtigal, Mark W

    2011-03-01

    Bioactivation of precursor proteins by members of the proprotein convertase (PC) family is essential for normal reproduction. The Pcsk6 gene is a member of the PC family that is expressed in numerous ovarian cell types including granulosa cells and oocytes. We hypothesized that loss of PCSK6 would produce adverse effects in the mouse ovary. Mice incapable of expressing PCSK6 (Pcsk6(tm1Rob)) were obtained, and reproductive parameters (serum hormones, whelping interval, estrus cyclicity, and fertility) were compared to Pcsk6(+/+) mice. While Pcsk6(tm1Rob) female mice are fertile, they manifest reduced reproductive capacity at an accelerated rate relative to Pcsk6(+/+) mice. Reproductive senescence is typically reached by 9 months of age and is correlated with loss of estrus cyclicity, elevated serum FSH levels, and gross alterations in ovarian morphology. A wide range of ovarian morphologies were identified encompassing mild, such as an apparent reduction in follicle number, to moderate--ovarian atrophy with a complete absence of follicles--to severe, manifesting as normal ovarian structures replaced by benign ovarian tumors, including tubulostromal adenomas. Targeted gene expression profiling highlighted changes in RNA expression of molecules involved in processes such as steroidogenesis, gonadotropin signaling, transcriptional regulation, autocrine/paracrine signaling, cholesterol handling, and proprotein bioactivation. These results show that PCSK6 activity plays a role in maintaining normal cellular and tissue homeostasis in the ovary.

  15. Strial microvascular pathology and age-associated endocochlear potential decline in NOD congenic mice

    PubMed Central

    Ohlemiller, Kevin K.; Rice, Mary E. Rybak; Gagnon, Patricia M.

    2008-01-01

    NOD/ShiLtJ (previously NOD/LtJ) inbred mice show polygenic autoimmune disease and are commonly used to model autoimmune-related Type I diabetes, as well as Sjogren’s syndrome. They also show rapidly progressing hearing loss, partly due to the combined effects of Cdh23ahl and Ahl2. Congenic NOD.NON-H2nb1/LtJ mice, which carry corrective alleles within the H2 histocompatibility gene complex, are free from diabetes and other overt signs of autoimmune disease, but still exhibit rapidly progressive hearing loss. Here we show that cochlear pathology in these congenics broadly includes hair cell and neuronal loss, plus endocochlear potential (EP) decline from initially normal values after 2 months of age. The EP reduction follows often dramatic degeneration of capillaries in stria vascularis, with resulting strial degeneration. The cochlear modiolus in the congenic mice also features perivascular inclusions that resemble those in some mouse autoimmune models. We posit that cochlear hair cell/neural and strial pathology in NOD.NON-H2nb1 mice arise independently. While sensory cell loss may be closely tied to Cdh23ahl and Ahl2, the strial microvascular pathology and modiolar anomalies we observe may arise from alleles on the NOD background related to immune function. Age-associated EP decline in NOD.NON-H2nb1 mice may model forms of strial age-related hearing loss caused principally by microvascular disease. The remarkable strial capillary loss in these mice may also be useful for studying the relation between strial vascular insufficiency and strial function. PMID:18727954

  16. Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes.

    PubMed

    Lucas, Elizabeth K; Jegarl, Anita; Clem, Roger L

    2014-11-01

    Activity-dependent brain-derived neurotrophic factor (BDNF) signaling through receptor tyrosine kinase B (TrkB) is required for cued fear memory consolidation and extinction. Although BDNF is primarily secreted from glutamatergic neurons, TrkB is expressed by other genetically defined cells whose contributions to the behavioral effects of BDNF remain poorly understood. Parvalbumin (PV)-positive interneurons, which are highly enriched in TrkB, are emerging as key regulators of fear memory expression. We therefore hypothesized that activity-dependent BDNF signaling in PV-interneurons may modulate emotional learning. To test this hypothesis, we utilized the LoxP/Cre system for conditional deletion of TrkB in PV-positive cells to examine the impact of cell-autonomous BDNF signaling on Pavlovian fear conditioning and extinction. However, behavioral abnormalities indicative of vestibular dysfunction precluded the use of homozygous conditional knockouts in tests of higher cognitive functioning. While vestibular dysfunction was apparent in both sexes, female conditional knockouts exhibited an exacerbated phenotype, including extreme motor hyperactivity and circling behavior, compared to their male littermates. Heterozygous conditional knockouts were spared of vestibular dysfunction. While fear memory consolidation was unaffected in heterozygotes of both sexes, males exhibited impaired extinction consolidation compared to their littermate controls. Our findings complement evidence from human and rodent studies suggesting that BDNF signaling promotes consolidation of extinction and point to PV-positive neurons as a discrete population that mediates these effects in a sex-specific manner.

  17. Erythrocytes encapsulated with phenylalanine hydroxylase exhibit improved pharmacokinetics and lowered plasma phenylalanine levels in normal mice.

    PubMed

    Yew, Nelson S; Dufour, Emmanuelle; Przybylska, Malgorzata; Putelat, Julie; Crawley, Cristin; Foster, Meta; Gentry, Sarah; Reczek, David; Kloss, Alla; Meyzaud, Aurélien; Horand, Françoise; Cheng, Seng H; Godfrin, Yann

    2013-08-01

    Enzyme replacement therapy is often hampered by the rapid clearance and degradation of the administered enzyme, limiting its efficacy and requiring frequent dosing. Encapsulation of therapeutic molecules into red blood cells (RBCs) is a clinically proven approach to improve the pharmacokinetics and efficacy of biologics and small molecule drugs. Here we evaluated the ability of RBCs encapsulated with phenylalanine hydroxylase (PAH) to metabolize phenylalanine (Phe) from the blood and confer sustained enzymatic activity in the circulation. Significant quantities of PAH were successfully encapsulated within murine RBCs (PAH-RBCs) with minimal loss of endogenous hemoglobin. While intravenously administered free PAH enzyme was rapidly eliminated from the blood within a few hours, PAH-RBCs persisted in the circulation for at least 10days. A single injection of PAH-RBCs was able to decrease Phe levels by nearly 80% in normal mice. These results demonstrate the ability of enzyme-loaded RBCs to metabolize circulating amino acids and highlight the potential to treat disorders of amino acid metabolism.

  18. Fucoidan Supplementation Improves Exercise Performance and Exhibits Anti-Fatigue Action in Mice

    PubMed Central

    Chen, Yi-Ming; Tsai, Yi-Hsin; Tsai, Tsung-Yu; Chiu, Yen-Shuo; Wei, Li; Chen, Wen-Chyuan; Huang, Chi-Chang

    2014-01-01

    Fucoidan (FCD) is a well-known bioactive constituent of seaweed extract that possess a wide spectrum of activities in biological systems, including anti-cancer, anti-inflammation and modulation of immune systems. However, evidence on the effects of FCD on exercise performance and physical fatigue is limited. Therefore, we investigated the potential beneficial effects of FCD on ergogenic and anti-fatigue functions following physiological challenge. Male ICR mice from three groups (n = 8 per group) were orally administered FCD for 21 days at 0, 310 and 620 mg/kg/day, which were, respectively, designated the vehicle, FCD-1X and FCD-2X groups. The results indicated that the FCD supplementations increased the grip strength (p = 0.0002) and endurance swimming time (p = 0.0195) in a dose-depend manner. FCD treatments also produced dose-dependent decreases in serum levels of lactate (p < 0.0001) and ammonia (p = 0.0025), and also an increase in glucose level (p < 0.0001) after the 15-min swimming test. In addition, FCD supplementation had few subchronic toxic effects. Therefore, we suggest that long-term supplementation with FCD can have a wide spectrum of bioactivities on health promotion, performance improvement and anti-fatigue. PMID:25558908

  19. Transgenic Mice Expressing Yeast CUP1 Exhibit Increased Copper Utilization from Feeds

    PubMed Central

    Chen, Zhenliang; Liao, Rongrong; Zhang, Xiangzhe; Wang, Qishan; Pan, Yuchun

    2014-01-01

    Copper is required for structural and catalytic properties of a variety of enzymes participating in many vital biological processes for growth and development. Feeds provide most of the copper as an essential micronutrient consumed by animals, but inorganic copper could not be utilized effectively. In the present study, we aimed to develop transgenic mouse models to test if copper utilization will be increased by providing the animals with an exogenous gene for generation of copper chelatin in saliva. Considering that the S. cerevisiae CUP1 gene encodes a Cys-rich protein that can bind copper as specifically as copper chelatin in yeast, we therefore constructed a transgene plasmid containing the CUP1 gene regulated for specific expression in the salivary glands by a promoter of gene coding pig parotid secretory protein. Transgenic CUP1 was highly expressed in the parotid and submandibular salivary glands and secreted in saliva as a 9-kDa copper-chelating protein. Expression of salivary copper-chelating proteins reduced fecal copper contents by 21.61% and increased body-weight by 12.97%, suggesting that chelating proteins improve the utilization and absorbed efficacy of copper. No negative effects on the health of the transgenic mice were found by blood biochemistry and histology analysis. These results demonstrate that the introduction of the salivary CUP1 transgene into animals offers a possible approach to increase the utilization efficiency of copper and decrease the fecal copper contents. PMID:25265503

  20. Fucoidan supplementation improves exercise performance and exhibits anti-fatigue action in mice.

    PubMed

    Chen, Yi-Ming; Tsai, Yi-Hsin; Tsai, Tsung-Yu; Chiu, Yen-Shuo; Wei, Li; Chen, Wen-Chyuan; Huang, Chi-Chang

    2014-12-31

    Fucoidan (FCD) is a well-known bioactive constituent of seaweed extract that possess a wide spectrum of activities in biological systems, including anti-cancer, anti-inflammation and modulation of immune systems. However, evidence on the effects of FCD on exercise performance and physical fatigue is limited. Therefore, we investigated the potential beneficial effects of FCD on ergogenic and anti-fatigue functions following physiological challenge. Male ICR mice from three groups (n = 8 per group) were orally administered FCD for 21 days at 0, 310 and 620 mg/kg/day, which were, respectively, designated the vehicle, FCD-1X and FCD-2X groups. The results indicated that the FCD supplementations increased the grip strength (p = 0.0002) and endurance swimming time (p = 0.0195) in a dose-depend manner. FCD treatments also produced dose-dependent decreases in serum levels of lactate (p < 0.0001) and ammonia (p = 0.0025), and also an increase in glucose level (p < 0.0001) after the 15-min swimming test. In addition, FCD supplementation had few subchronic toxic effects. Therefore, we suggest that long-term supplementation with FCD can have a wide spectrum of bioactivities on health promotion, performance improvement and anti-fatigue.

  1. Luteolin Inhibits Microglia and Alters Hippocampal-Dependent Spatial Working Memory in Aged Mice123

    PubMed Central

    Jang, Saebyeol; Dilger, Ryan N.; Johnson, Rodney W.

    2010-01-01

    A dysregulated overexpression of inflammatory mediators by microglia may facilitate cognitive aging and neurodegeneration. Considerable evidence suggests the flavonoid luteolin has antiinflammatory effects, but its ability to inhibit microglia, reduce inflammatory mediators, and improve hippocampal-dependent learning and memory in aged mice is unknown. In initial studies, pretreatment of BV-2 microglia with luteolin inhibited the induction of inflammatory genes and the release of inflammatory mediators after lipopolysaccharide (LPS) stimulation. Supernatants from LPS-stimulated microglia caused discernible death in Neuro.2a cells. However, treating microglia with luteolin prior to LPS reduced neuronal cell death caused by conditioned supernatants, indicating luteolin was neuroprotective. In subsequent studies, adult (3–6 mo) and aged (22–24 mo) mice were fed control or luteolin (20 mg/d)-supplemented diet for 4 wk and spatial working memory was assessed as were several inflammatory markers in the hippocampus. Aged mice fed control diet exhibited deficits in spatial working memory and expression of inflammatory markers in the hippocampus indicative of increased microglial cell activity. Luteolin consumption improved spatial working memory and restored expression of inflammatory markers in the hippocampus compared with that of young adults. Luteolin did not affect either spatial working memory or inflammatory markers in young adults. Taken together, the current findings suggest dietary luteolin enhanced spatial working memory by mitigating microglial-associated inflammation in the hippocampus. Therefore, luteolin consumption may be beneficial in preventing or treating conditions involving increased microglial cell activity and inflammation. PMID:20685893

  2. Experimental febrile seizures induce age-dependent structural plasticity and improve memory in mice.

    PubMed

    Tao, K; Ichikawa, J; Matsuki, N; Ikegaya, Y; Koyama, R

    2016-03-24

    Population-based studies have demonstrated that children with a history of febrile seizure (FS) perform better than age-matched controls at hippocampus-dependent memory tasks. Here, we report that FSs induce two distinct structural reorganizations in the hippocampus and bidirectionally modify future learning abilities in an age-dependent manner. Compared with age-matched controls, adult mice that had experienced experimental FSs induced by hyperthermia (HT) on postnatal day 14 (P14-HT) performed better in a cognitive task that requires dentate granule cells (DGCs). The enhanced memory performance correlated with an FS-induced persistent increase in the density of large mossy fiber terminals (LMTs) of the DGCs. The memory enhancement was not observed in mice that had experienced HT-induced seizures at P11 which exhibited abnormally located DGCs in addition to the increased LMT density. The ectopic DGCs of the P11-HT mice were abolished by the diuretic bumetanide, and this pharmacological treatment unveiled the masked memory enhancement. Thus, this work provides a novel basis for age-dependent structural plasticity in which FSs influence future brain function.

  3. Effects of Resveratrol Supplementation and Exercise Training on Exercise Performance in Middle-Aged Mice.

    PubMed

    Kan, Nai-Wen; Ho, Chin-Shan; Chiu, Yen-Shuo; Huang, Wen-Ching; Chen, Pei-Yu; Tung, Yu-Tang; Huang, Chi-Chang

    2016-05-18

    Resveratrol (RES) has antioxidative, anti-inflammatory, anticancer, antidiabetic, antiasthmatic, antalgic, and anti-fatigue activities. Exercise training (ET) improves frailty resulting from aging. This study evaluated the effects of a combination of RES supplementation and ET on the exercise performance of aged mice. C57BL/6J mice (16 months old) were randomly divided into four groups: an older control group (OC group), supplementation with RES group (RES group), ET group (ET group), and a combination of ET and RES supplementation group (ET+RES group). Other 10-week-old mice were used as a young control group (Y-Ctrl group). In this study, exercise performance was evaluated using forelimb grip strength and exhaustive swimming time, as well as levels of plasma lactate, ammonia, glucose, and creatine kinase after an acute swimming exercise. Our results showed that the forelimb grip strength of mice in the ET+RES group was significantly higher than those in the OC, RES, and ET groups (by 1.3-, 1.2-, and 1.1-fold, respectively, p < 0.05), and exhibited no difference with the Y-Ctrl group. The endurance swimming test showed that swimming times of the ET and ET+RES groups were significantly longer than those of the OC and RES groups. Moreover, plasma lactate and ammonia levels of the ET + RES group after acute swimming exercise were significantly lower compared to the OC group (p < 0.05). Thus, it was suggested that by combining RES supplementation with ET for 4 weeks, the muscle strength and endurance performance of aged mice were significantly improved compared to the single intervention with either RES or ET alone. This combination might help shorten the extent of deterioration accompanying the aging process.

  4. Mice Deficient in Proglucagon-Derived Peptides Exhibit Glucose Intolerance on a High-Fat Diet but Are Resistant to Obesity.

    PubMed

    Takagi, Yusuke; Kinoshita, Keita; Ozaki, Nobuaki; Seino, Yusuke; Murata, Yoshiharu; Oshida, Yoshiharu; Hayashi, Yoshitaka

    2015-01-01

    Homozygous glucagon-GFP knock-in mice (Gcggfp/gfp) lack proglucagon derived-peptides including glucagon and GLP-1, and are normoglycemic. We have previously shown that Gcggfp/gfp show improved glucose tolerance with enhanced insulin secretion. Here, we studied glucose and energy metabolism in Gcggfp/gfp mice fed a high-fat diet (HFD). Male Gcggfp/gfp and Gcggfp/+ mice were fed either a normal chow diet (NCD) or an HFD for 15-20 weeks. Regardless of the genotype, mice on an HFD showed glucose intolerance, and Gcggfp/gfp mice on HFD exhibited impaired insulin secretion whereas Gcggfp/+ mice on HFD exhibited increased insulin secretion. A compensatory increase in β-cell mass was observed in Gcggfp/+mice on HFD, but not in Gcggfp/gfp mice on the same diet. Weight gain was significantly lower in Gcggfp/gfp mice than in Gcggfp/+mice. Oxygen consumption was enhanced in Gcggfp/gfp mice compared to Gcggfp/+ mice on an HFD. HFD feeding significantly increased uncoupling protein 1 mRNA expression in brown adipose and inguinal white adipose tissues of Gcggfp/gfp mice, but not of Gcggfp/+mice. Treatment with the glucagon-like peptide-1 receptor agonist liraglutide (200 mg/kg) improved glucose tolerance in Gcggfp/gfp mice and insulin content in Gcggfp/gfp and Gcggfp/+ mice was similar after liraglutide treatment. Our findings demonstrate that Gcggfp/gfp mice develop diabetes upon HFD-feeding in the absence of proglucagon-derived peptides, although they are resistant to diet-induced obesity.

  5. Interleukin-27 exhibited anti-inflammatory activity during Plasmodium berghei infection in mice.

    PubMed

    Fazalul Rahiman, S S; Basir, R; Talib, H; Tie, T H; Chuah, Y K; Jabbarzare, M; Chong, W C; Mohd Yusoff, M A; Nordin, N; Yam, M F; Abdullah, W O; Abdul Majid, R

    2013-12-01

    Interleukin-27 (IL-27) has a pleiotropic role either as a pro-inflammatory or anti-inflammatory cytokine in inflammatory related diseases. The role and involvement of IL-27 during malaria was investigated and the effects of modulating its release on the production of major inflammatory cytokines and the histopathological consequences in major affected organs during the infection were evaluated. Results showed that IL-27 concentration was significantly elevated throughout the infection but no positive correlation with the parasitaemia development observed. Augmentation of IL-27 significantly elevated the release of anti-inflammatory cytokine, IL-10 whereas antagonising and neutralising IL-27 produced the opposite. A significant elevation of pro-inflammatory cytokines (IFN-γ and IL-6) was also observed, both during augmentation and inhibition of IL-27. Thus, it is suggested that IL-27 exerts an anti-inflammatory activity in the Th1 type response by signalling the production of IL-10 during malaria. Histopathological examination showed sequestration of PRBC in the microvasculature of major organs in malarial mice. Other significant histopathological changes include hyperplasia and hypertrophy of the Kupffer cells in the liver, hyaline membrane formation in lung tissue, enlargement of the white and red pulp followed by the disappearance of germinal centre of the spleen, and tubular vacuolation of the kidney tissues. In conclusion, it is suggested that IL-27 may possibly acts as an anti-inflammatory cytokine during the infection. Modulation of its release produced a positive impact on inflammatory cytokine production during the infection, suggesting its potential in malaria immunotherapy, in which the host may benefit from its inhibition.

  6. Accelerated features of age-related bone loss in zmpste24 metalloproteinase-deficient mice.

    PubMed

    Rivas, Daniel; Li, Wei; Akter, Rahima; Henderson, Janet E; Duque, Gustavo

    2009-10-01

    Age-related bone loss is associated with changes in bone cellularity, which include marrow fat infiltration and decreasing levels of osteoblastogenesis. The mechanisms that explain these changes remain unclear. Although nuclear lamina alterations occur in premature aging syndromes that include changes in body fat and severe osteoporosis, the role of proteins of the nuclear lamina in age-related bone loss remains unknown. Using the Zmpste24-null progeroid mice (Zmpste24(-/-)), which exhibit nuclear lamina defects and accumulate unprocessed prelamin A, we identified several alterations in bone cellularity in vivo. We found that defective prelamin A processing induced accelerated features of age-related bone loss including lower osteoblast and osteocyte numbers and higher levels of marrow adipogenesis. In summary, processing of prelamin A could become a new approach to regulate osteoblastogenesis and bone turnover and thus for the prevention and treatment of senile osteoporosis.

  7. Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis.

    PubMed

    Kowalik, Agnes S; Johnson, Charis L; Chadi, Sami A; Weston, Jacqueline Y; Fazio, Elena N; Pin, Christopher L

    2007-04-01

    Several animal models have been developed to investigate the pathobiology of pancreatitis, but few studies have examined the effects that altered pancreatic gene expression have in these models. In this study, the sensitivity to secretagogue-induced pancreatitis was examined in a mouse line that has an altered acinar cell environment due to the targeted deletion of Mist1. Mist1 is an exocrine specific transcription factor important for the complete differentiation and function of pancreatic acinar cells. Mice lacking the Mist1 gene [Mist1 knockout (KO) mice] exhibit cellular disorganization and functional defects in the exocrine pancreas but no gross morphological defects. Following the induction of pancreatitis with caerulein, a CCK analog, we observed elevated serum amylase levels, necrosis, and tissue damage in Mist1 KO mice, indicating increased pancreatic damage. There was also a delay in the regeneration of acinar tissue in Mist1 KO animals. Molecular profiling revealed an altered activation of stress response genes in Mist1 KO pancreatic tissue compared with wild-type (WT) tissue following the induction of pancreatitis. In particular, Western blot analysis for activating transcription factor 3 and phosphorylated eukaryotic initiation factor 2alpha (eIF2alpha), mediators of endoplasmic reticulum (ER) stress, indicated limited activation of this pathway in Mist1 KO animals compared with WT controls. Conversely, Mist1 KO pancreatic tissue exhibits increased expression of growth arrest and DNA damage inducible 34 protein, an inhibitor of eIF2alpha phosphorylation, before and after the induction of pancreatitis. These finding suggest that activation of the ER stress pathway is a protective event in the progression of pancreatitis and highlight the Mist1 KO mouse line as an important new model for studying the molecular events that contribute to the sensitivity to pancreatic injury.

  8. Age Sensitivity of Behavioral Tests and Brain Substrates of Normal Aging in Mice

    PubMed Central

    Kennard, John A.; Woodruff-Pak, Diana S.

    2011-01-01

    Knowledge of age sensitivity, the capacity of a behavioral test to reliably detect age-related changes, has utility in the design of experiments to elucidate processes of normal aging. We review the application of these tests in studies of normal aging and compare and contrast the age sensitivity of the Barnes maze, eyeblink classical conditioning, fear conditioning, Morris water maze, and rotorod. These tests have all been implemented to assess normal age-related changes in learning and memory in rodents, which generalize in many cases to age-related changes in learning and memory in all mammals, including humans. Behavioral assessments are a valuable means to measure functional outcomes of neuroscientific studies of aging. Highlighted in this review are the attributes and limitations of these measures in mice in the context of age sensitivity and processes of brain aging. Attributes of these tests include reliability and validity as assessments of learning and memory, well-defined neural substrates, and sensitivity to neural and pharmacological manipulations and disruptions. These tests engage the hippocampus and/or the cerebellum, two structures centrally involved in learning and memory that undergo functional and anatomical changes in normal aging. A test that is less well represented in studies of normal aging, the context pre-exposure facilitation effect (CPFE) in fear conditioning, is described as a method to increase sensitivity of contextual fear conditioning to changes in the hippocampus. Recommendations for increasing the age sensitivity of all measures of normal aging in mice are included, as well as a discussion of the potential of the under-studied CPFE to advance understanding of subtle hippocampus-mediated phenomena. PMID:21647305

  9. 3xTg-AD Mice Exhibit an Activated Central Stress Axis during Early-Stage Pathology

    PubMed Central

    Hebda-Bauer, Elaine K.; Simmons, Tracy A.; Sugg, Andrew; Ural, Eren; Stewart, James A.; Beals, James L.; Wei, Qiang; Watson, Stanley J.; Akil, Huda

    2012-01-01

    Activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in response to the organism’s innate need for homeostasis. The glucocorticoids (GCs) that are released into the circulation upon acute activation of the HPA axis perform stress-adaptive functions and provide negative feedback to turn off the HPA axis, but can be detrimental when in excess. Long-term activation of the HPA axis (such as with chronic stress) enhances susceptibility to neuronal dysfunction and death, and increases vulnerability to Alzheimer’s disease (AD). However, little is known how components of the HPA axis, upstream of GCs, impact vulnerability to AD. This study examined basal gene expression of stress-related molecules in brains of 3xTg-AD mice during early-stage pathology. Basal glucocorticoid levels and mRNA expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and corticotropic releasing hormone (CRH) in several stress- and emotionality-related brain regions were measured in 3–4-month-old 3xTg-AD mice. Despite normal glucocorticoid levels, young 3xTg-AD mice exhibit an activated central HPA axis, with altered mRNA levels of MR and GR in the hippocampus, GR and CRH in the paraventricular nucleus of the hypothalamus, GR and CRH in the central nucleus of the amygdala, and CRH in the bed nucleus of the stria terminalis. This HPA axis activation is present during early-stage neuropathology when 3xTg-AD mice show mild behavioral changes, suggesting an ongoing neuroendocrine regulation that precedes the onset of severe AD-like pathology and behavioral deficits. PMID:22976078

  10. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    SciTech Connect

    Wu, Hsu-Pin; Hsu, Shu-Yuan; Wu, Wen-Ai; Hu, Ji-Wei; Ouyang, Pin

    2014-01-03

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB{sup +/−} mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity.

  11. Effects of sleep deprivation and aging on long-term and remote memory in mice

    PubMed Central

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a month after training, sleep-deprived and control aged animals performed similarly, primarily due to remote memory decay in the control aged animals. Gene expression analysis supported the finding that SD has similar effects on the hippocampus in young and aged mice. PMID:25776037

  12. Palladium and Platinum Nanoparticles Attenuate Aging-Like Skin Atrophy via Antioxidant Activity in Mice

    PubMed Central

    Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

    2014-01-01

    Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1−/− mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1−/− mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage. PMID:25333617

  13. Palladium and platinum nanoparticles attenuate aging-like skin atrophy via antioxidant activity in mice.

    PubMed

    Shibuya, Shuichi; Ozawa, Yusuke; Watanabe, Kenji; Izuo, Naotaka; Toda, Toshihiko; Yokote, Koutaro; Shimizu, Takahiko

    2014-01-01

    Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1-/- mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1-/- mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage.

  14. 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…

  15. Mechanisms of aging in senescence-accelerated mice

    PubMed Central

    Carter, Todd A; Greenhall, Jennifer A; Yoshida, Shigeo; Fuchs, Sebastian; Helton, Robert; Swaroop, Anand; Lockhart, David J; Barlow, Carrolee

    2005-01-01

    Background Progressive neurological dysfunction is a key aspect of human aging. Because of underlying differences in the aging of mice and humans, useful mouse models have been difficult to obtain and study. We have used gene-expression analysis and polymorphism screening to study molecular senescence of the retina and hippocampus in two rare inbred mouse models of accelerated neurological senescence (SAMP8 and SAMP10) that closely mimic human neurological aging, and in a related normal strain (SAMR1) and an unrelated normal strain (C57BL/6J). Results The majority of age-related gene expression changes were strain-specific, with only a few common pathways found for normal and accelerated neurological aging. Polymorphism screening led to the identification of mutations that could have a direct impact on important disease processes, including a mutation in a fibroblast growth factor gene, Fgf1, and a mutation in and ectopic expression of the gene for the chemokine CCL19, which is involved in the inflammatory response. Conclusion We show that combining the study of inbred mouse strains with interesting traits and gene-expression profiling can lead to the discovery of genes important for complex phenotypes. Furthermore, full-genome polymorphism detection, sequencing and gene-expression profiling of inbred mouse strains with interesting phenotypic differences may provide unique insights into the molecular genetics of late-manifesting complex diseases. PMID:15960800

  16. Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice.

    PubMed

    Illien-Jünger, Svenja; Lu, Young; Qureshi, Sheeraz A; Hecht, Andrew C; Cai, Weijing; Vlassara, Helen; Striker, Gary E; Iatridis, James C

    2015-01-01

    Intervertebral disc (IVD) degeneration and pathological spinal changes are major causes of back pain, which is the top cause of global disability. Obese and diabetic individuals are at increased risk for back pain and musculoskeletal complications. Modern diets contain high levels of advanced glycation end products (AGEs), cyto-toxic components which are known contributors to obesity, diabetes and accelerated aging pathologies. There is little information about potential effects of AGE rich diet on spinal pathology, which may be a contributing cause for back pain which is common in obese and diabetic individuals. This study investigated the role of specific AGE precursors (e.g. methylglyoxal-derivatives (MG)) on IVD and vertebral pathologies in aging C57BL6 mice that were fed isocaloric diets with standard (dMG+) or reduced amounts of MG derivatives (dMG-; containing 60-70% less dMG). dMG+ mice exhibited a pre-diabetic phenotype, as they were insulin resistant but not hyperglycemic. Vertebrae of dMG+ mice displayed increased cortical-thickness and cortical-area, greater MG-AGE accumulation and ectopic calcification in vertebral endplates. IVD morphology of dMG+ mice exhibited ectopic calcification, hypertrophic differentiation and glycosaminoglycan loss relative to dMG- mice. Overall, chronic exposure to dietary AGEs promoted age-accelerated IVD degeneration and vertebral alterations involving ectopic calcification which occurred in parallel with insulin resistance, and which were prevented with dMG- diet. This study described a new mouse model for diet-induced spinal degeneration, and results were in support of the hypothesis that chronic AGE ingestion could be a factor contributing to a pre-diabetic state, ectopic calcifications in spinal tissues, and musculoskeletal complications that are more generally known to occur with chronic diabetic conditions.

  17. Chronic Ingestion of Advanced Glycation End Products Induces Degenerative Spinal Changes and Hypertrophy in Aging Pre-Diabetic Mice

    PubMed Central

    Illien-Jünger, Svenja; Lu, Young; Qureshi, Sheeraz A.; Hecht, Andrew C.; Cai, Weijing; Vlassara, Helen; Striker, Gary E.; Iatridis, James C.

    2015-01-01

    Intervertebral disc (IVD) degeneration and pathological spinal changes are major causes of back pain, which is the top cause of global disability. Obese and diabetic individuals are at increased risk for back pain and musculoskeletal complications. Modern diets contain high levels of advanced glycation end products (AGEs), cyto-toxic components which are known contributors to obesity, diabetes and accelerated aging pathologies. There is little information about potential effects of AGE rich diet on spinal pathology, which may be a contributing cause for back pain which is common in obese and diabetic individuals. This study investigated the role of specific AGE precursors (e.g. methylglyoxal-derivatives (MG)) on IVD and vertebral pathologies in aging C57BL6 mice that were fed isocaloric diets with standard (dMG+) or reduced amounts of MG derivatives (dMG-; containing 60-70% less dMG). dMG+ mice exhibited a pre-diabetic phenotype, as they were insulin resistant but not hyperglycemic. Vertebrae of dMG+ mice displayed increased cortical-thickness and cortical-area, greater MG-AGE accumulation and ectopic calcification in vertebral endplates. IVD morphology of dMG+ mice exhibited ectopic calcification, hypertrophic differentiation and glycosaminoglycan loss relative to dMG- mice. Overall, chronic exposure to dietary AGEs promoted age-accelerated IVD degeneration and vertebral alterations involving ectopic calcification which occurred in parallel with insulin resistance, and which were prevented with dMG- diet. This study described a new mouse model for diet-induced spinal degeneration, and results were in support of the hypothesis that chronic AGE ingestion could be a factor contributing to a pre-diabetic state, ectopic calcifications in spinal tissues, and musculoskeletal complications that are more generally known to occur with chronic diabetic conditions. PMID:25668621

  18. 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

  19. Cleopatra's Egypt. A Museum Exhibition Explores Egypt during the Age of the Ptolemies.

    ERIC Educational Resources Information Center

    Bianchi, Robert S.

    1989-01-01

    Describes the historical premises behind a traveling exhibit of Egyptian Hellenistic art from the Ptolemic Period. Focuses on the uniquely Egyptian characteristics of this art, including religious symbolism, costume elements, and characteristics of craftsmanship. (LS)

  20. Shortened estrous cycle length, increased FSH levels, FSH variance, oocyte spindle aberrations, and early declining fertility in aging senescence-accelerated mouse prone-8 (SAMP8) mice: concomitant characteristics of human midlife female reproductive aging.

    PubMed

    Bernstein, Lori R; Mackenzie, Amelia C L; Kraemer, Duane C; Morley, John E; Farr, Susan; Chaffin, Charles L; Merchenthaler, István

    2014-06-01

    Women experience a series of specific transitions in their reproductive function with age. Shortening of the menstrual cycle begins in the mid to late 30s and is regarded as the first sign of reproductive aging. Other early changes include elevation and increased variance of serum FSH levels, increased incidences of oocyte spindle aberrations and aneuploidy, and declining fertility. The goal of this study was to investigate whether the mouse strain senescence-accelerated mouse-prone-8 (SAMP8) is a suitable model for the study of these midlife reproductive aging characteristics. Midlife SAMP8 mice aged 6.5-7.85 months (midlife SAMP8) exhibited shortened estrous cycles compared with SAMP8 mice aged 2-3 months (young SAMP8, P = .0040). Midlife SAMP8 mice had high FSH levels compared with young SAMP8 mice, and mice with a single day of high FSH exhibited statistically elevated FSH throughout the cycle, ranging from 1.8- to 3.6-fold elevation on the days of proestrus, estrus, metestrus, and diestrus (P < .05). Midlife SAMP8 mice displayed more variance in FSH than young SAMP8 mice (P = .01). Midlife SAMP8 ovulated fewer oocytes (P = .0155). SAMP8 oocytes stained with fluorescently labeled antitubulin antibodies and scored in fluorescence microscopy exhibited increased incidence of meiotic spindle aberrations with age, from 2/126 (1.59%) in young SAMP8 to 38/139 (27.3%) in midlife SAMP8 (17.2-fold increase, P < .0001). Finally, SAMP8 exhibited declining fertility from 8.9 pups/litter in young SAMP8 to 3.5 pups/litter in midlife SAMP8 mice (P < .0001). The age at which these changes occur is younger than for most mouse strains, and their simultaneous occurrence within a single strain has not been described previously. We propose that SAMP8 mice are a model of midlife human female reproductive aging.

  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. Bupropion induced changes in exploratory and anxiety-like behaviour in NMRI male mice depends on the age.

    PubMed

    Carrasco, M Carmen; Vidal, Jose; Redolat, Rosa

    2013-09-01

    The aim of this study was to assess the effects of the antidepressant bupropion on anxiety and novelty-seeking in adolescent mice of different ages and adults. Behavioural differences between early adolescent, late adolescent and adult NMRI mice were measured both in the elevated plus-maze and the hole-board tasks following acute administration of bupropion (5, 10, 15, 20mg/kg) or saline. In the plus maze test, early and late adolescent mice treated with bupropion (10, 15mg/kg, respectively) had lower percentages of entries in the open-arms compared to their vehicle controls. Adult mice treated with bupropion did not differ from their vehicle controls. These results suggest that the effect of this drug on anxiety-like behaviour in mice depends on the age, showing adolescents an anxiogenic-like profile. In the hole-board, adolescents showed more elevated levels of novelty-seeking than adults, exhibiting shorter latency to the first head-dip (HD) and a higher number of HD's. Bupropion increases the latency to the first HD and decreases the number of HD's in all age-groups, indicating a decline in exploratory tendency. Findings reveal that the age can modulate the behaviour displayed by mice in both animal models, and that adolescents are more sensitive to bupropion's anxiogenic effects.

  3. Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin ("Ghrl"), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that "Gh...

  4. Differential Responses to Adjuvants of Macrophages from Young Virgin, Aging Virgin and Aging Breeder Mice.

    DTIC Science & Technology

    1985-12-01

    Rb-Ai.62 483 DIFFERENTIAL RESPONSES TO ADJUVANTS OF MACROPHAGES FROM i/i YOUNG VIRGIN AGIN (U) MINNESOTA UNIV DULUTH DEPT OF MEDICAL MICROBIOLOGY RN...ADDRESS (City, State. an ZI 0EC 18 198E- Dept. of Medical Microbiology & Immunology 800 N. Quincy Street E1 8 Duluth, MN 55812-2487 Arlington, VA 22217-5...Aging Breeder Mice by Pamela R. Petrequin and Arthur G. Johnson Dept. of Medical Microbiology /Immunology University of Minnesota-Duluth School of

  5. Triple-transgenic Alzheimer's disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology

    PubMed Central

    Desai, Maya K.; Sudol, Kelly L.; Janelsins, Michelle C.; Mastrangelo, Michael A.; Frazer, Maria E.; Bowers, William J.

    2008-01-01

    Alzheimer's disease (AD) is a progressively debilitating brain disorder pathologically defined by extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and synaptic disintegrity. AD has not been widely considered a disease of white matter, but more recent evidence suggests the existence of abnormalities in myelination patterns and myelin attrition in AD-afflicted human brains. Herein, we demonstrate that triple-transgenic AD (3xTg-AD) mice, which harbor the human amyloid precursor protein Swedish mutant transgene, presenilin knock-in mutation, and tau P301L mutant transgene, exhibit significant region-specific alterations in myelination patterns and in oligodendrocyte marker expression profiles at time points preceding the appearance of amyloid and tau pathology. These immunohistochemical signatures are coincident with age-related alterations in axonal and myelin sheath ultrastructure as visualized by comparative electron microscopic examination of 3xTg-AD and non-transgenic mouse brain tissue. Overall, these findings indicate 3xTg-AD mice represent a viable model in which to examine mechanisms underlying AD-related myelination and neural transmission defects that occur early during pre-symptomatic stages of the disease process. PMID:18661556

  6. Cytokinetic Failure-induced Tetraploidy Develops into Aneuploidy, Triggering Skin Aging in Phosphovimentin-deficient Mice.

    PubMed

    Tanaka, Hiroki; Goto, Hidemasa; Inoko, Akihito; Makihara, Hiroyuki; Enomoto, Atsushi; Horimoto, Katsuhisa; Matsuyama, Makoto; Kurita, Kenichi; Izawa, Ichiro; Inagaki, Masaki

    2015-05-22

    Tetraploidy, a state in which cells have doubled chromosomal sets, is observed in ∼20% of solid tumors and is considered to frequently precede aneuploidy in carcinogenesis. Tetraploidy is also detected during terminal differentiation and represents a hallmark of aging. Most tetraploid cultured cells are arrested by p53 stabilization. However, the fate of tetraploid cells in vivo remains largely unknown. Here, we analyze the ability to repair wounds in the skin of phosphovimentin-deficient (VIM(SA/SA)) mice. Early into wound healing, subcutaneous fibroblasts failed to undergo cytokinesis, resulting in binucleate tetraploidy. Accordingly, the mRNA level of p21 (a p53-responsive gene) was elevated in a VIM(SA/SA)-specific manner. Disappearance of tetraploidy coincided with an increase in aneuploidy. Thereafter, senescence-related markers were significantly elevated in VIM(SA/SA) mice. Because our tetraploidy-prone mouse model also exhibited subcutaneous fat loss at the age of 14 months, another premature aging phenotype, our data suggest that following cytokinetic failure, a subset of tetraploid cells enters a new cell cycle and develops into aneuploid cells in vivo, which promote premature aging.

  7. The Presentation of Self in the Age of Social Media: Distinguishing Performances and Exhibitions Online

    ERIC Educational Resources Information Center

    Hogan, Bernie

    2010-01-01

    Presentation of self (via Goffman) is becoming increasingly popular as a means for explaining differences in meaning and activity of online participation. This article argues that self-presentation can be split into performances, which take place in synchronous "situations," and artifacts, which take place in asynchronous "exhibitions." Goffman's…

  8. Pyrrolidine dithiocarbamate inhibits UVB-induced skin inflammation and oxidative stress in hairless mice and exhibits antioxidant activity in vitro.

    PubMed

    Ivan, Ana L M; Campanini, Marcela Z; Martinez, Renata M; Ferreira, Vitor S; Steffen, Vinicius S; Vicentini, Fabiana T M C; Vilela, Fernanda M P; Martins, Frederico S; Zarpelon, Ana C; Cunha, Thiago M; Fonseca, Maria J V; Baracat, Marcela M; Georgetti, Sandra R; Verri, Waldiceu A; Casagrande, Rúbia

    2014-09-05

    Ultraviolet B (UVB) irradiation may cause oxidative stress- and inflammation-dependent skin cancer and premature aging. Pyrrolidine dithiocarbamate (PDTC) is an antioxidant and inhibits nuclear factor-κB (NF-κB) activation. In the present study, the mechanisms of PDTC were investigated in cell free oxidant/antioxidant assays, in vivo UVB irradiation in hairless mice and UVB-induced NFκB activation in keratinocytes. PDTC presented the ability to scavenge 2,2'-azinobis-(3-ethyl benzothiazoline-6-sulfonic acid) radical (ABTS), 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH) and hydroxyl radical (OH); and also efficiently inhibited iron-dependent and -independent lipid peroxidation as well as chelated iron. In vivo, PDTC treatment significantly decreased UVB-induced skin edema, myeloperoxidase (MPO) activity, production of the proinflammatory cytokine interleukin-1β (IL-1β), matrix metalloproteinase-9 (MMP-9), increase of reduced glutathione (GSH) levels and antioxidant capacity of the skin tested by the ferric reducing antioxidant power (FRAP) and ABTS assays. PDTC also reduced UVB-induced IκB degradation in keratinocytes. These results demonstrate that PDTC presents antioxidant and anti-inflammatory effects in vitro, which line up well with the PDTC inhibition of UVB irradiation-induced skin inflammation and oxidative stress in mice. These data suggest that treatment with PDTC may be a promising approach to reduce UVB irradiation-induced skin damages and merits further pre-clinical and clinical studies.

  9. Age-related increase in food spilling by laboratory mice may lead to significant overestimation of actual food consumption: implications for studies on dietary restriction, metabolism, and dose calculations.

    PubMed

    Starr, Marlene E; Saito, Hiroshi

    2012-10-01

    It is widely accepted that food consumption in humans declines with advanced age; however, data from mice remain controversial. Based on our previous observation that mice spill a considerable amount of food while eating, we hypothesized that increased food spillage in old mice masks actual food intake. To investigate whether mice exhibit age-associated declines in food consumption, we evaluated the actual food consumption of C57BL/6 mice at various ages by measuring both the amount of food in the food receptacle and the amount dropped to the cage bottom during feeding. We found that old mice dropped significantly more food (36% ± 8%) than young mice (18% ± 5%), which led to overestimations of food consumption, particularly in old mice. Although actual food consumption decreased in very old mice, food intake per body weight did not significantly change. These findings suggest that caution should be taken to accurately quantify food consumption by aged animals.

  10. Macronutrient balance, reproductive function, and lifespan in aging mice

    PubMed Central

    Solon-Biet, Samantha M.; Walters, Kirsty A.; Simanainen, Ulla K.; McMahon, Aisling C.; Ruohonen, Kari; Ballard, John William O.; Raubenheimer, David; Le Couteur, David G.; Simpson, Stephen J.

    2015-01-01

    In invertebrates, reproductive output and lifespan are profoundly impacted by dietary macronutrient balance, with these traits achieving their maxima on different diet compositions, giving the appearance of a resource-based tradeoff between reproduction and longevity. For the first time in a mammal, to our knowledge, we evaluate the effects of dietary protein (P), carbohydrate (C), fat (F), and energy (E) on lifespan and reproductive function in aging male and female mice. We show that, as in invertebrates, the balance of macronutrients has marked and largely opposing effects on reproductive and longevity outcomes. Mice were provided ad libitum access to one of 25 diets differing in P, C, F, and E content, with reproductive outcomes assessed at 15 months. An optimal balance of macronutrients exists for reproductive function, which, for most measures, differs from the diets that optimize lifespan, and this response differs with sex. Maximal longevity was achieved on diets containing a P:C ratio of 1:13 in males and 1:11 for females. Diets that optimized testes mass and epididymal sperm counts (indicators of gamete production) contained a higher P:C ratio (1:1) than those that maximized lifespan. In females, uterine mass (an indicator of estrogenic activity) was also greatest on high P:C diets (1:1) whereas ovarian follicle number was greatest on P:C 3:1 associated with high-F intakes. By contrast, estrous cycling was more likely in mice on lower P:C (1:8), and the number of corpora lutea, indicative of recent ovulations, was greatest on P:C similar to those supporting greatest longevity (1:11). PMID:25733862

  11. AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice.

    PubMed

    Zhou, Sheng; Lu, Wanli; Chen, Liang; Ge, Qiting; Chen, Dongyang; Xu, Zhihong; Shi, Dongquan; Dai, Jin; Li, Jianxin; Ju, Huangxian; Cao, Yi; Qin, Jinzhong; Chen, Shuai; Teng, Huajian; Jiang, Qing

    2017-02-22

    Osteoarthritis (OA) is a progressive degenerative disease of the joints that is associated with both joint injury and ageing. Here, we investigated the role of the energy sensor AMP-activated protein kinase (AMPK) in maintaining a healthy state of articular cartilage and in OA development. Using cartilage-specific, tamoxifen-inducible AMPKα1 conditional knockout (AMPKα1 cKO), AMPKα2 conditional knockout (AMPKα2 cKO) and AMPKα1α2 conditional double knockout (AMPKα cDKO) mice, we found that compared with wild-type (WT) littermates, mutant mice displayed accelerated severity of surgically induced OA, especially AMPKα cDKO mice. Furthermore, male but not female AMPKα cDKO mice exhibited severely spontaneous ageing-associated OA lesions at 12 months of age. The chondrocytes isolated from AMPKα cDKO mice resulted in an enhanced interleukin-1β (IL-1β)-stimulated catabolic response. In addition, upregulated expression of matrix metalloproteinase-3 (MMP-3), MMP-13 and phospho-nuclear factor-κB (phospho-NF-κB) p65 and increased levels of apoptotic markers were detected in the cartilage of AMPKα cDKO mice compared with their WT littermates in vivo. Thus, our findings suggest that AMPK activity in chondrocytes is important in maintaining joint homeostasis and OA development.

  12. AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice

    PubMed Central

    Zhou, Sheng; Lu, Wanli; Chen, Liang; Ge, Qiting; Chen, Dongyang; Xu, Zhihong; Shi, Dongquan; Dai, Jin; Li, Jianxin; Ju, Huangxian; Cao, Yi; Qin, Jinzhong; Chen, Shuai; Teng, Huajian; Jiang, Qing

    2017-01-01

    Osteoarthritis (OA) is a progressive degenerative disease of the joints that is associated with both joint injury and ageing. Here, we investigated the role of the energy sensor AMP-activated protein kinase (AMPK) in maintaining a healthy state of articular cartilage and in OA development. Using cartilage-specific, tamoxifen-inducible AMPKα1 conditional knockout (AMPKα1 cKO), AMPKα2 conditional knockout (AMPKα2 cKO) and AMPKα1α2 conditional double knockout (AMPKα cDKO) mice, we found that compared with wild-type (WT) littermates, mutant mice displayed accelerated severity of surgically induced OA, especially AMPKα cDKO mice. Furthermore, male but not female AMPKα cDKO mice exhibited severely spontaneous ageing-associated OA lesions at 12 months of age. The chondrocytes isolated from AMPKα cDKO mice resulted in an enhanced interleukin-1β (IL-1β)-stimulated catabolic response. In addition, upregulated expression of matrix metalloproteinase-3 (MMP-3), MMP-13 and phospho-nuclear factor-κB (phospho-NF-κB) p65 and increased levels of apoptotic markers were detected in the cartilage of AMPKα cDKO mice compared with their WT littermates in vivo. Thus, our findings suggest that AMPK activity in chondrocytes is important in maintaining joint homeostasis and OA development. PMID:28225087

  13. Dexmedetomidine improves early postoperative cognitive dysfunction in aged mice.

    PubMed

    Qian, Xiao-Lan; Zhang, Wei; Liu, Ming-Zheng; Zhou, Yu-Bing; Zhang, Jing-Min; Han, Li; Peng, You-Mei; Jiang, Jin-hua; Wang, Qing-Duan

    2015-01-05

    Postoperative cognitive dysfunction (POCD) is a frequent complication following major surgery in the elderly. However, the exact pathogenic mechanisms are still unknown. Dexmedetomidine, a selective alpha 2 adrenal receptor agonist, was revealed anesthesia and brain protective role. The present study aimed to examine whether dexmedetomdine protects against POCD induced by major surgical trauma under general anesthesia in aged mice. In the present study, cognitive function was assessed by Y-maze. Proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α), apoptosis-related factor caspase-3 and Bax were detected by real-time PCR, Western blot or immunohistochemistry. The results showed that anesthesia alone caused weak cognitive dysfunction on the first day after general anesthesia. Cognitive function in mice with splenectomy under general anesthesia was significantly exacerbated at the first and third days after surgery, and was significantly improved by dexmedetomidine administration. Splenectomy increased the expression of IL-1β, TNF-α, Bax and caspase-3 in hippocampus. These changes were significantly inversed by dexmedetomidine. These results suggest that hippocampal inflammatory response and neuronal apoptosis may contribute to POCD, and selective alpha 2 adrenal receptor excitation play a protective role.

  14. Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour.

    PubMed

    Maccarrone, Mauro; Valverde, Olga; Barbaccia, Maria L; Castañé, Anna; Maldonado, Rafael; Ledent, Catherine; Parmentier, Marc; Finazzi-Agrò, Alessandro

    2002-04-01

    Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the most active endocannabinoids at brain (CB1) cannabinoid receptors. CD1 mice lacking the CB1 receptors ("knockout" [KO] mutants) were compared with wildtype (WT) littermates for their ability to degrade AEA through an AEA membrane transporter (AMT) and an AEA hydrolase (fatty acid amide hydrolase, FAAH). The age dependence of AMT and FAAH activity were investigated in 1- or 4-month-old WT and KO animals, and found to increase with age in KO, but not WT, mice and to be higher in the hippocampus than in the cortex of all animals. AEA and 2-AG were detected in nmol/mg protein (microm) concentrations in both regions, though the hippocampus showed approximately twice the amount found in the cortex. In the same regions, 2-AG failed to change across groups, while AEA was significantly decreased (approximately 30%) in hippocampus, but not in cortex, of old KO mice, when compared with young KO or age-matched WT animals. In the open-field test under bright light and in the lit-dark exploration model of anxiety, young KO mice, compared with old KO, exhibited a mild anxiety-related behaviour. In contrast, neither the increase in memory performance assessed by the object recognition test, nor the reduction of morphine withdrawal symptoms, showed age dependence in CB1 KO mice. These results suggest that invalidation of the CB1 receptor gene is associated with age-dependent adaptive changes of endocannabinoid metabolism which appear to correlate with the waning of the anxiety-like behaviour exhibited by young CB1 KO mice.

  15. Cross-Age Peer Coaching: Enhancing the Peer Interactions of Children Exhibiting Symptoms of ADHD

    ERIC Educational Resources Information Center

    Vilardo, Brigid A.; DuPaul, George J.; Kern, Lee; Hojnoski, Robin L.

    2013-01-01

    Previous research demonstrates that children with attention-deficit/hyperactivity disorder (ADHD) can experience social difficulties. Therefore, the current study examined the effects of cross-age peer coaching on social behaviors of first graders with significant symptoms of ADHD using a multiple baseline design. Four students who met criteria…

  16. Geotropic sensitivity exhibited by single hornets: The influence of caste, age, light and temperature

    NASA Astrophysics Data System (ADS)

    Ishay, Jacob S.; Rosenzweig, Eyal; Abir, Irit

    Hornet (Vespa orientalis, Hymenoptera: Vespinae) workers, queens and males, aged 0-24 hours (i.e. juveniles) and 24 hours and more (i.e. adults) were tested for their responses to changes in the direction of the gravitational force while placed on a flat surface gradually tilted between 0.5° and 180°. The tests were run on non-blind and blind hornets, at temperatures ranging between 18°C and 35°C, in daylight as well as in the dark. Up to 18 hours of age, negative phototaxis prevailed among the hornets, which displayed a clear preference for remaining in the dark regardless of the geotropic position. Between 18-24 hours of age, there was gradual appearance of a sensitivity to change in the geotropic position. Above 24 hr of age, the hornets became sensitive to changes in their declinations, with workers becoming sensitive at a 3-5° declination, queens at 4-5° and males at a declination of 8-19° from the horizontal. Hornet response takes the form of an upward climb, to the highest point of the test surface. Such response required a temperature exceeding 24.8-25°C for workers, 23.2°C for queens and 20.8-21°C for males.

  17. Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature

    PubMed Central

    Brunetti, Orazio; Imbrici, Paola; Botti, Fabio Massimo; Pettorossi, Vito Enrico; D'Adamo, Maria Cristina; Valentino, Mario; Zammit, Christian; Mora, Marina; Gibertini, Sara; Di Giovanni, Giuseppe; Muscat, Richard; Pessia, Mauro

    2012-01-01

    Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K+ channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1V408A/+). Here, we investigated the neuromuscular transmission of Kv1.1V408A/+ ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve–muscle from Kv1.1+/+ and Kv1.1V408A/+ mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca2 + signals that occurred abnormally only in preparations dissected from Kv1.1V408A/+ mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca2 + homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K+ channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or

  18. Emotionality, exploratory behavior, and locomotion in aging inbred strains of mice.

    PubMed

    Elias, P K; Elias, M F; Eleftheriou, B E

    1975-01-01

    Two inbred strains of mice, C57BL/6J and DBA/2J, ranging in age from 2 to 38 months, were tested in an open field using the free exploration method. Scores were obtained for locomotor activity, exploratory behavior and emotionality. Strain differences were observed for all three variables. Beginning at late maturity (12 months), locomotor activity decreased with increasing age. Exploratory behavior was at a low level for DBA/2J mice at all ages. For C57BL/6J mice, exploratory behavior decreased significantly between 2 and 6 months and remained stable thereafter. Emotionality remained unchanged with advancing age for both strains of mice.

  19. Mice lacking α1,3-fucosyltransferase 9 exhibit modulation of in vivo immune responses against pathogens.

    PubMed

    Kashiwazaki, Hiromi; Kakizaki, Masatoshi; Ikehara, Yuzuru; Togayachi, Akira; Narimatsu, Hisashi; Watanabe, Rihito

    2014-05-01

    Carbohydrate structures, including Lewis X (Le(x)), which is not synthesized in mutant mice that lack α1,3-fucosyltransferase 9 (Fut9(-/-)), are involved in cell-cell recognition and inflammation. However, immunological alteration in Fut9(-/-) mice has not been studied. Thus, the inflammatory response of Fut9(-/-) mice was examined using the highly neurovirulent mouse hepatitis virus (MHV) JHMV srr7 strain. Pathological study revealed that inflammation induced in the brains of Fut9(-/-) mice after infection was more extensive compared with that of wild-type mice, although viral titers obtained from the brains of mutant mice were lower than those of wild-type mice. Furthermore, the reduction in cell numbers in the spleens of wild-type mice after infection was not observed in the infected Fut9(-/-) mice. Although there were no clear differences in the levels of cytokines examined in the brains between Fut9(-/-) and wild-type mice except for interferon-β expression, some of those in the spleens, including interferon-γ, interleukin-6, and monocyte chemoattractant protein 1, showed higher levels in Fut9(-/-) than in wild-type mice. Furthermore, Fut9(-/-) mice were refractory to the in vivo inoculation of endotoxin (LPS) compared with wild-type mice. These results indicate that Le(x) structures are involved in host responses against viral or bacterial challenges.

  20. Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice

    PubMed Central

    Buchanan, J.B.; Sparkman, N.L.; Chen, J.; Johnson, R.W.

    2008-01-01

    Summary Peripheral immune stimulation as well as certain types of psychological stress increases brain levels of inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNFα). We have demonstrated that aged mice show greater increases in central inflammatory cytokines, as well as greater cognitive deficits, compared to adults in response to peripheral lipopolysaccharide (LPS) administration. Because aged mice are typically more sensitive to systemic stressors such as LPS, and certain psychological stressors induce physiological responses similar to those that follow LPS, we hypothesized that aged mice would be more sensitive to the physiological and cognitive effects of mild stress than adult mice. Here, adult (3–5 mo) and aged (22–23 mo) male BALB/c mice were trained in the Morris water maze for 5 days. Mice were then exposed to a mild restraint stress of 30 minutes before being tested in a working memory version of the water maze over a 3 day period. On day 4 mice were stressed and then killed for collection of blood and brain. In a separate group of animals, mice were killed immediately after one, two or three 30 min restraint sessions and blood for peripheral corticosterone and cytokine protein measurement, and brains were dissected for central cytokine mRNA measurement. Stress disrupted spatial working memory in both adult and aged mice but to a much greater extent in the aged mice. In addition, aged mice showed an increase in stress-induced expression of hippocampal IL-1β mRNA and MHC class II protein compared to non-stressed controls while expression in adult mice was unaffected by stress. These data show that aged mice are more sensitive to both the cognitive and inflammatory effects of mild stress than are adult mice and suggest a possible a role for IL-1β. PMID:18407425

  1. 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

  2. Postural finger tremor exhibited by Parkinson patients and age-matched subjects.

    PubMed

    Palmer, S S; Hutton, J T

    1995-09-01

    Physiological correlates of postural tremor of the finger seen in Parkinson's disease patients are different from those seen in age-matched control subjects. A significant correlation between the spectral peak of acceleration and the spectral peak of rectified electromyographic activity from the muscle responsible for finger extension was found in Parkinson's disease patients. This correlation was not seen in age-matched control subjects. Any neural drive imposed on the motoneuron pool from supraspinal levels would enhance the electromyographic activity. Likewise, any feedback effects via spinal stretch reflexes or supraspinal stretch responses would be mediated through the motoneuron pool and electromyographic activity. The results of this research support the theory that Parkinson tremor is a centrally driven rhythm that may be influenced by feedback effects, whereas physiological tremor is due to a complex interaction of central, feedback, and mechanical effects.

  3. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.

    PubMed

    Toth, Peter; Tarantini, Stefano; Ashpole, Nicole M; Tucsek, Zsuzsanna; Milne, Ginger L; Valcarcel-Ares, Noa M; Menyhart, Akos; Farkas, Eszter; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2015-12-01

    Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.

  4. Mice overexpressing murine oncostatin M (OSM) exhibit changes in hematopoietic and other organs that are distinct from those of mice overexpressing human OSM or bovine OSM.

    PubMed

    Juan, T S-C; Bolon, B; Lindberg, R A; Sun, Y; Van, G; Fletcher, F A

    2009-01-01

    Oncostatin M (OSM) and leukemia inhibitory factor (LIF) belong to the interleukin-6 family of cytokines. The authors' previous in vitro work demonstrated that in mouse cells mouse OSM (mOSM) signals through a heterodimeric receptor complex incorporating the mOSM-specific receptor mOSMRbeta while human OSM (hOSM) and bovine OSM (bOSM) use the mouse LIF receptor mLIFRbeta rather than mOSMRbeta. These in vitro data suggest that prior studies in mouse systems with hOSM or bOSM (the usual molecules used in early studies) reflect LIF rather than OSM biology. The current work assessed whether or not this divergence in actions among these three OSMs also occurs in vivo in mouse models. Adult female (C57BL/6J x DBA/2J) F(1) mice were engineered to stably overexpress mOSM, hOSM, or bOSM by retrovirus-mediated gene transfer (n = 10 or more per group). After 4 weeks, molecular and hematologic profiles and anatomic phenotypes in multiple organs were assessed by standard techniques. Animals overexpressing either hOSM or bOSM had an identical phenotype resembling that associated with LIF activation, including significant hematologic abnormalities (anemia, neutrophilia, lymphopenia, eosinopenia, and thrombocytosis); weight loss; profound enlargement (lymph node, spleen) and/or structural reorganization (lymph node, spleen, thymus) of lymphoid organs; and severe osteosclerosis. In contrast, mice overexpressing mOSM did not develop hematologic changes, weight loss, or osteosclerosis and exhibited more modest and anatomically distinct restructuring of lymphoid organs. These data indicate that activities imputed to OSM and the mOSMRbeta signaling pathway using in vitro and in vivo mouse experimental systems are unique to mOSM.

  5. Age-related changes in bone structure and strength in female and male BALB/c mice.

    PubMed

    Willinghamm, Mark D; Brodt, Michael D; Lee, Kristen L; Stephens, Abby L; Ye, Jiaxin; Silva, Matthew J

    2010-06-01

    Mice may be useful for studies of skeletal aging, but there are limited data on changes in bone structure and strength over their life span. We obtained bones from female and male BALB/c mice at ages 2, 4, 7, 12, and 20 months and evaluated their structural, densitometric, and mechanical properties. MicroCT of the mid-diaphysis of the femur and radius indicated that during skeletal growth (2-7 months) bone cross-sectional size (area, moment of inertia) increased rapidly; during aging (7-20 months) cortical area was maintained, while moment of inertia continued to increase. Bones from females were smaller than those from males at young ages but not at later ages. Changes in whole-bone stiffness and strength reflected the changes in bone size, with a rapid increase from 2 to 7 months, followed by little or no change. In contrast, energy-to-fracture declined with aging. Cortical tissue mineral density increased during growth and was maintained with aging. MicroCT of trabecular bone revealed age-related changes that were site-dependent. The proximal tibia showed a clear pattern of age-related decline in trabecular BV/TV, with progressive decreases after 4 months in both sexes; lumbar vertebra L5 had more modest age-related declines; in contrast, caudal vertebra Ca7 had increasing BV/TV with aging. Overall, we found no evidence that females had more pronounced age-related deterioration than males. We conclude that bones from aging female and male BALB/c mice exhibit many of the changes seen in humans and are therefore a clinically relevant model for studies of skeletal aging.

  6. Investigation of the ageing effects exhibited by AR coatings exposed to ultraviolet laser irradiation

    NASA Astrophysics Data System (ADS)

    Botha, Roelene; Bischof, David; Vetsch, Bernhard; Scherrer, Ueli; Michler, Markus; Rinner, Stefan J.; Ettemeyer, Andreas; Ziolek, Carsten

    2016-12-01

    Optical coatings used in ultraviolet applications are often exposed to harsh environments operating at elevated temperatures. In order to study the impact of the ageing effects optical coatings experience at various operating temperatures, an ultraviolet laser-induced degradation test system has been developed. It allows for flexible use in both a long-term stability test bench as well as in an LIDT measurement system. This work contains the preliminary results of optical degradation tests at 355 nm performed on anti-reflective coatings. As a subsequent step, the LIDT of the samples were measured using a Q-Switched Nd:YAG laser operating at 1064nm.

  7. Anti-Aging Effect of Nigella Sativa Fixed Oil on D-Galactose-Induced Aging in Mice

    PubMed Central

    Shahroudi, Mahdieh Jafari; Mehri, Soghra; Hosseinzadeh, Hossein

    2017-01-01

    Objectives: Aging is an unconscious and gradual process that can lead to changes in biological systems. Induction of oxidative stress and apoptosis, hepatotoxicity and neurotoxicity are involved in the aging process. Regarding the antioxidant property of black seed oil, the aim of this study was to evaluate the anti-aging effect of Nigella sativa (N. sativa) oil on d-galactose-induced aging in mice. Methods: For induction of aging, D-galactose (500 mg/kg, subcoutaneously SC) was administrated to male mice for 42 days. Animals were treated with D-galactose alone or with b lack seed oil (0.1, 0.2, 0.5 mL/kg, intraperitoneally (ip)). Additionally, vitamin E (200 mg/kg) was used as a positive control. At the end of treatment, the malondialdehyde (MDA) and the glutathione (GSH) contents in brain and liver tissues were measured. Also, enzymes in serum, including aspartate aminotransferase (AST) and alanine amino transferase (ALT), were determined. The levels of the proteins Bax, Bcl2, caspase-3 (pro and cleaved) in brain and liver tissues were evaluated. Results: Administration of D-galactose (500 mg/kg, SC) for 42 days increased serum levels of ALT and AST, as well as the MDA content, in brain and liver tissues, but decreased the GSH content. Additionally, the levels of apoptotic proteins, including Bax, procaspase-3 and caspase-3 cleaved, were markedly increased. N. sativa oil (0.1 and 0.2 mL/kg) diminished the levels of the biochemical markers ALT and AST. Administration of black seed oil (0.1, 0.2 and 0.5 mL/kg) reduced lipid peroxidation and at doses 0.1 and 0.2 mL/kg significantly recovered the GSH content. The oil decreased Bax/Bcl2 levels and at 0.1 mL/kg down-regulated the expressions of caspase-3 (pro and cleaved) proteins in brain and liver tissues. Conclusion: Through its antioxidant and anti-apoptosis properties, black seed oil exhibited an anti-aging effect in a model of aging induced with D-galactose. PMID:28392960

  8. Nuclear envelope alterations generate an aging-like epigenetic pattern in mice deficient in Zmpste24 metalloprotease.

    PubMed

    Osorio, Fernando G; Varela, Ignacio; Lara, Ester; Puente, Xose S; Espada, Jesús; Santoro, Raffaella; Freije, José M P; Fraga, Mario F; López-Otín, Carlos

    2010-12-01

    Mutations in the nuclear envelope protein lamin A or in its processing protease ZMPSTE24 cause human accelerated aging syndromes, including Hutchinson-Gilford progeria syndrome. Similarly, Zmpste24-deficient mice accumulate unprocessed prelamin A and develop multiple progeroid symptoms, thus representing a valuable animal model for the study of these syndromes. Zmpste24-deficient mice also show marked transcriptional alterations associated with chromatin disorganization, but the molecular links between both processes are unknown. We report herein that Zmpste24-deficient mice show a hypermethylation of rDNA that reduces the transcription of ribosomal genes, being this reduction reversible upon treatment with DNA methyltransferase inhibitors. This alteration has been previously described during physiological aging in rodents, suggesting its potential role in the development of the progeroid phenotypes. We also show that Zmpste24-deficient mice present global hypoacetylation of histones H2B and H4. By using a combination of RNA sequencing and chromatin immunoprecipitation assays, we demonstrate that these histone modifications are associated with changes in the expression of several genes involved in the control of cell proliferation and metabolic processes, which may contribute to the plethora of progeroid symptoms exhibited by Zmpste24-deficient mice. The identification of these altered genes may help to clarify the molecular mechanisms underlying aging and progeroid syndromes as well as to define new targets for the treatment of these dramatic diseases.

  9. Transgenic sickle cell trait mice do not exhibit abnormal thermoregulatory and stress responses to heat shock exposure.

    PubMed

    Chen, Yifan; Islam, Aminul

    2016-07-01

    There remains controversy over whether individuals with sickle cell trait (SCT) are vulnerable to health risks during physical activity in high temperatures. We examined thermoregulatory and stress-related responses to heat exposure in SCT and wild-type (WT) mice. No significant differences in core temperature (Tc) were observed between SCT and WT mice during heat exposure. There was no correlation between peak Tc during heat exposure and levels of hemoglobin S in SCT mice. Basal levels of circulating inflammatory and stress-related markers were not significantly different between SCT and WT mice. Although heat exposure caused significant increases in plasma interleukins 1β and 6, and 8-isoprostane in SCT and WT mice, no differences were found between SCT and WT mice with similar thermal response profiles during heat exposure. SCT mice had significantly higher expression of heat shock protein 72 in heart, liver and gastrocnemius muscle than WT mice under control and post-heat conditions. In conclusion, there is neither thermoregulatory dysfunction nor abnormal stress-related response in SCT mice exposed to moderate heat. The hemoglobin variant in mice is associated with altered tissue stress protein homeostasis.

  10. [The activity of gas metabolism, thermoregulation, and antioxidant enzymes in aging C57Bl/6 mice].

    PubMed

    Utko, N O; Pishel', I M; Bezrukov, V V; Muradian, Kh K

    2008-01-01

    The distribution type and correlative links between physiological and biochemical indices characterizing functional condition of the systems of gaseous exchange (V(O2) and V(CO2)), thermoregulation (body temperature and coefficient of thermoconductivity) and antioxidant defense have been studied in 62 young (3-5 mo.) and 58 old (23-26 mo.) male C57Bl/ 6 mice. The coefficients of variation differed significantly depending on the variable but not the age-group. Mean values of V(O2) and V(CO2), body temperature and thermoconductivity, but not activities of the antioxidant enzymes, declined in aging. Moreover, the activities of catalase, glutathione-peroxidase and glutathionereductase, i.e. enzymes involved in regulation of hydrogen peroxide level, increased in aging. The correlations between V(O2) and V(CO2), V(O2) and body temperature or V(O2) and the liver pH, as well as between the antioxidant enzyme activities exhibited little age-changes. However, three-dimensional non-linear models revealed significant age-changes in relations between the studied variables.

  11. Suppression of oxidative stress by resveratrol after isometric contractions in gastrocnemius muscles of aged mice.

    PubMed

    Ryan, Michael J; Jackson, Janna R; Hao, Yanlei; Williamson, Courtney L; Dabkowski, Erinne R; Hollander, John M; Alway, Stephen E

    2010-08-01

    This study tested the hypothesis that resveratrol supplementation would lower oxidative stress in exercised muscles of aged mice. Young (3 months) and aged (27 months) C57BL/6 mice received a control or a 0.05% trans-resveratrol-supplemented diet for 10 days. After 7 days of dietary intervention, 20 maximal electrically evoked isometric contractions were obtained from the plantar flexors of one limb in anesthetized mice. Exercise was conducted for three consecutive days. Resveratrol supplementation blunted the exercise-induced increase in xanthine oxidase activity in muscles from young (25%) and aged (53%) mice. Resveratrol lowered H(2)O(2) levels in control (13%) and exercised (38%) muscles from aged animals, reduced Nox4 protein in both control and exercised muscles of young (30%) and aged mice (40%), and increased the ratio of reduced glutathione to oxidized glutathione in exercised muscles from young (38%) and aged (135%) mice. Resveratrol prevented the increase in lipid oxidation, increased catalase activity, and increased MnSOD activity in exercised muscles from aged mice. These data show that dietary resveratrol suppresses muscle indicators of oxidative stress in response to isometric contractions in aged mice.

  12. Intake of Wild Blueberry Powder Improves Episodic-Like and Working Memory during Normal Aging in Mice.

    PubMed

    Beracochea, Daniel; Krazem, Ali; Henkouss, Nadia; Haccard, Guillaume; Roller, Marc; Fromentin, Emilie

    2016-08-01

    The number of Americans older than 65 years old is projected to more than double in the next 40 years. Cognitive changes associated to aging can affect an adult's day-to-day functioning. Among these cognitive changes, reasoning, episodic memory, working memory, and processing speed decline gradually over time. Early memory changes include a decline in both working and episodic memory. The aim of the present study was to determine whether chronic (up to 75 days) daily administration of wild blueberry extract or a wild blueberry full spectrum powder would help prevent memory failure associated with aging in tasks involving various forms of memory. Both blueberry ingredients were used in a study comparing young mice (6 months old) to aged mice (18 months old). At this age, mice exhibit memory decline due to aging, which is exacerbated first by a loss in working and contextual (episodic-like) memory. Contextual memory (episodic-like memory) was evaluated using the contextual serial discrimination test. Working and spatial memory were evaluated using the Morris-Water maze test and the sequential alternation test. Statistical analysis was performed using an ANOVA with the Bonferroni post-hoc test. Supplementation with wild blueberry full spectrum powder and wild blueberry extract resulted in significant improvement of contextual memory, while untreated aged mice experienced a decline in such memory. Only the wild blueberry full spectrum powder significantly contributed to an improvement of spatial and working memory versus untreated aged mice. These improvements of cognitive performance may be related to brain oxidative status, acetylcholinesterase activity, neuroprotection, or attenuation of immunoreactivity.

  13. Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice.

    PubMed

    Currais, Antonio; Prior, Marguerite; Lo, David; Jolivalt, Corinne; Schubert, David; Maher, Pamela

    2012-12-01

    Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age-associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence-accelerated prone 8 (SAMP8) and senescence-resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in the development of cognitive deficits in SAMR1 mice similar to those seen in age-matched, nondiabetic SAMP8 mice. No further cognitive deficits were observed when the SAMP8 mice were made diabetic. T1D dramatically increased Aβ and glial fibrillary acidic protein immunoreactivity in the hippocampus of SAMP8 mice and to a lesser extent in age-matched SAMR1 mice. Further analysis revealed aggregated Aβ within astrocyte processes surrounding vessels. Western blot analyses from T1D SAMP8 mice showed elevated amyloid precursor protein processing and protein glycation along with increased inflammation. T1D elevated tau phosphorylation in the SAMR1 mice but did not further increase it in the SAMP8 mice where it was already significantly higher. These data suggest that aberrant glucose metabolism potentiates the aging phenotype in old mice and contributes to early stage central nervous system pathology in younger animals.

  14. Mice deficient in Group VIB phospholipase A2 (iPLA2γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet

    PubMed Central

    Song, Haowei; Wohltmann, Mary; Bao, Shunzhong; Ladenson, Jack H.; Semenkovich, Clay F.

    2010-01-01

    Phospholipases A2 (PLA2) play important roles in metabolic processes, and the Group VI PLA2 family is comprised of intracellular enzymes that do not require Ca2+ for catalysis. Mice deficient in Group VIA PLA2 (iPLA2β) develop more severe glucose intolerance than wild-type (WT) mice in response to dietary stress. Group VIB PLA2 (iPLA2γ) is a related enzyme distributed in membranous organelles, including mitochondria, and iPLA2γ knockout (KO) mice exhibit altered mitochondrial morphology and function. We have compared metabolic responses of iPLA2γ-KO and WT mice fed a Western diet (WD) with a high fat content. We find that KO mice are resistant to WD-induced increases in body weight and adiposity and in blood levels of cholesterol, glucose, and insulin, even though WT and KO mice exhibit similar food consumption and dietary fat digestion and absorption. KO mice are also relatively resistant to WD-induced insulin resistance, glucose intolerance, and altered patterns of fat vs. carbohydrate fuel utilization. KO skeletal muscle exhibits impaired mitochondrial β-oxidation of fatty acids, as reflected by accumulation of larger amounts of long-chain acylcarnitine (LCAC) species in KO muscle and liver compared with WT in response to WD feeding. This is associated with increased urinary excretion of LCAC and much reduced deposition of triacylglycerols in liver by WD-fed KO compared with WT mice. The iPLA2γ-deficient genotype thus results in a phenotype characterized by impaired mitochondrial oxidation of fatty acids and relative resistance to the metabolic abnormalities induced by WD. PMID:20179248

  15. Attenuated pain response of obese mice (B6.Cg-lep(ob)) is affected by aging and leptin but not sex.

    PubMed

    Rodgers, Helen M; Liban, Suadi; Wilson, Linda M

    2014-01-17

    Genetically obese mice (B6.Cg-lep(ob)) manifest decreased responses to noxious thermal stimuli (hotplate test) suggesting endogenous analgesia (Roy et al., 1981). To examine further the analgesic response of these mice, we conducted 4 experiments. Experiment 1 assessed the response of ob/ob mice to tail flick, another noxious thermal test. Tail-flick testing was performed on B6.Cg-lep(ob) mice (n=14) and B6.Cg-lep(OB/?) (n=12) across a range of temperatures. Ob/ob mice exhibited longer latencies than control mice at all temperatures tested. In Experiment 2, potential sex differences were examined. Tail-flick latencies in male and female ob/ob mice (n=6/group) did not differ. The final 2 experiments examined factors that could modulate endogenous analgesia. Experiment 3 assessed the effects of aging in ob/ob mice (n=10/group). Older mice displayed longer tail-flick latencies than did younger mice. Experiment 4 examined the effect of leptin administration in the leptin-deficient ob/ob mice. Two groups (n=10/group) of ob/ob mice received osmotic pump implants filled with either leptin or vehicle, and were tail-flick tested at days 7 and 14 post-implantation. Ob/ob mice receiving leptin showed shorter latencies than did vehicle-receiving ob/ob mice. Taken together, these results support earlier reports of heightened analgesia in ob/ob mice and suggest that aging further reduces the already impaired pain response. Furthermore, leptin deficiency partially contributes to decreased pain sensation of ob/ob mice.

  16. Glial dysfunction in parkin null mice: effects of aging.

    PubMed

    Solano, Rosa M; Casarejos, Maria J; Menéndez-Cuervo, Jamie; Rodriguez-Navarro, Jose A; García de Yébenes, Justo; Mena, Maria A

    2008-01-16

    Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals, and abnormal neurotransmitter release. The role of glia in parkin deficiency is little known. We cultured midbrain glia from wild-type (WT) and parkin knock-out (PK-KO) mice. After 18-20 d in vitro, PK-KO glial cultures had less astrocytes, more microglia, reduced proliferation, and increased proapoptotic protein expression. PK-KO glia had greater levels of intracellular glutathione (GSH), increased mRNA expression of the GSH-synthesizing enzyme gamma-glutamylcysteine synthetase, and greater glutathione S-transferase and lower glutathione peroxidase activities than WT. The reverse happened in glia cultured in serum-free defined medium (EF12) or in old cultures. PK-KO glia was more susceptible than WT to transference to EF12 or neurotoxins (1-methyl-4-phenylpyridinium, blockers of GSH synthesis or catalase, inhibitors of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3 kinases), aging of the culture, or combination of these insults. PK-KO glia was less susceptible than WT to Fe2+ plus H2O2 and less responsive to protection by deferoxamine. Old WT glia increased the expression of heat shock protein 70, but PK-KO did not. Glia conditioned medium (GCM) from PK-KO was less neuroprotective and had lower levels of GSH than WT. GCM from WT increased the levels of dopamine markers in midbrain neuronal cultures transferred to EF12 more efficiently than GCM from PK-KO, and the difference was corrected by supplementation with GSH. PK-KO-GCM was a less powerful suppressor of apoptosis and microglia in neuronal cultures. Our data prove that abnormal glial function is critical in parkin mutations, and its role increases with aging.

  17. AMPD3-deficient mice exhibit increased erythrocyte ATP levels but anemia not improved due to PK deficiency.

    PubMed

    Cheng, Jidong; Morisaki, Hiroko; Toyama, Keiko; Ikawa, Masahito; Okabe, Masaru; Morisaki, Takayuki

    2012-11-01

    AMP deaminase (AMPD) catalyzes AMP to IMP and plays an important role in energy charge and nucleotide metabolism. Human AMPD3 deficiency is a type of erythrocyte-specific enzyme deficiency found in individuals without clinical symptoms, although an increased level of ATP in erythrocytes has been reported. To better understand the physiological and pathological roles of AMPD3 deficiency, we established a line of AMPD3-deficient [A3(-/-)] mice. No AMPD activity and a high level of ATP were observed in erythrocytes of these mice, similar to human RBC-AMPD3 deficiency, while other characteristics were unremarkable. Next, we created AMPD3 and pyruvate kinase (PK) double-deficient [PKA(-/-,-/-)] mice by mating A3(-/-) mice with CBA-Pk-1slc/Pk-1slc mice [PK(-/-)], a spontaneous PK-deficient strain showing hemolytic anemia. In PKA(-/-,-/-) mice, the level of ATP in red blood cells was increased 1.5 times as compared to PK(-/-) mice, although hemolytic anemia in those animals was not improved. In addition, we observed osmotic fragility of erythrocytes in A3(-/-) mice under fasting conditions. In contrast, the ATP level in erythrocytes was elevated in A3(-/-) mice as compared to the control. In conclusion, AMPD3 deficiency increases the level of ATP in erythrocytes, but does not improve anemia due to PK deficiency and leads to erythrocyte dysfunction.

  18. Changes of Ovarian microRNA Profile in Long-Living Ames Dwarf Mice during Aging

    PubMed Central

    Schneider, Augusto; Matkovich, Scot J.; Victoria, Berta; Spinel, Lina; Bartke, Andrzej; Golusinski, Pawel; Masternak, Michal M.

    2017-01-01

    The Ames dwarf (df/df) mice have extended longevity and can preserve the ovarian reserve longer than Normal (N) mice. Based on this, the aim of our study was to evaluate the ovarian microRNA (miRNA) profile in young and aged df/df and N mice. Ovarian tissue was collected at 5–6 months and at 21–22 months of age for miRNA sequencing. We detected a total of 404 miRNAs in the ovarian samples, from which the abundance of 22 and 33 miRNAs changed with age in N and df/df mice, respectively. Of these, only three miRNAs were commonly regulated with age between N and df/df mice, indicating a very divergent miRNA profile between genotypes. We also detected that 46 miRNAs were regulated between N and df/df mice, of which 23 were regulated exclusively in young mice, 12 exclusively in old mice and 12 commonly regulated at young and old ages. Many genes likely to be targeted by these miRNAs are involved in the FoxO, mTOR, PI3k/Akt and insulin signaling pathways. These results suggest that the aging process has a differential impact on the ovarian miRNA profile in df/df mice, and suggest that these miRNAs can be central players in the maintenance of a younger ovarian phenotype. PMID:28046124

  19. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

    PubMed

    Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

    2014-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD.

  20. Caspr3-Deficient Mice Exhibit Low Motor Learning during the Early Phase of the Accelerated Rotarod Task

    PubMed Central

    Hirata, Haruna; Takahashi, Aki; Shimoda, Yasushi; Koide, Tsuyoshi

    2016-01-01

    Caspr3 (Contactin-associated protein-like 3, Cntnap3) is a neural cell adhesion molecule belonging to the Caspr family. We have recently shown that Caspr3 is expressed abundantly between the first and second postnatal weeks in the mouse basal ganglia, including the striatum, external segment of the globus pallidus, subthalamic nucleus, and substantia nigra. However, its physiological role remains largely unknown. In this study, we conducted a series of behavioral analyses on Capsr3-knockout (KO) mice and equivalent wild-type (WT) mice to investigate the role of Caspr3 in brain function. No significant differences were observed in most behavioral traits between Caspr3-KO and WT mice, but we found that Caspr3-KO mice performed poorly during the early phase of the accelerated rotarod task in which latency to falling off a rod rotating with increasing velocity was examined. In the late phase, the performance of the Caspr3-KO mice caught up to the level of WT mice, suggesting that the deletion of Caspr3 caused a delay in motor learning. We then examined changes in neural activity after training on the accelerated rotarod by conducting immunohistochemistry using antibody to c-Fos, an indirect marker for neuronal activity. Experience of the accelerated rotarod task caused increases in the number of c-Fos-positive cells in the dorsal striatum, cerebellum, and motor cortex in both Caspr3-KO and WT mice, but the number of c-Fos-positive cells was significantly lower in the dorsal striatum of Caspr3-KO mice than in that of WT mice. The expression of c-Fos in the ventral striatum of Caspr3-KO and WT mice was not altered by the training. Our findings suggest that reduced activation of neural cells in the dorsal striatum in Caspr3-KO mice leads to a decline in motor learning in the accelerated rotarod task. PMID:26807827

  1. Manipulation of Ovarian Function Significantly Influenced Sarcopenia in Postreproductive-Age Mice

    PubMed Central

    Peterson, Rhett L.

    2016-01-01

    Previously, transplantation of ovaries from young cycling mice into old postreproductive-age mice increased life span. We anticipated that the same factors that increased life span could also influence health span. Female CBA/J mice received new (60 d) ovaries at 12 and 17 months of age and were evaluated at 16 and 25 months of age, respectively. There were no significant differences in body weight among any age or treatment group. The percentage of fat mass was significantly increased at 13 and 16 months of age but was reduced by ovarian transplantation in 16-month-old mice. The percentages of lean body mass and total body water were significantly reduced in 13-month-old control mice but were restored in 16- and 25-month-old recipient mice by ovarian transplantation to the levels found in six-month-old control mice. In summary, we have shown that skeletal muscle mass, which is negatively influenced by aging, can be positively influenced or restored by reestablishment of active ovarian function in aged female mice. These findings provide strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females. PMID:27747096

  2. Exogenous Testosterone, Aging, and Changes in Behavioral Response of Gonadally Intact Male Mice

    PubMed Central

    Onaolapo, Olakunle J.; Onaolapo, Adejoke Y.; Omololu, Tope A.; Oludimu, Adedunke T.; Segun-Busari, Toluwalase; Omoleke, Taofeeq

    2016-01-01

    This study tested the hypothesis that aging significantly affects the influence of exogenous testosterone on neurobehavior in gonadally intact male mice. Groups of prepubertal and aged male mice received daily vehicle or testosterone propionate (TP; 2.5 or 5.0 mg/kg intraperitoneal [i.p.]) for 21 days. Behaviors were assessed on days 1 and 21. Weight gain was significant in prepubertal mice. Locomotion and rearing increased in prepubertal mice after first dose and decreased after last dose of TP. Rearing was suppressed in aged mice throughout. Suppression of grooming occurred in both age groups at day 21. Significant increase in working memory in both age groups was seen in the radial-arm maze (at specific doses) and in prepubertal mice in the Y-maze. Elevated plus maze test showed mixed anxiolytic/anxiogenic effects. Aged mice had higher serum testosterone. In conclusion, age is an important determinant for the influence of exogenous testosterone on behavior in gonadally intact male mice. PMID:27158222

  3. Anti-aging effect of Blakeslea trispora powder on adult mice.

    PubMed

    Hu, Weilian; Dai, Dehui; Li, Wei

    2013-08-01

    Blakeslea trispora powder that contains 1.9 % lycopene was tested for its anti-aging effect on adult mice. 48 adult mice were administered with the powder at 0, 267, 534, 1,068 mg lycopene kg(-1) body daily for 30 days. The body weight, hematology, clinical chemical and antioxidant activities in major organs of adult mice were measured. The powder had no effect on the body weight, hematology, clinical chemical parameters of adult mice but improved the antioxidant activities in major organs of adult mice. Increased activities of superoxide dismutase, catalase and glutathione peroxidase and a decreased amount of malondialdehyde in liver, brain, kidney and skin of adult mice when a high-dose of the B. trispora powder was administered, suggests that it has the ability to enhance the antioxidation system and improve the anti-aging abilities of adult mice.

  4. Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

    PubMed

    Imai, Rika; Asai, Kanae; Hanai, Jun-ichi; Takenaka, Masaru

    2015-07-01

    Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

  5. Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice

    PubMed Central

    Stranahan, Alexis M.; Lee, Kim; Becker, Kevin G.; Zhang, Yonqing; Maudsley, Stuart; Martin, Bronwen; Cutler, Roy G.; Mattson, Mark P.

    2009-01-01

    Physical activity preserves cognition in the aging brain, but the mechanisms remain obscure. In order to identify candidate genes and pathways responsible for the preservation of cognitive function by exercise, we trained mice that had been exposed to lifelong running or sedentary lifestyle for 16 months in the hippocampus-dependent water maze. After water maze training, we analyzed the expression of 24,000 genes in the hippocampus using Illumina bead microarray. Runners show greater activation of genes associated with synaptic plasticity and mitochondrial function, and also exhibit significant downregulation of genes associated with oxidative stress and lipid metabolism. Running also modified the effects of learning on the expression of genes involved in cell excitability, energy metabolism, and insulin, MAP kinase and Wnt signaling. These results suggest that the enhancement of cognitive function by lifelong exercise is associated with an altered transcriptional profile following learning. PMID:19070401

  6. Minocycline improves postoperative cognitive impairment in aged mice by inhibiting astrocytic activation.

    PubMed

    Jin, Wen-Jie; Feng, Shan-Wu; Feng, Zhou; Lu, Shun-Mei; Qi, Tao; Qian, Yan-Ning

    2014-01-08

    Astrocytes are proving to be critical for the development of cognitive functions. In addition, astrocytic activation contributes to cognitive impairment induced by chronic cerebral hypoperfusion. Minocycline has been shown to exhibit long-term neuroprotective effects in vascular cognitive impairment rat models through the inhibition of astrogliosis, and has demonstrated potential for the prevention and treatment of postoperative cognitive decline in elderly patients. This study aimed to examine the effect of minocycline on hippocampal astrocytes and long-term postoperative cognitive dysfunction in aged mice. Mice were intraperitoneally injected with 45 mg/kg minocycline once a day for 30 days after 70% hepatectomy. Hippocampus-dependent spatial memory ability was evaluated using the Morris water maze test. The expression levels of hippocampal glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 were evaluated by western blotting, and the hippocampal mRNA relative expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were tested using real-time PCR. The Morris water maze test showed that escape latency and swim distance were significantly prolonged by the surgery, but the extent of impairment was mitigated by minocycline treatment. Hippocampal GFAP levels and mRNA levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 showed corresponding changes that were consistent with the variations in spatial memory. Minocycline was able to alleviate hepatectomy-related long-term spatial memory impairment in aged mice, and was associated with reduced levels of hippocampal GFAP and proinflammatory cytokines resulting from astrocytic activation.

  7. Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction

    PubMed Central

    Sahu, Ravi P.; DaSilva, Sonia C.; Rashid, Badri; Martel, Kellie Clay; Jernigan, Danielle; Mehta, Shama R.; Mohamed, Deena R.; Rezania, Samin; Bradish, Joshua R.; Armstrong, Andrew B.; Warren, Simon; Konger, Raymond L.

    2012-01-01

    Recent studies suggest that peroxisome proliferator-activated receptor gamma (PPARγ) agonists may have cancer chemopreventive activity. Other studies have shown that loss of epidermal PPARγ results in enhanced chemical carcinogenesis in mice via unknown mechanisms. However, ultraviolet B (UVB) exposure represents the primary etiological agent for skin cancer formation and the role of PPARγ in photobiology and photocarcinogenesis is unknown. In previous studies, we demonstrated that UVB irradiation of cells results in the formation of oxidized glycerophosphocholines that exhibit PPARγ ligand activity. We therefore hypothesized that PPARγ would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPARγ agonist species in vivo. We then generated SKH-1 hairless, albino mice deficient in epidermal Pparg (Pparg−/−epi) using a cytokeratin 14 driven Cre-LoxP strategy. Using a chronic model of UVB photocarcinogenesis, we next showed that Pparg−/−epi mice exhibit an earlier onset of tumor formation, increased tumor burden, and tumor progression. Increased tumor burden in Pparg−/−epi mice was accompanied by a significant increase in epidermal hyperplasia and p53 positive epidermal cells in surrounding skin lacking tumors. Following acute UVB irradiation, Pparg−/−epi mice exhibited an augmentation of both UVB-induced caspase 3/7 activity and inflammation. Increased apoptosis and inflammation was also observed following treatment with the PPARγ antagonist GW9662. With chronic UVB irradiation, Pparg−/−epi mice exhibited a sustained increase in erythema and transepidermal water loss relative to wildtype littermates. This suggests that PPARγ agonists could have possible chemopreventive activity in non-melanoma skin cancer. PMID:22467332

  8. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    SciTech Connect

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani; Gupta, Sanjeev; Singhal, Pravin C.

    2013-08-15

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level.

  9. Establishment of a model of acetaminophen-induced hepatotoxicity in different weekly-aged ICR mice.

    PubMed

    Taguchi, K; Tokuno, M; Yamasaki, K; Kadowaki, D; Seo, H; Otagiri, M

    2015-10-01

    Acetaminophen (APAP), a widely used analgesic and antipyretic drug, has the potential to cause lethal hepatotoxicity. Mice are widely used for developing murine models of APAP-induced hepatotoxicity, and many researchers have used these models for APAP-related studies including the fields of biology, pharmacology and toxicology. Although drug-induced hepatotoxicity is dependent on a number of factors (species, gender and age), very few studies have investigated the effect of aging on APAP hepatotoxicity. In this study, we evaluated the effect of age on APAP-induced hepatotoxicity in different weekly-aged mice to establish a model of APAP-induced hepatotoxicity that is an accurate reflection of general experimental conditions. Male ICR mice 4, 6, 8, 10 and 12 weeks old were given APAP intraperitoneally, and mortality, hepatic damage and the plasma concentration of APAP metabolites were evaluated. It was found that younger male ICR mice were relatively resistant to hepatotoxicity induced by intraperitoneal APAP administration. In addition, the APAP-glucuronide concentration in plasma remained essentially the same among the differently-aged mice, while APAP-sulfate levels were dramatically decreased in an age-dependent manner. Thus, it is recommended that mice of the same ages be used in studies related to APAP-induced hepatotoxixity. These results provide evidence in support of not only the age-related changes in susceptibility to APAP-derived hepatotoxicity in mice but also in developing mouse models for APAP-related studies.

  10. The relationship between pupils' age and the content of conversations generated at three types of animal exhibits

    NASA Astrophysics Data System (ADS)

    Tunnicliffe, Sue Dale

    1996-12-01

    This paper reports a study designed to reveal the contents of the conversations of two main age groups of primary children who visited three types of animal exhibits, at a museum: live animals at the zoo; and, animated dinosaurs and preserved animals. The data show that the age of the child within a group had little effect on the content of the conversations. This finding gives rise to some concem. Furthermore, the data suggest that teachers were not developing the observations made by the children in ways appropriate for their stage of development. Whilst the data showed that observations were made at the animal exhibits and that there were more comments about affective issues as children developed, the lack of an age specific different emphasis on particular aspects such as body parts, that are important as defining attributes, is of concern. Zoology is an observational science and, as children develop, the data would be expected to have shown a focus on relevant concepts and attributes of the animals if effective science teaching was occurring.

  11. Early Signs of Pathological Cognitive Aging in Mice Lacking High-Affinity Nicotinic Receptors.

    PubMed

    Konsolaki, Eleni; Tsakanikas, Panagiotis; Polissidis, Alexia V; Stamatakis, Antonios; Skaliora, Irini

    2016-01-01

    In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. A deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic receptors (β2-/-), which have been proposed as an animal model of accelerated/premature cognitive aging. Our aim was to identify behavioral signs that could serve as indicators or predictors of impending cognitive decline. We used test batteries in order to assess cognitive functions and additional tasks to investigate spontaneous behaviors, such as species-specific activities and exploration/locomotion in a novel environment. Our data confirm the hypothesis that β2-/- animals exhibit age-related cognitive impairments in spatial learning. In addition, they document age-related deficits in other areas, such as recognition memory, burrowing and nesting building, thereby extending the validity of this animal model for the study of pathological aging. Finally, our data reveal deficits in spontaneous behavior and habituation processes that precede the onset of cognitive decline and could therefore be useful as a non-invasive behavioral screen for identifying animals at risk. To our knowledge, this is the first study to perform an extensive behavioral assessment of an animal model of premature cognitive aging, and our results suggest that β2-nAChR dependent cognitive deterioration progressively evolves from initial subtle behavioral changes to global dementia due to the combined effect of the neuropathology and aging.

  12. Early Signs of Pathological Cognitive Aging in Mice Lacking High-Affinity Nicotinic Receptors

    PubMed Central

    Konsolaki, Eleni; Tsakanikas, Panagiotis; Polissidis, Alexia V.; Stamatakis, Antonios; Skaliora, Irini

    2016-01-01

    In order to address pathological cognitive decline effectively, it is critical to adopt early preventive measures in individuals considered at risk. It is therefore essential to develop approaches that identify such individuals before the onset of irreversible dementia. A deficient cholinergic system has been consistently implicated as one of the main factors associated with a heightened vulnerability to the aging process. In the present study we used mice lacking high affinity nicotinic receptors (β2-/-), which have been proposed as an animal model of accelerated/premature cognitive aging. Our aim was to identify behavioral signs that could serve as indicators or predictors of impending cognitive decline. We used test batteries in order to assess cognitive functions and additional tasks to investigate spontaneous behaviors, such as species-specific activities and exploration/locomotion in a novel environment. Our data confirm the hypothesis that β2-/- animals exhibit age-related cognitive impairments in spatial learning. In addition, they document age-related deficits in other areas, such as recognition memory, burrowing and nesting building, thereby extending the validity of this animal model for the study of pathological aging. Finally, our data reveal deficits in spontaneous behavior and habituation processes that precede the onset of cognitive decline and could therefore be useful as a non-invasive behavioral screen for identifying animals at risk. To our knowledge, this is the first study to perform an extensive behavioral assessment of an animal model of premature cognitive aging, and our results suggest that β2-nAChR dependent cognitive deterioration progressively evolves from initial subtle behavioral changes to global dementia due to the combined effect of the neuropathology and aging. PMID:27199738

  13. Age-Dependent Loss of Tolerance to an Immunodominant Epitope of Glutamic Acid Decarboxylase in Diabetic prone RIP-B7/DR4 Mice

    PubMed Central

    Gebe, John A.; Unrath, Kellee A; Falk, Ben A.; Ito, Kouichi; Wen, Li; Daniels, Terri L.; Lernmark, Åke; Nepom, Gerald T.

    2007-01-01

    We have identified for the first time an age-dependent spontaneous loss of tolerance to two self-antigenic epitopes derived from putative diabetes associated antigens glutamic acid decarboxylase (GAD65) and glial fibrillary acidic protein (GFAP) in RIP-B7/DRB1*0404 HLA transgenic mice. Diabetic and older non-diabetic mice exhibited a proliferative response to an immunodominant epitope from GAD65 (555-567) and also from GFAP (240-252) but not from an immunogenic epitope from diabetes associated islet-specific glucose-6-phosphatase catalytic subunit-related protein. The response to both of these self-antigens is not observed in young mice but is observed in older non-diabetic mice, and is accompanied by histological evidence of insulitis in the absence of overt diabetes. Islet infiltrates in older non-diabetic mice and diabetic mice contain CD4+/FoxP3+ cells and suggest the presence of a regulatory mechanism prior and during diabetic disease. Diabetes penetrance in RIP-B7/DR0404 mice is 23% with a mean onset age of 40 weeks and is similar to that reported for RIP-B7/DR0401 mice. A gender preference is observed in that 38% of female mice become diabetic compared to 8% of male mice. PMID:16979383

  14. Age-dependent loss of tolerance to an immunodominant epitope of glutamic acid decarboxylase in diabetic-prone RIP-B7/DR4 mice.

    PubMed

    Gebe, John A; Unrath, Kellee A; Falk, Ben A; Ito, Kouichi; Wen, Li; Daniels, Terri L; Lernmark, Ake; Nepom, Gerald T

    2006-12-01

    We have identified for the first time an age-dependent spontaneous loss of tolerance to two self-antigenic epitopes derived from putative diabetes-associated antigens glutamic acid decarboxylase (GAD65) and glial fibrillary acidic protein (GFAP) in RIP-B7/DRB1*0404 HLA transgenic mice. Diabetic and older non-diabetic mice exhibited a proliferative response to an immunodominant epitope from GAD65 (555-567) and also from GFAP (240-252) but not from an immunogenic epitope from diabetes-associated islet-specific glucose-6-phosphatase catalytic subunit-related protein. The response to both of these self-antigens is not observed in young mice but is observed in older non-diabetic mice and is accompanied by histological evidence of insulitis in the absence of overt diabetes. Islet infiltrates in older non-diabetic mice and diabetic mice contain CD4(+)/FoxP3(+) cells and suggest the presence of a regulatory mechanism prior and during diabetic disease. Diabetes penetrance in RIP-B7/DR0404 mice is 23% with a mean onset age of 40 weeks and is similar to that reported for RIP-B7/DR0401 mice. A gender preference is observed in that 38% of female mice become diabetic compared to 8% of male mice.

  15. Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice

    ERIC Educational Resources Information Center

    Verbitsky, Miguel; Yonan, Amanda L.; Malleret, Gael; Kandel, Eric R.; Gilliam, T. Conrad; Pavlidis, Paul

    2004-01-01

    We have carried out a global survey of age-related changes in mRNA levels in the 57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged…

  16. Cardiac Adipose-Derived Stem Cells Exhibit High Differentiation Potential to Cardiovascular Cells in C57BL/6 Mice.

    PubMed

    Nagata, Hiroki; Ii, Masaaki; Kohbayashi, Eiko; Hoshiga, Masaaki; Hanafusa, Toshiaki; Asahi, Michio

    2016-02-01

    Adipose-derived stem cells (AdSCs) have recently been shown to differentiate into cardiovascular lineage cells. However, little is known about the fat tissue origin-dependent differences in AdSC function and differentiation potential. AdSC-rich cells were isolated from subcutaneous, visceral, cardiac (CA), and subscapular adipose tissue from mice and their characteristics analyzed. After four different AdSC types were cultured with specific differentiation medium, immunocytochemical analysis was performed for the assessment of differentiation into cardiovascular cells. We then examined the in vitro differentiation capacity and therapeutic potential of AdSCs in ischemic myocardium using a mouse myocardial infarction model. The cell density and proliferation activity of CA-derived AdSCs were significantly increased compared with the other adipose tissue-derived AdSCs. Immunocytochemistry showed that CA-derived AdSCs had the highest appearance rates of markers for endothelial cells, vascular smooth muscle cells, and cardiomyocytes among the AdSCs. Systemic transfusion of CA-derived AdSCs exhibited the highest cardiac functional recovery after myocardial infarction and the high frequency of the recruitment to ischemic myocardium. Moreover, long-term follow-up of the recruited CA-derived AdSCs frequently expressed cardiovascular cell markers compared with the other adipose tissue-derived AdSCs. Cardiac adipose tissue could be an ideal source for isolation of therapeutically effective AdSCs for cardiac regeneration in ischemic heart diseases. Significance: The present study found that cardiac adipose-derived stem cells have a high potential to differentiate into cardiovascular lineage cells (i.e., cardiomyocytes, endothelial cells, and vascular smooth muscle cells) compared with stem cells derived from other adipose tissue such as subcutaneous, visceral, and subscapular adipose tissue. Notably, only a small number of supracardiac adipose-derived stem cells that were

  17. IMMMUNOPHENOTYPE OF SPONTANEOUS HEMATOLYMPHOID TUMORS OCCURRING IN YOUNG AND AGING FEMALE CD-1 MICE

    PubMed Central

    Rehg, Jerold E.; Rahija, Richard; Bush, Dorothy; Bradley, Alys; Ward, Jerrold M.

    2015-01-01

    A few reports indicated the incidence of hematolymphoid neoplasms in old CD-1 mice, but the cellular lineage of CD-1 mouse neoplasms has not be published. In this study, immunohistochemistry (IHC) was used to characterize the cellular lineage of spontaneous hematolymphoid neoplasms arising in young female CD-1 mice used as health monitoring sentinels and aging female CD-1 mice used as controls in 80 wk carcinogenesis studies. Lymphoblastic lymphomas of T-cell and B-cell lineage were common in mice 12 mo or less of age, whereas a wide range of non-lymphoblastic B-cell lymphomas and lymphoblastic T-cell lymphomas were common in mice > 12 mo old. Renal hyaline droplets positive for lysozyme were observed in aged mice with a histiocytic-associated large B-cell lymphoma (HA-BCL) and a myeloid leukemia. Endogenous ecotropic MuLV genes have been recovered from CD-1 mice, but MuLV protein expression has not been previously demonstrated. We reported for the first time the expression of MuLV protein by IHC in lymphomas and some normal tissues of both young and aging CD-1 mice. This report should help to differentiate spontaneous lymphomas and leukemias in CD-1 mice from those induced by chemicals and other methods. PMID:26224701

  18. Corticotropin-releasing factor-overexpressing mice exhibit reduced neuronal activation in the arcuate nucleus and food intake in response to fasting.

    PubMed

    Stengel, Andreas; Goebel, Miriam; Million, Mulugeta; Stenzel-Poore, Mary P; Kobelt, Peter; Mönnikes, Hubert; Taché, Yvette; Wang, Lixin

    2009-01-01

    Corticotropin-releasing factor (CRF) overexpressing (OE) mice are a genetic model that exhibits features of chronic stress. We investigated whether the adaptive feeding response to a hypocaloric challenge induced by food deprivation is impaired under conditions of chronic CRF overproduction. Food intake response to a 16-h overnight fast and ip injection of gut hormones regulating food intake were compared in CRF-OE and wild type (WT) littermate mice along with brain Fos expression, circulating ghrelin levels, and gastric emptying of a nonnutrient meal. CRF-OE mice injected ip with saline showed a 47 and 44% reduction of 30-min and 4-h cumulative food intake response to an overnight fast, respectively, compared with WT. However, the 30-min food intake decrease induced by ip cholecystokinin (3 microg/kg) and increase by ghrelin (300 microg/kg) were similar in CRF-OE and WT mice. Overnight fasting increased the plasma total ghrelin to similar levels in CRF-OE and WT mice, although CRF-OE mice had a 2-fold reduction of nonfasting ghrelin levels. The number of Fos-immunoreactive cells induced by fasting in the arcuate nucleus was reduced by 5.9-fold in CRF-OE compared with WT mice whereas no significant changes were observed in other hypothalamic nuclei. In contrast, fasted CRF-OE mice displayed a 5.6-fold increase in Fos-immunoreactive cell number in the dorsal motor nucleus of the vagus nerve and a 34% increase in 20-min gastric emptying. These findings indicate that sustained overproduction of hypothalamic CRF in mice interferes with fasting-induced activation of arcuate nucleus neurons and the related hyperphagic response.

  19. A Modified Bacillus Calmette-Guérin (BCG) Vaccine with Reduced Activity of Antioxidants and Glutamine Synthetase Exhibits Enhanced Protection of Mice despite Diminished in Vivo Persistence.

    PubMed

    Shoen, Carolyn M; DeStefano, Michelle S; Hager, Cynthia C; Tham, Kyi-Toe; Braunstein, Miriam; Allen, Alexandria D; Gates, Hiriam O; Cynamon, Michael H; Kernodle, Douglas S

    2013-01-11

    Early attempts to improve BCG have focused on increasing the expression of prominent antigens and adding recombinant toxins or cytokines to influence antigen presentation. One such modified BCG vaccine candidate has been withdrawn from human clinical trials due to adverse effects. BCG was derived from virulent Mycobacterium bovis and retains much of its capacity for suppressing host immune responses. Accordingly, we have used a different strategy for improving BCG based on reducing its immune suppressive capacity. We made four modifications to BCG Tice to produce 4dBCG and compared it to the parent vaccine in C57Bl/6 mice. The modifications included elimination of the oxidative stress sigma factor SigH, elimination of the SecA2 secretion channel, and reductions in the activity of iron co-factored superoxide dismutase and glutamine synthetase. After IV inoculation of 4dBCG, 95% of vaccine bacilli were eradicated from the spleens of mice within 60 days whereas the titer of BCG Tice was not significantly reduced. Subcutaneous vaccination with 4dBCG produced greater protection than vaccination with BCG against dissemination of an aerosolized challenge of M. tuberculosis to the spleen at 8 weeks post-challenge. At this time, 4dBCG-vaccinated mice also exhibited altered lung histopathology compared to BCG-vaccinated mice and control mice with less well-developed lymphohistiocytic nodules in the lung parenchyma. At 26 weeks post-challenge, 4dBCG-vaccinated mice but not BCG-vaccinated mice had significantly fewer challenge bacilli in the lungs than control mice. In conclusion, despite reduced persistence in mice a modified BCG vaccine with diminished antioxidants and glutamine synthetase is superior to the parent vaccine in conferring protection against M. tuberculosis. The targeting of multiple immune suppressive factors produced by BCG is a promising strategy for simultaneously improving vaccine safety and effectiveness.

  20. Mice deficient in Endothelin-Converting Enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord

    PubMed Central

    Miller, L.K.; Hou, X.; Rodriguiz, R.M.; Gagnidze, K.; Sweedler, J. V.; Wetsel, W.C.; Devi, L.A.

    2011-01-01

    An increasing body of evidence suggests that Endothelin-converting enzyme-2 (ECE-2) is a non-classical neuropeptide processing enzyme. Similar to other neuropeptide processing enzymes, ECE-2 exhibits restricted neuroendocrine distribution, intracellular localization, and an acidic pH optimum. However, unlike classical neuropeptide processing enzymes, ECE-2 exhibits a non-classical cleavage site preference for aliphatic and aromatic residues. We previously reported that ECE-2 cleaves a number of neuropeptides at non-classical sites in vitro; however its role in peptide processing in vivo is poorly understood. Given the recognized roles of neuropeptides in pain and opiate responses, we hypothesized that ECE-2 knockout (KO) mice might show altered pain and morphine responses compared to wild-type (WT) mice. We find that ECE-2 KO mice show decreased response to a single injection of morphine in hot-plate and tail-flick tests. ECE-2 KO mice also show more rapid development of tolerance with prolonged morphine treatment and fewer signs of naloxone-precipitated withdrawal. Peptidomic analyses revealed changes in the levels of a number of spinal cord peptides in ECE-2 KO as compared to WT mice. Taken together, our findings suggest a role for ECE-2 in the non-classical processing of spinal cord peptides and morphine responses; however, the precise mechanisms through which ECE-2 influences morphine tolerance and withdrawal remain unclear. PMID:21972895

  1. In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice.

    PubMed

    Logan, Angela; Shabalina, Irina G; Prime, Tracy A; Rogatti, Sebastian; Kalinovich, Anastasia V; Hartley, Richard C; Budd, Ralph C; Cannon, Barbara; Murphy, Michael P

    2014-08-01

    In mtDNA mutator mice, mtDNA mutations accumulate leading to a rapidly aging phenotype. However, there is little evidence of oxidative damage to tissues, and when analyzed ex vivo, no change in production of the reactive oxygen species (ROS) superoxide and hydrogen peroxide by mitochondria has been reported, undermining the mitochondrial oxidative damage theory of aging. Paradoxically, interventions that decrease mitochondrial ROS levels in vivo delay onset of aging. To reconcile these findings, we used the mitochondria-targeted mass spectrometry probe MitoB to measure hydrogen peroxide within mitochondria of living mice. Mitochondrial hydrogen peroxide was the same in young mutator and control mice, but as the mutator mice aged, hydrogen peroxide increased. This suggests that the prolonged presence of mtDNA mutations in vivo increases hydrogen peroxide that contributes to an accelerated aging phenotype, perhaps through the activation of pro-apoptotic and pro-inflammatory redox signaling pathways.

  2. Anti-inflammaging effects of Lactobacillus brevis OW38 in aged mice.

    PubMed

    Jeong, J-J; Kim, K A; Hwang, Y-J; Han, M J; Kim, D-H

    2016-11-30

    In the present study, lactic acid bacteria (LAB) strains were collected from kimchi and were screened to isolate strains that inhibit lipopolysaccharide (LPS) production by Escherichia coli and p16 expression and nuclear factor-kappa B (NF-κB) activation in LPS-stimulated macrophages. Oral administration of Lactobacillus brevis OW38 (1×10(9) cfu/mouse) to aged mice (male, 18 months old) for 8 weeks reduced the LPS level in colon fluid and blood. In addition, OW38 treatment also reduced the ratio of Firmicutes or Proteobacteria to Bacteroidetes, which was significantly higher in aged mice than in young mice. Treatment with OW38 in aged mice inhibited the expression of inflammatory markers, such as myeloperoxidase, tumour necrosis factor (TNF), and interleukin (IL)-1β, and inhibited NF-κB activation. Furthermore, it induced the expression of colonic tight junction proteins zonula occludens-1, occludin, and claudin-1. OW38 treatment also suppressed the expression of senescence markers p16, p53, and SAMHD1 in the colon and the hippocampus of aged mice. In addition, it significantly restored spontaneous alternation as well as the expression of brain-derived neurotrophic factor and doublecortin in aged mice compared to that in young mice (P<0.05). Based on these findings, we conclude that OW38 treatment may ameliorate aging-associated colitis and memory impairment by inhibiting gut microbiota LPS production, NF-κB activation, and p16 expression.

  3. Age-associated changes in hippocampal-dependent cognition in Diversity Outbred mice.

    PubMed

    Koh, Ming Teng; Spiegel, Amy M; Gallagher, Michela

    2014-11-01

    Episodic memory impairment due to aging has been linked to hippocampal dysfunction. Evidence exists for alterations in specific circuits within the hippocampal system that are closely coupled to individual differences in the presence and severity of such memory loss. Here, we used the newly developed Diversity Outbred (DO) mouse that was designed to model the genetic diversity in human populations. Young and aged DO mice were tested in a hippocampal-dependent water maze task. Young mice showed higher proficiency and more robust memory compared to the overall performance of aged mice. A substantial number of the older mice, however, performed on par with the normative performance of the younger mice. Stereological quantification of somatostatin-immunoreactive neurons in the dentate hilus showed that high-performing young and unimpaired aged mice had similar numbers of somatostatin-positive interneurons, while aged mice that were impaired in the spatial task had significantly fewer such neurons. These data in the DO model tie loss of hilar inhibitory network integrity to age-related memory impairment, paralleling data in other rodent models.

  4. Mice doubly deficient in the midkine and pleiotrophin genes exhibit deficits in the expression of beta-tectorin gene and in auditory response.

    PubMed

    Zou, Peng; Muramatsu, Hisako; Sone, Michihiko; Hayashi, Hideo; Nakashima, Tsutomu; Muramatsu, Takashi

    2006-07-01

    alpha-Tectorin and beta-tectorin are major noncollagenous proteins of the tectorial membrane, which plays a crucial role in the reception of sonic signals in the cochlea. Midkine and pleiotrophin are closely related proteins that serve as growth factors and cytokines. In mice doubly deficient in the midkine gene and pleiotrophin gene, expression of beta-tectorin mRNA was nearly abolished in the cochlea on day 1 and 7 after birth. Expression of alpha-tectorin mRNA was unaffected in the double knockout mice, and expression of beta-tectorin mRNA was not altered in mice deficient in only the midkine or pleiotrophin gene. In newborn wild-type mice, both midkine and pleiotrophin were expressed in the greater epithelial ridge of the cochlea, in which beta-tectorin mRNA was strongly expressed. These results indicate that either midkine or pleiotrophin is required for significant expression of beta-tectorin. In agreement with the view that beta-tectorin is essential for normal auditory function, mice doubly deficient in both midkine and pleiotrophin genes exhibited very severe auditory deficits. We observed that mice deficient in either midkine or pleiotrophin gene were also impaired in their auditory response, but the level of the deficit was generally low or moderate. The present finding illustrates the importance of growth factor expression in the cochlea for auditory function.

  5. Eurycoma longifolia Jack enhances sexual motivation in middle-aged male mice.

    PubMed

    Ang, Hooi Hoon; Lee, Kheng Leng; Kiyoshi, Matsumoto

    2003-01-01

    Eurycoma longifolia Jack was investigated for sexual motivation activity in adult, middle-aged male mice and in retired breeders, using the modified open field and the modified runway choice methods. Each mouse received 500 mg/kg of one of 4 fractions of E. longifolia Jack, viz. chloroform, methanol, butanol, and water, whereas the mice in the control and yohimbine groups received 3 ml/kg of normal saline and 30 mg/kg of yohimbine daily respectively for 10 d. The results show a transient increase in the percentage of male mice responding to the right choice after chronic consumption of the fractions with 50 percent of the adult middle-aged male mice treated with E. longifolia Jack and yohimbine scoring the right choice after 8 and 5 days post-treatment respectively. In conclusion, this study has shown that E. longifolia Jack continues to enhance sexual motivation in adult, middle-aged male mice and in retired breeders.

  6. Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice.

    PubMed

    Mistry, Akshitkumar M; Thompson, Christopher H; Miller, Alison R; Vanoye, Carlos G; George, Alfred L; Kearney, Jennifer A

    2014-05-01

    Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a(+/-)) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a(+/-) mice on strain 129S6/SvEvTac (129.Scn1a(+/-)) have no overt phenotype and normal survival compared with Scn1a(+/-) mice bred to C57BL/6J (F1.Scn1a(+/-)) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21-24 (P21-24) 129.Scn1a(+/-) or F1.Scn1a(+/-) mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a(+/-) mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a(+/-) mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a(+/-) and F1.Scn1a(+/-) mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a(+/-) neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a(+/-) animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a(+/-) mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21-24 correlates with age-dependent onset of lethality in F1.Scn1a(+/-) mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution

  7. Glutaminyl cyclase knock-out mice exhibit slight hypothyroidism but no hypogonadism: implications for enzyme function and drug development.

    PubMed

    Schilling, Stephan; Kohlmann, Stephanie; Bäuscher, Christoph; Sedlmeier, Reinhard; Koch, Birgit; Eichentopf, Rico; Becker, Andreas; Cynis, Holger; Hoffmann, Torsten; Berg, Sabine; Freyse, Ernst-Joachim; von Hörsten, Stephan; Rossner, Steffen; Graubner, Sigrid; Demuth, Hans-Ulrich

    2011-04-22

    Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) residues at the N terminus of peptides and proteins. Hypothalamic pGlu hormones, such as thyrotropin-releasing hormone and gonadotropin-releasing hormone are essential for regulation of metabolism and fertility in the hypothalamic pituitary thyroid and gonadal axes, respectively. Here, we analyzed the consequences of constitutive genetic QC ablation on endocrine functions and on the behavior of adult mice. Adult homozygous QC knock-out mice are fertile and behave indistinguishably from wild type mice in tests of motor function, cognition, general activity, and ingestion behavior. The QC knock-out results in a dramatic drop of enzyme activity in the brain, especially in hypothalamus and in plasma. Other peripheral organs like liver and spleen still contain QC activity, which is most likely caused by its homolog isoQC. The serum gonadotropin-releasing hormone, TSH, and testosterone concentrations were not changed by QC depletion. The serum thyroxine was decreased by 24% in homozygous QC knock-out animals, suggesting a mild hypothyroidism. QC knock-out mice were indistinguishable from wild type with regard to blood glucose and glucose tolerance, thus differing from reports of thyrotropin-releasing hormone knock-out mice significantly. The results suggest a significant formation of the hypothalamic pGlu hormones by alternative mechanisms, like spontaneous cyclization or conversion by isoQC. The different effects of QC depletion on the hypothalamic pituitary thyroid and gonadal axes might indicate slightly different modes of substrate conversion of both enzymes. The absence of significant abnormalities in QC knock-out mice suggests the presence of a therapeutic window for suppression of QC activity in current drug development.

  8. Differential response to intrahippocampal interleukin-4/interleukin-13 in aged and exercise mice.

    PubMed

    Littlefield, Alyssa; Kohman, Rachel A

    2017-02-20

    Normal aging is associated with low-grade neuroinflammation that results from age-related priming of microglial cells. Further, aging alters the response to several anti-inflammatory factors, including interleukin (IL)-4 and IL-13. One intervention that has been shown to modulate microglia activation in the aged brain, both basally and following an immune challenge, is exercise. However, whether engaging in exercise can improve responsiveness to anti-inflammatory cytokines is presently unknown. The current study evaluated whether prior exercise training increases sensitivity to anti-inflammatory cytokines that promote the M2 (alternative) microglia phenotype in adult (5-month-old) and aged (23-month-old) C57BL/6J mice. After 8weeks of exercise or control housing, mice received bilateral hippocampal injections of an IL-4/IL-13 cocktail or vehicle. Twenty-four hours later hippocampal samples were collected and analyzed for expression of genes associated with the M1 (inflammatory) and M2 microglia phenotypes. Results show that IL-4/IL-13 administration increased expression of the M2-associated genes found in inflammatory zone 1 (Fizz1), chitinase-like 3 (Ym1), Arginase-1 (Arg1), SOCS1, IL-1ra, and CD206. In response to IL-4/IL-13 administration, aged mice showed increased hippocampal expression of the M2-related genes Arg1, SOCS1, Ym1, and CD206 relative to adult mice. Aged mice also showed increased expression of IL-1β relative to adults, which was unaffected by wheel running or IL-4/IL-13. Wheel running was found to have modest effects on expression of Ym1 and Fizz1 in aged and adult mice. Collectively, our findings indicate that aged mice show a differential response to anti-inflammatory cytokines relative to adult mice and that exercise has limited effects on modulating this response.

  9. Age-Dependent Changes in the Inflammatory Nociceptive Behavior of Mice

    PubMed Central

    King-Himmelreich, Tanya S.; Möser, Christine V.; Wolters, Miriam C.; Olbrich, Katrin; Geisslinger, Gerd; Niederberger, Ellen

    2015-01-01

    The processing of pain undergoes several changes in aging that affect sensory nociceptive fibers and the endogenous neuronal inhibitory systems. So far, it is not completely clear whether age-induced modifications are associated with an increase or decrease in pain perception. In this study, we assessed the impact of age on inflammatory nociception in mice and the role of the hormonal inhibitory systems in this context. We investigated the nociceptive behavior of 12-month-old versus 6–8-week-old mice in two behavioral models of inflammatory nociception. Levels of TRP channels, and cortisol as well as cortisol targets, were measured by qPCR, ELISA, and Western blot in the differently aged mice. We observed an age-related reduction in nociceptive behavior during inflammation as well as a higher level of cortisol in the spinal cord of aged mice compared to young mice, while TRP channels were not reduced. Among potential cortisol targets, the NF-κB inhibitor protein alpha (IκBα) was increased, which might contribute to inhibition of NF-κB and a decreased expression and activity of the inducible nitric oxide synthase (iNOS). In conclusion, our results reveal a reduced nociceptive response in aged mice, which might be at least partially mediated by an augmented inflammation-induced increase in the hormonal inhibitory system involving cortisol. PMID:26593904

  10. Manganese-mediated acceleration of age-related hearing loss in mice

    PubMed Central

    Ohgami, Nobutaka; Yajima, Ichiro; Iida, Machiko; Li, Xiang; Oshino, Reina; Kumasaka, Mayuko Y.; Kato, Masashi

    2016-01-01

    Despite the fact that manganese (Mn) is known to be a neurotoxic element relevant to age-related disorders, the risk of oral exposure to Mn for age-related hearing loss remains unclear. In this study, we orally exposed wild-type young adult mice to Mn (Mn-exposed WT-mice) at 1.65 and 16.50 mg/L for 4 weeks. Mn-exposed WT-mice showed acceleration of age-related hearing loss. Mn-exposed WT-mice had neurodegeneration of spiral ganglion neurons (SGNs) with increased number of lipofuscin granules. Mn-exposed WT-mice also had increased hypoxia-inducible factor-1 alpha (Hif-1α) protein with less hydroxylation at proline 564 and decreased c-Ret protein in SGNs. Mn-mediated acceleration of age-related hearing loss involving neurodegeneration of SGNs was rescued in RET-transgenic mice carrying constitutively activated RET. Thus, oral exposure to Mn accelerates age-related hearing loss in mice with Ret-mediated neurodegeneration of SGNs. PMID:27824154

  11. Joint dysfunction and functional decline in middle age myostatin null mice.

    PubMed

    Guo, Wen; Miller, Andrew D; Pencina, Karol; Wong, Siu; Lee, Amanda; Yee, Michael; Toraldo, Gianluca; Jasuja, Ravi; Bhasin, Shalender

    2016-02-01

    Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn(-/-)), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3-6months) to middle age (12-15months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn(-/-) mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn(-/-) mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn(-/-) mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway.

  12. Bone turnover markers in peripheral blood and marrow plasma reflect trabecular bone loss but not endocortical expansion in aging mice.

    PubMed

    Shahnazari, Mohammad; Dwyer, Denise; Chu, Vivian; Asuncion, Frank; Stolina, Marina; Ominsky, Michael; Kostenuik, Paul; Halloran, Bernard

    2012-03-01

    We examined age-related changes in biochemical markers and regulators of osteoblast and osteoclast activity in C57BL/6 mice to assess their utility in explaining age-related changes in bone. Several recently discovered regulators of osteoclasts and osteoblasts were also measured to assess concordance between their systemic levels versus their levels in marrow plasma, to which bone cells are directly exposed. MicroCT of 6-, 12-, and 24-month-old mice indicated an early age-related loss of trabecular bone volume and surface, followed by endocortical bone loss and periosteal expansion. Trabecular bone loss temporally correlated with reductions in biomarkers of bone formation and resorption in both peripheral blood and bone marrow. Endocortical bone loss and periosteal bone gain were not reflected in these protein biomarkers, but were well correlated with increased expression of osteocalcin, rank, tracp5b, and cathepsinK in RNA extracted from cortical bone. While age-related changes in bone turnover markers remained concordant in blood versus marrow, aging led to divergent changes in blood versus marrow for the bone cell regulators RANKL, OPG, sclerostin, DKK1, and serotonin. Bone expression of runx2 and osterix increased progressively with aging and was associated with an increase in the number of osteoprogenitors and osteoclast precursors. In summary, levels of biochemical markers of bone turnover in blood and bone marrow plasma were predictive of an age-related loss of trabecular surfaces in adult C57BL/6 mice, but did not predict gains in cortical surfaces resulting from cortical expansion. Unlike these turnover markers, a panel of bone cell regulatory proteins exhibited divergent age-related changes in marrow versus peripheral blood, suggesting that their circulating levels may not reflect local levels to which osteoclasts and osteoblasts are directly exposed.

  13. Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

    PubMed Central

    Kessler, Sean P.; Obery, Dana R.; de la Motte, Carol

    2015-01-01

    Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD. PMID:26448758

  14. Pseudouridine synthase 1 deficient mice, a model for Mitochondrial Myopathy with Sideroblastic Anemia, exhibit muscle morphology and physiology alterations

    PubMed Central

    Mangum, Joshua E.; Hardee, Justin P.; Fix, Dennis K.; Puppa, Melissa J.; Elkes, Johnathon; Altomare, Diego; Bykhovskaya, Yelena; Campagna, Dean R.; Schmidt, Paul J.; Sendamarai, Anoop K.; Lidov, Hart G. W.; Barlow, Shayne C.; Fischel-Ghodsian, Nathan; Fleming, Mark D.; Carson, James A.; Patton, Jeffrey R.

    2016-01-01

    Mitochondrial myopathy with lactic acidosis and sideroblastic anemia (MLASA) is an oxidative phosphorylation disorder, with primary clinical manifestations of myopathic exercise intolerance and a macrocytic sideroblastic anemia. One cause of MLASA is recessive mutations in PUS1, which encodes pseudouridine (Ψ) synthase 1 (Pus1p). Here we describe a mouse model of MLASA due to mutations in PUS1. As expected, certain Ψ modifications were missing in cytoplasmic and mitochondrial tRNAs from Pus1−/− animals. Pus1−/− mice were born at the expected Mendelian frequency and were non-dysmorphic. At 14 weeks the mutants displayed reduced exercise capacity. Examination of tibialis anterior (TA) muscle morphology and histochemistry demonstrated an increase in the cross sectional area and proportion of myosin heavy chain (MHC) IIB and low succinate dehydrogenase (SDH) expressing myofibers, without a change in the size of MHC IIA positive or high SDH myofibers. Cytochrome c oxidase activity was significantly reduced in extracts from red gastrocnemius muscle from Pus1−/− mice. Transmission electron microscopy on red gastrocnemius muscle demonstrated that Pus1−/− mice also had lower intermyofibrillar mitochondrial density and smaller mitochondria. Collectively, these results suggest that alterations in muscle metabolism related to mitochondrial content and oxidative capacity may account for the reduced exercise capacity in Pus1−/− mice. PMID:27197761

  15. An inherited mild middle-aged adiposity in wild mice.

    PubMed Central

    Wallace, M. E.; MacSwiney, F. M.

    1979-01-01

    In a warfarin-resistant population of wild mice reared in the laboratory, a dominant gene for adiposity, Ad, was found to segregate. The onset of obesity is at 4--6 months, and adipose mice suffer from hyperinsulinaemia; the sexes differ in penetrance, males having greater penetrance then females. Linkage backcrosses show the gene to be situated on chromosome 7 with about 25% recombination with the closely linked warfarin-resistance genes War, and frizzy, fr. The finding of adipose in two other wild populations also carrying War is discussed as an ecological and physiological problem. PMID:429792

  16. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies.

    PubMed

    Selesniemi, Kaisa; Lee, Ho-Joon; Muhlhauser, Ailene; Tilly, Jonathan L

    2011-07-26

    Increased meiotic spindle abnormalities and aneuploidy in oocytes of women of advanced maternal ages lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Despite the significance of the problem, strategies to sustain oocyte quality with age have remained elusive. Here we report that adult female mice maintained under 40% caloric restriction (CR) did not exhibit aging-related increases in oocyte aneuploidy, chromosomal misalignment on the metaphase plate, meiotic spindle abnormalities, or mitochondrial dysfunction (aggregation, impaired ATP production), all of which occurred in oocytes of age-matched ad libitum-fed controls. The effects of CR on oocyte quality in aging females were reproduced by deletion of the metabolic regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Thus, CR during adulthood or loss of PGC-1α function maintains female germline chromosomal stability and its proper segregation during meiosis, such that ovulated oocytes of aged female mice previously maintained on CR or lacking PGC-1α are comparable to those of young females during prime reproductive life.

  17. Reduced COX-2 Expression in Aged Mice Is Associated With Impaired Fracture Healing

    PubMed Central

    Naik, Amish A; Xie, Chao; Zuscik, Michael J; Kingsley, Paul; Schwarz, Edward M; Awad, Hani; Guldberg, Robert; Drissi, Hicham; Puzas, J Edward; Boyce, Brendan; Zhang, Xinping; O'Keefe, Regis J

    2009-01-01

    The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX-2), the inducible regulator of prostaglandin E2 (PGE2) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7–9 or 52–56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX-2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX-2 is expressed primarily in early cartilage precursors that co-express col-2. COX-2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX-2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX-2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging. PMID:18847332

  18. Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit.

    PubMed

    Wang, Hongkai; Li, Chengren; Wang, Hanzhi; Mei, Feng; Liu, Zhi; Shen, Hai-Ying; Xiao, Lan

    2013-04-01

    Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

  19. Mitragyna speciosa Leaf Extract Exhibits Antipsychotic-Like Effect with the Potential to Alleviate Positive and Negative Symptoms of Psychosis in Mice

    PubMed Central

    Vijeepallam, Kamini; Pandy, Vijayapandi; Kunasegaran, Thubasni; Murugan, Dharmani D.; Naidu, Murali

    2016-01-01

    In this study, we investigated the antipsychotic-like effect of methanolic extract of Mitragyna speciosa leaf (MMS) using in vivo and ex vivo studies. In vivo studies comprised of apomorphine-induced climbing behavior, haloperidol-induced catalepsy, and ketamine-induced social withdrawal tests in mice whereas the ex vivo study was conducted utilizing isolated rat vas deferens preparation. Acute oral administration of MMS (50–500 mg/kg) showed an inverted bell-shaped dose-response in apomorphine-induced cage climbing behavior in mice. The effective inhibitory doses of MMS (75 and 100 mg/kg, p.o.) obtained from the apomorphine study was further tested on haloperidol (subcataleptic dose; 0.1 mg/kg, i.p.)-induced catalepsy in the mouse bar test. MMS (75 and 100 mg/kg, p.o.) significantly potentiated the haloperidol-induced catalepsy in mice. Interestingly, MMS at the same effective doses (75 and 100 mg/kg, p.o.) significantly facilitated the social interaction in ketamine-induced social withdrawal mice. Furthermore, MMS inhibited the dopamine-induced contractile response dose-dependently in the isolated rat vas deferens preparations. In conclusion, this investigation provides first evidence that MMS exhibits antipsychotic-like activity with potential to alleviate positive as well as negative symptoms of psychosis in mice. This study also suggests the antidopaminergic activity of MMS that could be responsible for alleviating positive symptoms of psychosis. PMID:27999544

  20. Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice

    PubMed Central

    Aso, Kazuyoshi; Tsuruhara, Akitoshi; Takagaki, Kentaro; Oki, Katsuyuki; Ota, Megumi; Nose, Yasuhiro; Tanemura, Hideki; Urushihata, Naoki; Sasanuma, Jinichi; Sano, Masayuki; Hirano, Atsuyuki; Aso, Rio; McGhee, Jerry R.; Fujihashi, Kohtaro

    2016-01-01

    It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old) mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA) and plasma IgG antibody (Ab) responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer’s patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice. PMID:26840058

  1. Telomere shortening in diaphragm and tibialis anterior muscles of aged mdx mice.

    PubMed

    Lund, Troy C; Grange, Robert W; Lowe, Dawn A

    2007-09-01

    The progression of Duchenne muscular dystrophy (DMD) is, in part, due to satellite cell senescence driven by high replicative pressure as these muscle stem cells repeatedly divide and fuse to damaged muscle fibers. We hypothesize that telomere shortening in satellite cells underlies their senescence. To test this hypothesis, we evaluated the diaphragm and a leg muscle from dystrophic mice of various ages for telomere dynamics. We found 30% telomere shortening in tibialis anterior muscles from 600-day-old mdx mice relative to age-matched wildtype mice. We also found a more severe shortening of telomere length in diaphragm muscles of old mdx mice. In those muscles, telomeres were shortened by approximately 15% and 40% in 100- and 600-day-old mdx mice, respectively. These findings indicate that satellite cells undergo telomere erosion, which may contribute to the inability of these cells to perpetually repair DMD muscle.

  2. Normal aging of offspring mice of mothers with induced inflammation during pregnancy.

    PubMed

    Golan, H; Stilman, M; Lev, V; Huleihel, M

    2006-09-15

    Intrauterine inflammation is a major risk for offspring neurodevelopmental brain damage and may result in cognitive limitations and poor cognitive and perceptual outcomes. In the present study we tested the possibility that prenatal exposure to a high level of inflammatory factors may increase the risk for neurodegeneration in aging. The effect of systemic maternal inflammation (MI), induced by lipopolysaccharide (LPS) on offspring brain aging, was examined in 8 month old (adult) and 20 month old (aged) offspring mice. A significant effect of age was found in the distance and velocity of exploration in the open field in both groups. In addition, MI aged offspring covered longer distances and enter frequently to the center of the field compared with the aged control group. Although only little difference was found in the aged MI offspring compared with the control offspring, the overall profile of behavior of these mice differs from that of the control group, as detected by clustering analysis. The expression of the death-associated protein FAS-ligand and the amount of apoptotic cell death were examined in the brains of aged offspring. Similar levels of FAS-ligand expression and parallel density of apoptotic cells were detected in the brains of aged mice of control and MI groups. Altogether, moderate systemic MI was not found to increase the risk for cell death in the aged offspring; limited effect was found in mice profile of behavior.

  3. Exposure to light at night accelerates aging and spontaneous uterine carcinogenesis in female 129/Sv mice

    PubMed Central

    Popovich, Irina G.; Zabezhinski, Mark A.; Panchenko, Andrei V.; Piskunova, Tatiana S.; Semenchenko, Anna V.; Tyndyk, Maragriata L.; Yurova, Maria N.; Anisimov, Vladimir N.

    2013-01-01

    The effect of the constant illumination on the development of spontaneous tumors in female 129/Sv mice was investigated. Forty-six female 129/Sv mice starting from the age of 2 mo were kept under standard light/dark regimen [12 h light (70 lx):12hr dark; LD, control group], and 46 of 129/Sv mice were kept under constant illumination (24 h a day, 2,500 lx, LL) from the age of 5 mo until to natural death. The exposure to the LL regimen significantly accelerated body weight gain, increased body temperature as well as acceleration of age-related disturbances in estrous function, followed by significant acceleration of the development of the spontaneous uterine tumors in female 129/Sv mice. Total tumor incidence as well as a total number of total or malignant tumors was similar in LL and LD group (p > 0.05). The mice from the LL groups survived less than those from the LD group (χ2 = 8.5; p = 0.00351, log-rank test). According to the estimated parameters of the Cox’s regression model, constant light regimen increased the relative risk of death in female mice compared with the control (LD) group (p = 0.0041). The data demonstrate in the first time that the exposure to constant illumination was followed by the acceleration of aging and spontaneous uterine tumorigenesis in female 129/Sv mice. PMID:23656779

  4. N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice.

    PubMed

    Yu, Hai-Ling; Deng, Xian-Qing; Li, Ying-Jun; Li, Ying-Chun; Quan, Zhe-Shan; Sun, Xian-Yu

    2011-01-01

    The antidepressant-like effects of N-palmitoylethanolamide (PEA), a putative endocannabinoid, was investigated in mice using the tail suspension test (TST) and the forced swimming test (FST). In TST, PEA (10, 20, and 40 mg/kg) produced a statistically significant reduction in immobility (50, 32, and 34%, respectively, vs. the control group), whereas fluoxetine (20 mg/kg) reduced immobility by 38%. In FST, PEA (5, 10, and 20 mg/kg) produced a statistically significant reduction in immobility (15, 21, and 36%, respectively), whereas fluoxetine (20 mg/kg) reduced immobility by 18%. Moreover, PEA (20 mg/kg) did not significantly change motor activity in a spontaneous behavioral test. In conclusion, PEA (dose range of 5-40 mg/kg) administered orally reduced immobility in TST and FST, comparable to the antidepressant effect of fluoxetine, and had no effect on spontaneous activity in mice.

  5. Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin

    PubMed Central

    Zheng, Chunlei; Zhu, Min; Tao, Jiayi; Vasievich, Matthew P.; Baines, Andrea; Kim, Jinoh; Schekman, Randy; Kaufman, Randal J.; Ginsburg, David

    2011-01-01

    The type 1-transmembrane protein LMAN1 (ERGIC-53) forms a complex with the soluble protein MCFD2 and cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Mutations in either LMAN1 or MCFD2 cause the combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D), suggesting an ER-to-Golgi cargo receptor function for the LMAN1-MCFD2 complex. Here we report the analysis of LMAN1-deficient mice. Levels of plasma FV and FVIII, and platelet FV, are all reduced to ∼ 50% of wild-type in Lman1−/− mice, compared with the 5%-30% levels typically observed in human F5F8D patients. Despite previous reports identifying cathepsin C, cathepsin Z, and α1-antitrypsin as additional potential cargoes for LMAN1, no differences were observed between wild-type and Lman1−/− mice in the levels of cathepsin C and cathepsin Z in liver lysates or α1-antitrypsin levels in plasma. LMAN1 deficiency had no apparent effect on COPII-coated vesicle formation in an in vitro assay. However, the ER in Lman1−/− hepatocytes is slightly distended, with significant accumulation of α1-antitrypsin and GRP78. An unexpected, partially penetrant, perinatal lethality was observed for Lman1−/− mice, dependent on the specific inbred strain genetic background, suggesting a potential role for other, as yet unidentified LMAN1-dependent cargo proteins. PMID:21795745

  6. Glucagon-like peptide-2 but not imipramine exhibits antidepressant-like effects in ACTH-treated mice.

    PubMed

    Iwai, Takashi; Ohnuki, Tomoko; Sasaki-Hamada, Sachie; Saitoh, Akiyoshi; Sugiyama, Azusa; Oka, Jun-Ichiro

    2013-04-15

    We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) against refractory depression in adrenocorticotropic hormone (ACTH)-treated mice as a model of tricyclic antidepressant (TCA)-resistant depression. Chronic ACTH treatment (0.45 mg/kg, s.c., 14 days) weakened the antidepressant-like effects of imipramine (20 mg/kg, i.p., 6 days) in the forced-swim test (FST). Conversely, GLP-2 (3 μg/mice, i.c.v., 6 days) induced antidepressant-like effects in the ACTH-treated mice in the FST. ACTH-treatment increased basal serum corticosterone levels, with an additional increase induced by the FST. Imipramine or GLP-2 had no effect on the basal corticosterone level, but GLP-2 attenuated the additional increase caused by the FST. Moreover, GLP-2 increased 5-HT levels, but not 5-HIAA. These results suggest that GLP-2 induced antidepressant-like effects under imipramine-resistant conditions through increase in 5-HT levels.

  7. Biofilm-Forming Methicillin-Resistant Staphylococcus aureus Survive in Kupffer Cells and Exhibit High Virulence in Mice

    PubMed Central

    Oyama, Takuto; Miyazaki, Motoyasu; Yoshimura, Michinobu; Takata, Tohru; Ohjimi, Hiroyuki; Jimi, Shiro

    2016-01-01

    Although Staphylococcus aureus is part of the normal body flora, heavy usage of antibiotics has resulted in the emergence of methicillin-resistant strains (MRSA). MRSA can form biofilms and cause indwelling foreign body infections, bacteremia, soft tissue infections, endocarditis, and osteomyelitis. Using an in vitro assay, we screened 173 clinical blood isolates of MRSA and selected 20 high-biofilm formers (H-BF) and low-biofilm formers (L-BF). These were intravenously administered to mice and the general condition of mice, the distribution of bacteria, and biofilm in the liver, lung, spleen, and kidney were investigated. MRSA count was the highest in the liver, especially within Kupffer cells, which were positive for acid polysaccharides that are associated with intracellular biofilm. After 24 h, the general condition of the mice worsened significantly in the H-BF group. In the liver, bacterial deposition and aggregation and the biofilm-forming spot number were all significantly greater for H-BF group than for L-BF. CFU analysis revealed that bacteria in the H-BF group survived for long periods in the liver. These results indicate that the biofilm-forming ability of MRSA is a crucial factor for intracellular persistence, which could lead to chronic infections. PMID:27376326

  8. Sheep-passaged bovine spongiform encephalopathy agent exhibits altered pathobiological properties in bovine-PrP transgenic mice.

    PubMed

    Espinosa, Juan Carlos; Andréoletti, Olivier; Castilla, Joaquín; Herva, María Eugenia; Morales, Mónica; Alamillo, Elia; San-Segundo, Fayna Díaz; Lacroux, Caroline; Lugan, Séverine; Salguero, Francisco Javier; Langeveld, Jan; Torres, Juan María

    2007-01-01

    Sheep can be experimentally infected with bovine spongiform encephalopathy (BSE), and the ensuing disease is similar to scrapie in terms of pathogenesis and clinical signs. BSE infection in sheep is an animal and human health concern. In this study, the transmission in BoPrP-Tg110 mice of prions from BSE-infected sheep was examined and compared to the transmission of original cattle BSE in cattle and sheep scrapie prions. Our results indicate no transmission barrier for sheep BSE prions to infect BoPrP-Tg110 mice, but the course of the disease is accelerated compared to the effects of the original BSE isolate. The shortened incubation period of sheep BSE in the model was conserved in subsequent passage in BoPrP-Tg110 mice, indicating that it is not related to infectious titer differences. Biochemical signature, lesion profile, and PrP(Sc) deposition pattern of both cattle and sheep BSE were similar. In contrast, all three sheep scrapie isolates tested showed an evident transmission barrier and further adaptation in subsequent passage. Taken together, those data indicate that BSE agent can be altered by crossing a species barrier, raising concerns about the virulence of this new prion towards other species, including humans. The BoPrP-Tg110 mouse bioassay should be considered as a valuable tool for discriminating scrapie and BSE in sheep.

  9. Comparison of mice with accelerated aging caused by distinct mechanisms

    PubMed Central

    Gurkar, Aditi U.; Niedernhofer, Laura J.

    2015-01-01

    Aging is the primary risk factor for numerous chronic, debilitating diseases. These diseases impact quality of life of the elderly and consume a large portion of health care costs. The cost of age-related diseases will only increase as the world's population continues to live longer. Thus it would be advantageous to consider aging itself as a therapeutic target, potentially stemming multiple age-related diseases simultaneously. While logical, this is extremely challenging as the molecular mechanisms that drive aging are still unknown. Furthermore, clinical trials to treat aging are impractical. Even in preclinical models, testing interventions to extend healthspan in old age is lengthy and therefore costly. One approach to expedite aging studies is to take advantage of mouse strains that are engineered to age rapidly. These strains are genetically and phenotypically quite diverse. This review aims to offer a comparison of several of these strains to highlight their relative strengths and weaknesses as models of mammalian and more specifically human aging. Additionally, careful identification of commonalities amongst the strains may lead to the identification of fundamental pathways of aging. PMID:25617508

  10. Young pigs exhibit differential exploratory behavior during novelty preference tasks in response to age, sex, and delay.

    PubMed

    Fleming, Stephen A; Dilger, Ryan N

    2017-03-15

    Novelty preference paradigms have been widely used to study recognition memory and its neural substrates. The piglet model continues to advance the study of neurodevelopment, and as such, tasks that use novelty preference will serve especially useful due to their translatable nature to humans. However, there has been little use of this behavioral paradigm in the pig, and previous studies using the novel object recognition paradigm in piglets have yielded inconsistent results. The current study was conducted to determine if piglets were capable of displaying a novelty preference. Herein a series of experiments were conducted using novel object recognition or location in 3- and 4-week-old piglets. In the novel object recognition task, piglets were able to discriminate between novel and sample objects after delays of 2min, 1h, 1 day, and 2 days (all P<0.039) at both ages. Performance was sex-dependent, as females could perform both 1- and 2-day delays (P<0.036) and males could perform the 2-day delay (P=0.008) but not the 1-day delay (P=0.347). Furthermore, 4-week-old piglets and females tended to exhibit greater exploratory behavior compared with males. Such performance did not extend to novel location recognition tasks, as piglets were only able to discriminate between novel and sample locations after a short delay (P>0.046). In conclusion, this study determined that piglets are able to perform the novel object and location recognition tasks at 3-to-4 weeks of age, however performance was dependent on sex, age, and delay.

  11. 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.

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

    PubMed Central

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

    2014-01-01

    Summary 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) litter-mates, 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, proinflammatory 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. PMID:23927039

  13. Preoperative Fasting Protects against Renal Ischemia-Reperfusion Injury in Aged and Overweight Mice

    PubMed Central

    Jongbloed, Franny; de Bruin, Ron W. F.; Pennings, Jeroen L. A.; Payán-Gómez, César; van den Engel, Sandra; van Oostrom, Conny T.; de Bruin, Alain; Hoeijmakers, Jan H. J.; van Steeg, Harry; IJzermans, Jan N. M.; Dollé, Martijn E. T.

    2014-01-01

    Ischemia-reperfusion injury (IRI) is inevitable during kidney transplantation leading to oxidative stress and inflammation. We previously reported that preoperative fasting in young-lean male mice protects against IRI. Since patients are generally of older age with morbidities possibly leading to a different response to fasting, we investigated the effects of preoperative fasting on renal IRI in aged-overweight male and female mice. Male and female F1-FVB/C57BL6-hybrid mice, average age 73 weeks weighing 47.2 grams, were randomized to preoperative ad libitum feeding or 3 days fasting, followed by renal IRI. Body weight, kidney function and survival of the animals were monitored until day 28 postoperatively. Kidney histopathology was scored for all animals and gene expression profiles after fasting were analyzed in kidneys of young and aged male mice. Preoperative fasting significantly improved survival after renal IRI in both sexes compared with normal fed mice. Fasted groups had a better kidney function shown by lower serum urea levels after renal IRI. Histopathology showed less acute tubular necrosis and more regeneration in kidneys from fasted mice. A mRNA analysis indicated the involvement of metabolic processes including fatty acid oxidation and retinol metabolism, and the NRF2-mediated stress response. Similar to young-lean, healthy male mice, preoperative fasting protects against renal IRI in aged-overweight mice of both genders. These findings suggest a general protective response of fasting against renal IRI regardless of age, gender, body weight and genetic background. Therefore, fasting could be a non-invasive intervention inducing increased oxidative stress resistance in older and overweight patients as well. PMID:24959849

  14. Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

    PubMed

    Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

    1999-01-01

    Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

  15. Tigecycline exhibits inhibitory activity against Clostridium difficile in the colon of mice and does not promote growth or toxin production.

    PubMed

    Jump, Robin L P; Li, Yuejin; Pultz, Michael J; Kypriotakis, Georgios; Donskey, Curtis J

    2011-02-01

    Tigecycline is a broad-spectrum glycylcycline antibiotic with potent in vitro activity against Clostridium difficile. We used a mouse model to test the hypothesis that tigecycline has a low propensity to promote colonization and toxin production by C. difficile due to inhibitory activity in the colon. Mice (5 to 8 per group) received subcutaneous injections of tigecycline (low and high doses) alone or in combination with clindamycin for 6 days. Growth of and toxin production by 3 strains of C. difficile (tigecycline MICs ≤ 0.012 μg/ml) were measured in cecal contents collected 6 h or 3 days after the final antibiotic dose. Antibiotic concentrations were measured using a bioassay, and concentrations of total anaerobes and Bacteroides spp. were measured. The effects of tigecycline on rendering mice susceptible to colonization with and reducing the burden of C. difficile were also examined. In comparison to saline controls, clindamycin promoted the growth of C. difficile (P < 0.001) in cecal contents, whereas tigecycline did not. Tigecycline did not suppress total anaerobes or Bacteroides spp. in comparison to saline controls. Concurrent administration of tigecycline prevented clindamycin-induced promotion of C. difficile in cecal contents collected 6 h or 3 days (high dose only) after the final antibiotic dose. Tigecycline did not promote the establishment of colonization in mice, yet it did not reduce concentrations of C. difficile in animals with established colonization. In summary, tigecycline did not promote the growth of or toxin production by C. difficile, probably due to inhibitory activity against C. difficile and relative sparing of indigenous anaerobic microflora.

  16. Improved Learning and Memory in Aged Mice Deficient in Amyloid β-Degrading Neutral Endopeptidase

    PubMed Central

    Walther, Thomas; Albrecht, Doris; Becker, Matthias; Schubert, Manja; Kouznetsova, Elena; Wiesner, Burkard; Maul, Björn; Schliebs, Reinhard; Grecksch, Gisela; Furkert, Jens; Sterner-Kock, Anja; Schultheiss, Heinz-Peter; Becker, Axel; Siems, Wolf-Eberhard

    2009-01-01

    Background Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-β (Aβ) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-like symptoms in mice. Methodology/Principal Findings We found that while endogenous Aβ concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Aβ deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Aβ degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice. Conclusions/Significance Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases. PMID:19240795

  17. Age and sex differences in immune response following LPS treatment in mice.

    PubMed

    Cai, Kyle Chiman; van Mil, Spencer; Murray, Emma; Mallet, Jean-François; Matar, Chantal; Ismail, Nafissa

    2016-11-01

    Puberty is an important developmental event that is marked by the reorganizing and remodeling of the brain. Exposure to stress during this critical period of development can have enduring effects on both reproductive and non-reproductive behaviors. The purpose of this study was to investigate age and sex differences in immune response by examining sickness behavior, body temperature changes, and serum cytokine levels following an immune challenge. The effects of circulating gonadal hormones on age and sex differences in immune response were also examined. Results showed that male mice display more sickness behavior and greater fluctuations in body temperature following LPS treatment than female mice. Moreover, adult male mice display more sickness behavior and a greater drop in body temperature following LPS treatment compared to pubertal male mice. Following gonadectomy, pubertal and adult males displayed steeper and prolonged drops in body temperature compared to sham-operated counterparts. Gonadectomy did not eliminate sex differences in LPS-induced body temperature changes, suggesting that additional factors contribute to the observed differences. LPS treatment increased cytokine levels in all mice. However, the increase in pro-inflammatory cytokines was higher in adult compared to pubertal mice, while the increase in anti-inflammatory cytokines was greater in pubertal than in adult mice. Our findings contribute to a better understanding of age and sex differences in acute immune response following LPS treatment and possible mechanisms involved in the enduring alterations in behavior and brain function following pubertal exposure to LPS.

  18. Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling

    PubMed Central

    Delire, Bénédicte; Lebrun, Valérie; Selvais, Charlotte; Henriet, Patrick; Bertrand, Amélie; Horsmans, Yves; Leclercq, Isabelle A.

    2017-01-01

    Clinical data identify age as a factor for severe liver fibrosis. We evaluate whether and how aging modulates the fibrotic response in a mouse model. Liver fibrosis was induced by CCl4 injections (thrice weekly for 2 weeks) in 7 weeks- and 15 months-old mice (young and old, respectively). Livers were analyzed for fibrosis, inflammation and remodeling 48 and 96 hours after the last injection. Old mice developed more severe fibrosis compared to young ones as evaluated by sirius red morphometry. Expression of pro-fibrogenic genes was equally induced in the two age-groups but enhanced fibrolysis in young mice was demonstrated by a significantly higher Mmp13 induction and collagenase activity. While fibrosis resolution occurred in young mice within 96 hours, no significant fibrosis attenuation was observed in old mice. Although recruitment of monocytes-derived macrophages was similar in young and old livers, young macrophages had globally a remodeling phenotype while old ones, a pro-fibrogenic phenotype. Moreover, we observed a higher proportion of thick fibers and enhanced expression of enzymes involved in collagen maturation in old mice. Conclusion Impaired fibrolysis of a matrix less prone to remodeling associated with a pro-inflammatory phenotype of infiltrated macrophages contribute to a more severe fibrosis in old mice. PMID:27941216

  19. Age-related changes in pial arterial structure and blood flow in mice.

    PubMed

    Kang, Hye-Min; Sohn, Inkyung; Jung, Junyang; Jeong, Joo-Won; Park, Chan

    2016-01-01

    Age-related cerebral blood flow decreases are thought to deteriorate cognition and cause senescence, although the related mechanism is unclear. To investigate the relationships between aging and changes in cerebral blood flow and vasculature, we obtained fluorescence images of young (2-month-old) and old (12-month-old) mice using indocyanine green (ICG). First, we found that the blood flow in old mice's brains is lower than that in young mice and that old mice had more curved pial arteries and fewer pial artery junctions than young mice. Second, using Western blotting, we determined that the ratio of collagen to elastin (related to cerebral vascular wall distensibility) increased with age. Finally, we found that the peak ICG intensity and blood flow index decreased, whereas the mean transit time increased, with age in the middle cerebral artery and superior sagittal sinus. Age-related changes in pial arterial structure and composition, concurrent with the observed changes in the blood flow parameters, suggest that age-related changes in the cerebral vasculature structure and distensibility may induce altered brain blood flow.

  20. Evidence for loss of synaptic AMPA receptors in anterior piriform cortex of aged mice.

    PubMed

    Gocel, James; Larson, John

    2013-01-01

    It has been suggested that age-related impairments in learning and memory may be due to age-related deficits in long-term potentiation of glutamatergic synaptic transmission. For example, olfactory discrimination learning is significantly affected by aging in mice and this may be due, in part, to diminished synaptic plasticity in piriform cortex. In the present study, we tested for alterations in electrophysiological properties and synaptic transmission in this simple cortical network. Whole-cell recordings were made from principal neurons in slices of anterior piriform cortex from young (3-6 months old) and old (24-28 months) C57Bl/6 mice. Miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were collected from cells in presence of tetrodotoxin (TTX) and held at -80 mV in voltage-clamp. Amplitudes of mEPSCs were significantly reduced in aged mice, suggesting that synaptic AMPA receptor expression is decreased during aging. In a second set of experiments, spontaneous excitatory postsynaptic currents (s/mEPSCs) were recorded in slices from different cohorts of young and old mice, in the absence of TTX. These currents resembled mEPSCs and were similarly reduced in amplitude in old mice. The results represent the first electrophysiological evidence for age-related declines in glutamatergic synaptic function in the mammalian olfactory system.

  1. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    PubMed

    Park, Jung Yoon; Cho, Mi-Ook; Leonard, Shanique; Calder, Brent; Mian, I Saira; Kim, Woo Ho; Wijnhoven, Susan; van Steeg, Harry; Mitchell, James; van der Horst, Gijsbertus T J; Hoeijmakers, Jan; Cohen, Pinchas; Vijg, Jan; Suh, Yousin

    2008-06-11

    Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD) mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD) mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD) mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD) mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  2. Aging-associated changes in motor axon voltage-gated Na(+) channel function in mice.

    PubMed

    Moldovan, Mihai; Rosberg, Mette Romer; Alvarez, Susana; Klein, Dennis; Martini, Rudolf; Krarup, Christian

    2016-03-01

    Accumulating myelin abnormalities and conduction slowing occur in peripheral nerves during aging. In mice deficient of myelin protein P0, severe peripheral nervous system myelin damage is associated with ectopic expression of Nav1.8 voltage-gated Na(+) channels on motor axons aggravating the functional impairment. The aim of the present study was to investigate the effect of regular aging on motor axon function with particular emphasis on Nav1.8. We compared tibial nerve conduction and excitability measures by threshold tracking in 12 months (mature) and 20 months (aged) wild-type (WT) mice. With aging, deviations during threshold electrotonus were attenuated and the resting current-threshold slope and early refractoriness were increased. Modeling indicated that, in addition to changes in passive membrane properties, motor fibers in aged WT mice were depolarized. An increased Nav1.8 isoform expression was found by immunohistochemistry. The depolarizing excitability features were absent in Nav1.8 null mice, and they were counteracted in WT mice by a Nav1.8 blocker. Our data suggest that alteration in voltage-gated Na(+) channel isoform expression contributes to changes in motor axon function during aging.

  3. FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice

    PubMed Central

    Ahlenius, Henrik; Chanda, Soham; Webb, Ashley E.; Yousif, Issa; Karmazin, Jesse; Prusiner, Stanley B.; Brunet, Anne; Südhof, Thomas C.; Wernig, Marius

    2016-01-01

    We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development. PMID:27402759

  4. Intrahippocampal glucocorticoids generated by 11β-HSD1 affect memory in aged mice.

    PubMed

    Yau, Joyce L W; Wheelan, Nicola; Noble, June; Walker, Brian R; Webster, Scott P; Kenyon, Christopher J; Ludwig, Mike; Seckl, Jonathan R

    2015-01-01

    11Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) locally amplifies active glucocorticoids within specific tissues including in brain. In the hippocampus, 11β-HSD1 messenger RNA increases with aging. Here, we report significantly greater increases in intrahippocampal corticosterone (CORT) levels in aged wild-type (WT) mice during the acquisition and retrieval trials in a Y-maze than age-matched 11β-HSD1(-/-) mice, corresponding to impaired and intact spatial memory, respectively. Acute stress applied to young WT mice led to increases in intrahippocampal CORT levels similar to the effects of aging and impaired retrieval of spatial memory. 11β-HSD1(-/-) mice resisted the stress-induced memory impairment. Pharmacologic inhibition of 11β-HSD1 abolished increases in intrahippocampal CORT levels during the Y-maze trials and prevented spatial memory impairments in aged WT mice. These data provide the first in vivo evidence that dynamic increases in hippocampal 11β-HSD1 regenerated CORT levels during learning and retrieval play a key role in age- and stress-associated impairments of spatial memory.

  5. CD36 expression contributes to age induced cardiomyopathy in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cardiac remodeling and impaired cardiac performance in the elderly significantly increase the risk of developing heart disease. Although vascular abnormalities associated with aging contribute to the age-related decline in cardiac function, myocardium-specific events may also be involved. We show th...

  6. Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice

    PubMed Central

    Biljes, Daniel; Hammerschmidt-Kamper, Christiane; Kadow, Stephanie; Diel, Patrick; Weigt, Carmen; Burkart, Volker; Esser, Charlotte

    2015-01-01

    Disturbed homeostasis of glucose and lipid metabolism are dominant features of the so-called metabolic syndrome (MetS) and can increase the risk for the development of type 2 diabetes (T2D), a severe metabolic disease. T2D prevalence increases with age. The aryl hydrocarbon receptor (AHR) is a sensor of small molecules including dietary components. AHR has been identified as potential regulator of glucose homeostasis and lipid metabolism. Epidemiologically, exposure to xenobiotic AHR ligands such as polycyclic aromatic hydrocarbons is linked to T2D. We assess here the potential role of the AHR in disturbances of glucose and lipid metabolism in young (age 2-5 months) and old (age > 1,5 years) AHR-deficient (AHR KO) mice. Fasted young wildtype (WT) and AHR-KO mice displayed similar blood glucose kinetics after challenge with intra-peritoneal glucose injection. However, old AHR-KO mice showed lower tolerance than WT to i.p. administered glucose, i.e. glucose levels rose higher and returned more slowly to normal levels. Old mice had overall higher insulin levels than young mice, and old AHR-KO had a somewhat disturbed insulin kinetic in the serum after glucose challenge. Surprisingly, young AHR-KO mice had significantly lower triglycerides, cholesterol, high density lipoprotein values than WT, i.e., a dyslipidemic profile. With ageing, AHR-KO and WT mice did not differ in these lipid levels, except for slightly reduced levels of triglycerides and cholesterol. In conclusion, our findings in AHR KO mice suggest that AHR expression is relevant for the maintenance of glucose and lipid homeostasis in old mice. PMID:26664351

  7. Longitudinal Attentional Engagement Rescues Mice from Age-Related Cognitive Declines and Cognitive Inflexibility

    ERIC Educational Resources Information Center

    Matzel, Louis D.; Light, Kenneth R.; Wass, Christopher; Colas-Zelin, Danielle; Denman-Brice, Alexander; Waddel, Adam C.; Kolata, Stefan

    2011-01-01

    Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm…

  8. Mammary glands exhibit molecular laterality and undergo left-right asymmetric ductal epithelial growth in MMTV-cNeu mice.

    PubMed

    Robichaux, J P; Hallett, R M; Fuseler, J W; Hassell, J A; Ramsdell, A F

    2015-04-09

    Significant left-right (L-R) differences in tumor incidence and disease outcome occur for cancers of paired organs, including the breasts; however, the basis for this laterality is unknown. Here, we show that despite their morphologic symmetry, left versus right mammary glands in wild-type mice have baseline differences in gene expression that are L-R independently regulated during pubertal development, including genes that regulate luminal progenitor cell renewal, luminal cell differentiation, mammary tumorigenesis, tamoxifen sensitivity and chemotherapeutic resistance. In MMTV-cNeu(Tg/Tg) mice, which model HER2/Neu-amplified breast cancer, baseline L-R differences in mammary gene expression are amplified, sustained or inverted in a gene-specific manner and the mammary ductal epithelium undergoes L-R asymmetric growth and patterning. Comparative genomic analysis of mouse L-R mammary gene expression profiles with gene expression profiles of human breast tumors revealed significant linkage between right-sided gene expression and decreased breast cancer patient survival. Collectively, these findings are the first to demonstrate that mammary glands are lateralized organs, and, moreover, that mammary glands have L-R differential susceptibility to HER2/Neu oncogene-mediated effects on ductal epithelial growth and differentiation. We propose that intrinsic molecular laterality may have a role in L-R asymmetric breast tumor incidence and, furthermore, that interplay between the L-R molecular landscape and oncogene activity may contribute to the differential disease progression and patient outcome that are associated with tumor situs.

  9. Age-dependent inhibition of pentobarbital sleeping time by ozone in mice and rats

    SciTech Connect

    Canada, A.T.; Calabrese, E.J.; Leonard, D.

    1986-09-01

    The effect of age on the metabolism of pentobarbital in mice and rats was investigated following exposure to 0.3 ppm of ozone for 3.75 hr. Young animals were 2.5 months of age and the mature were 18 months. The pentobarbital sleeping time was significantly prolonged following the ozone exposure in both the mice and rats when compared with an air control. No ozone effect on sleeping time was found in the young animals. The results indicate that there may be an age-related sensitivity to the occurrence of ozone-related inhibition of pentobarbital metabolism.

  10. Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice.

    PubMed

    Kim, In Hee; Xu, Jun; Liu, Xiao; Koyama, Yukinori; Ma, Hsiao-Yen; Diggle, Karin; You, Young-Hyun; Schilling, Jan M; Jeste, Dilip; Sharma, Kumar; Brenner, David A; Kisseleva, Tatiana

    2016-08-01

    We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10 months old) and old (20 months old) aged, male C57BL/6N mice were fed either a low-fat diet (4 % fat) or HFD (60 % fat) for 4 months. Young (3 months old) aged mice were included as control group. HFD-induced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-α, IL-1β, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-α1, αSMA, TGF-β1, TGF-β2, TGFβRII, PDGF, PDGFRβII, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between old-aged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or

  11. Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice

    PubMed Central

    Reis, Felipe C. G.; Branquinho, Jéssica L. O.; Brandão, Bruna B.; Guerra, Beatriz A.; Silva, Ismael D.; Frontini, Andrea; Thomou, Thomas; Sartini, Loris; Cinti, Saverio; Kahn, C. Ronald; Festuccia, William T.; Kowaltowski, Alicia J.; Mori, Marcelo A.

    2016-01-01

    Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance. PMID:27241713

  12. Adverse Effects of Diabetes Mellitus on the Skeleton of Aging Mice.

    PubMed

    Portal-Núñez, Sergio; Ardura, Juan Antonio; Lozano, Daniel; Bolívar, Oskarina Hernández; López-Herradón, Ana; Gutiérrez-Rojas, Irene; Proctor, Alexander; van der Eerden, Bram; Schreuders-Koedam, Marijke; van Leeuwen, Johannes; Alcaraz, María José; Mulero, Francisca; de la Fuente, Mónica; Esbrit, Pedro

    2016-03-01

    In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery.

  13. Tooth loss early in life accelerates age-related bone deterioration in mice.

    PubMed

    Kurahashi, Minori; Kondo, Hiroko; Iinuma, Mitsuo; Tamura, Yasuo; Chen, Huayue; Kubo, Kin-ya

    2015-01-01

    Both osteoporosis and tooth loss are health concerns that affect many older people. Osteoporosis is a common skeletal disease of the elderly, characterized by low bone mass and microstructural deterioration of bone tissue. Chronic mild stress is a risk factor for osteoporosis. Many studies showed that tooth loss induced neurological alterations through activation of a stress hormone, corticosterone, in mice. In this study, we tested the hypothesis that tooth loss early in life may accelerate age-related bone deterioration using a mouse model. Male senescence-accelerated mouse strain P8 (SAMP8) mice were randomly divided into control and toothless groups. Removal of the upper molar teeth was performed at one month of age. Bone response was evaluated at 2, 5 and 9 months of age. Tooth loss early in life caused a significant increase in circulating corticosterone level with age. Osteoblast bone formation was suppressed and osteoclast bone resorption was activated in the toothless mice. Trabecular bone volume fraction of the vertebra and femur was decreased in the toothless mice with age. The bone quality was reduced in the toothless mice at 5 and 9 months of age, compared with the age-matched control mice. These findings indicate that tooth loss early in life impairs the dynamic homeostasis of the bone formation and bone resorption, leading to reduced bone strength with age. Long-term tooth loss may have a cumulative detrimental effect on bone health. It is important to take appropriate measures to treat tooth loss in older people for preventing and/or treating senile osteoporosis.

  14. Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling.

    PubMed

    Koopman, Jacob J E; van Heemst, Diana; van Bodegom, David; Bonkowski, Michael S; Sun, Liou Y; Bartke, Andrzej

    2016-03-01

    Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species.

  15. Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling

    PubMed Central

    Koopman, Jacob J.E.; van Heemst, Diana; van Bodegom, David; Bonkowski, Michael S.; Sun, Liou Y.; Bartke, Andrzej

    2016-01-01

    Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species. PMID:26959761

  16. Effect of age on testicular germ cell apoptosis and sperm aneuploidy in MF-1 mice.

    PubMed

    Brinkworth, M H; Schmid, T E

    2003-01-01

    The spontaneous mutation rate in the male germ-line increases with age. The reason for this is unknown, but presumably involves an age-related degeneration in the efficacy of cellular processes. To investigate the possibility that rates of apoptosis and genetic damage (represented by aneuploidy) might vary with age in mice, the testes and sperm of 2- and 12-month-old male MF-1 mice were examined by a modified TUNEL technique and 3-colour sperm-FISH assay, respectively. Sperm were labeled with probes to chromosomes 8, X and Y and 20,000 sperm scored from each of 5 animals per group. A significant increase in gonosomal disomy was found in the aged mice, especially X-X-8. This suggests that advanced paternal age is associated primarily with meiosis II rather than meiosis I disjunction errors. Neither diploidy nor autosomal disomy was affected in the older group. The rate of germ cell apoptosis (apoptotic cells per seminiferous tubule cross-section per animal per group) was higher in the old mice than controls, but not significantly. Considerable inter-animal variability was observed in the older group. The finding of an increase in levels of sperm aneuploidy is novel for 1-year-old mice and confirms the genotoxic effect of ageing in mice. Since apoptosis is assumed to eliminate cells with unrepaired damage, it may be that the apoptotic response in older mice is compromised, resulting in the higher levels of aneuploidy in sperm. However, given the inter-animal variability in testicular germ cell apoptosis, this awaits confirmation.

  17. Peripheral surgical wounding may induce cognitive impairment through interlukin-6-dependent mechanisms in aged mice

    PubMed Central

    Dong, Yuanlin; Xu, Zhipeng; Huang, Lining; Zhang, Yiying; Xie, Zhongcong

    2016-01-01

    Post-operative cognitive dysfunction (POCD) is associated with morbidity, mortality and increased cost of medical care. However, the neuropathogenesis and targeted interventions of POCD remain largely to be determined. We have found that the peripheral surgical wounding induces an age-dependent Aβ accumulation, neuroinflammation and cognitive impairment in aged mice. Pro-inflammatory cytokine interlukin-6 (IL-6) has been reported to be associated with cognitive impairment in rodents and humans. However, the role of IL-6 in the neuropathogenesis of POCD is unknown. We therefore employed pharmacological (IL-6 antibody) and genetic (knockout of IL-6) approach to investigate whether IL-6 contributed to the peripheral surgical wounding-induced cognitive impairment in aged mice. Abdominal surgery under local anesthesia (peripheral surgical wounding) was established in 18-month-old wild-type and IL-6 knockout mice (n = 6 to 10 in each group). Brain level of IL-6 and cognitive function in the mice were determined by western blot, ELISA at the end of procedure, and Fear Conditioning System at 7 days after the procedure. The peripheral surgical wounding increased the level of IL-6 in the hippocampus of aged wild-type, but not IL-6 knockout mice. IL-6 antibody ameliorated the peripheral surgical wounding-induced cognitive impairment in the aged wild-type mice. Finally, the peripheral surgical wounding did not induce cognitive impairment in the aged IL-6 knockout mice. These data suggested that IL-6 would be a required pro-inflammatory cytokine for the peripheral surgical wounding-induced cognitive impairment. Given this, further studies are warranted to investigate the role of IL-6 in the neuropathogenesis and targeted interventions of POCD. PMID:28217289

  18. Age and isolation influence steroids release and chemical signaling in male mice.

    PubMed

    Mucignat-Caretta, Carla; Cavaggioni, Andrea; Redaelli, Marco; Da Dalt, Laura; Zagotto, Giuseppe; Gabai, Gianfranco

    2014-05-01

    Social interactions in mice involve olfactory signals, which convey information about the emitter. In turn, the mouse social and physiological status may modify the release of chemical cues. In this study, the influences of age and social isolation on the endocrine response and the release of chemical signals were investigated in male CD1 mice, allocated into four groups: Young Isolated (from weaning till 60days; N=6), Adult Isolated (till 180days; N=6), Young Grouped (6 mice/cage; till 60days; N=18), Adult Grouped (6 mice/cage; till 180days; N=18). Mice were transferred in a clean cage to observe the micturition pattern and then sacrificed. Body and organs weights, serum testosterone, dehydroepiandrosterone, corticosterone and the ratio Major Urinary Protein/creatinine were measured. Urinary volatile molecules potentially involved in pheromonal communication were identified. Androgen secretion was greater in isolated mice (P<0.05), suggesting a greater reactivity of the Hypothalamic-Pituitary-Gonadal axis. Grouped mice presented a higher degree of adrenal activity, and young mice showed a higher serum corticosterone (P<0.05) suggesting a greater stimulation of the Hypothalamic-Pituitary-Adrenal axis. The micturition pattern typical of dominant male, consisting in voiding numerous droplets, was observed in Young Isolated mice only, which showed a higher protein/creatinine ratio (P<0.05). Urinary 2-s-butyl-thiazoline was higher in both Young and Adult Isolated mice (P<0.005). Young Isolated mice showed the most prominent difference in both micturition pattern and potentially active substance emission, while long term isolation resulted in a less extreme phenotype; therefore social isolation had a higher impact on young mice hormone and pheromone release.

  19. Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner.

    PubMed

    He, Qiuming; Morillon, Y Maurice; Spidale, Nicholas A; Kroger, Charles J; Liu, Bo; Sartor, R Balfour; Wang, Bo; Tisch, Roland

    2013-12-15

    Inefficient thymic negative selection of self-specific T cells is associated with several autoimmune diseases, including type 1 diabetes. The factors that influence the efficacy of thymic negative selection, as well as the kinetics of thymic output of autoreactive T cells remain ill-defined. We investigated thymic production of β cell-specific T cells using a thymus-transplantation model. Thymi from different aged NOD mice, representing distinct stages of type 1 diabetes, were implanted into NOD.scid recipients, and the diabetogenicity of the resulting T cell pool was examined. Strikingly, the development of diabetes-inducing β cell-specific CD4(+) and CD8(+) T cells was regulated in an age-dependent manner. NOD.scid recipients of newborn NOD thymi developed diabetes. However, recipients of thymi from 7- and 10-d-old NOD donor mice remained diabetes-free and exhibited a progressive decline in islet infiltration and β cell-specific CD4(+) and CD8(+) T cells. A similar temporal decrease in autoimmune infiltration was detected in some, but not all, tissues of recipient mice implanted with thymi from NOD mice lacking expression of the autoimmune regulator transcription factor, which develop multiorgan T cell-mediated autoimmunity. In contrast, recipients of 10 d or older thymi lacked diabetogenic T cells but developed severe colitis marked by increased effector T cells reactive to intestinal microbiota. These results demonstrate that thymic development of autoreactive T cells is limited to a narrow time window and occurs in a reciprocal manner compared with colonic microbiota-responsive T cells in NOD mice.

  20. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.

    PubMed

    Ochiai, Wataru; Kaneta, Mitsumasa; Nagae, Marina; Yuzuhara, Ami; Li, Xin; Suzuki, Haruka; Hanagata, Mika; Kitaoka, Satoshi; Suto, Wataru; Kusunoki, Yoshiki; Kon, Risako; Miyashita, Kazuhiko; Masukawa, Daiki; Ikarashi, Nobutomo; Narita, Minoru; Suzuki, Tsutomu; Sugiyama, Kiyoshi

    2016-09-20

    The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain.

  1. Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice.

    PubMed

    Yarian, Connie S; Toroser, Dikran; Sohal, Rajindar S

    2006-01-01

    The activities of the citric acid cycle enzymes were determined in mitochondria isolated from kidneys of relatively young, middle age, and old mice. Aconitase exhibited the most significant decrease in activity with age. The activity of alpha-ketoglutarate dehydrogenase exhibited a modest decrease in activity, while NADP(+)-isocitrate dehydrogenase (NADP(+)-ICD) activity increased moderately with age. Activities of citrate synthase, NAD(+)-isocitrate dehydrogenase (NAD(+)-ICD), succinyl-CoA synthetase (SCS), succinate dehydrogenase (SD), fumarase (FUM), and malate dehydrogenase (MD) were not affected. The molar ratio of the intra-mitochondrial redox indicator, NADPH:NADP(+), was higher in young compared to old animals, while the NADH:NAD(+) molar ratio remained unchanged. It is suggested that an age-related decrease in aconitase activity along with relatively subtle alterations in activities of some other citric acid cycle enzymes are likely to contribute to a decline in the overall efficiency of mitochondrial bioenergetics. The biological consequences of such alterations include age-related fluctuations in the citric acid cycle intermediates, which are precursors of protein synthesis, activators of fatty acid synthesis, and can also act as ligands for orphan G-protein coupled receptors.

  2. The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice

    PubMed Central

    Fu, Ailing; Zhou, Rumei; Xu, Xingran

    2014-01-01

    The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive function during the mammalian lifespan. However, thyroid hormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4; 1.6 μg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cytoskeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60% to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were increased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deficits. PMID:25206902

  3. Gene Transcriptional and Metabolic Profile Changes in Mimetic Aging Mice Induced by D-Galactose

    PubMed Central

    Zhou, Yue-Yue; Zhu, Xiao-Juan; Li, Rong-Hua; Mu, Chang-Kao; Wang, Chun-Lin; Song, Wei-Wei

    2015-01-01

    D-galactose injection has been shown to induce many changes in mice that represent accelerated aging. This mouse model has been widely used for pharmacological studies of anti-aging agents. The underlying mechanism of D-galactose induced aging remains unclear, however, it appears to relate to glucose and 1ipid metabolic disorders. Currently, there has yet to be a study that focuses on investigating gene expression changes in D-galactose aging mice. In this study, integrated analysis of gas chromatography/mass spectrometry-based metabonomics and gene expression profiles was used to investigate the changes in transcriptional and metabolic profiles in mimetic aging mice injected with D-galactose. Our findings demonstrated that 48 mRNAs were differentially expressed between control and D-galactose mice, and 51 potential biomarkers were identified at the metabolic level. The effects of D-galactose on aging could be attributed to glucose and 1ipid metabolic disorders, oxidative damage, accumulation of advanced glycation end products (AGEs), reduction in abnormal substance elimination, cell apoptosis, and insulin resistance. PMID:26176541

  4. Gene Transcriptional and Metabolic Profile Changes in Mimetic Aging Mice Induced by D-Galactose.

    PubMed

    Zhou, Yue-Yue; Ji, Xiong-Fei; Fu, Jian-Ping; Zhu, Xiao-Juan; Li, Rong-Hua; Mu, Chang-Kao; Wang, Chun-Lin; Song, Wei-Wei

    2015-01-01

    D-galactose injection has been shown to induce many changes in mice that represent accelerated aging. This mouse model has been widely used for pharmacological studies of anti-aging agents. The underlying mechanism of D-galactose induced aging remains unclear, however, it appears to relate to glucose and 1ipid metabolic disorders. Currently, there has yet to be a study that focuses on investigating gene expression changes in D-galactose aging mice. In this study, integrated analysis of gas chromatography/mass spectrometry-based metabonomics and gene expression profiles was used to investigate the changes in transcriptional and metabolic profiles in mimetic aging mice injected with D-galactose. Our findings demonstrated that 48 mRNAs were differentially expressed between control and D-galactose mice, and 51 potential biomarkers were identified at the metabolic level. The effects of D-galactose on aging could be attributed to glucose and 1ipid metabolic disorders, oxidative damage, accumulation of advanced glycation end products (AGEs), reduction in abnormal substance elimination, cell apoptosis, and insulin resistance.

  5. Involvement of oxidative stress in SAMP10 mice with age-related neurodegeneration.

    PubMed

    Wang, Jun; Lei, Hongtao; Hou, Jincai; Liu, Jianxun

    2015-05-01

    Age-related changes in the brain tissue are reflected in many aspects. We sought to determine the morphology, Nissl bodies, behavioral appearance and oxidative stress in the brain using SAMP10 mice, a substrain of the senescence-accelerated mouse. SAMP10 mice groups divided by different ages (3, 5, 8 and 14 months) were compared with those of control groups with the above corresponding ages. Cortical thickness, Nissl bodies, behavioral appearance and oxidative stress were evaluated through image software, thionine staining, step-down test and colorimetry, respectively. The weight and cortical thickness of the brain in SAMP10 mice significantly reduced from 8 months of age. The results showed that the number of Nissl bodies decreased or Nissl bodies shrank with dark staining in histology. The same result appeared in a step-down test. As the SAMP10 mice grew older, the oxidative stress-related markers superoxide dismutase decreased and malondialdehyde increased after 8 months. Glutathione peroxidase activities showed no age-related changes. The changes of brain morphology and productions of oxidative stress in the brain tissue might contribute to the behavioral abnormality. Deceleration of age-related production of oxidative stress might be expected to be a potent strategy for anti-aging interventions.

  6. Susceptibility to glaucoma damage related to age and connective tissue mutations in mice.

    PubMed

    Steinhart, Matthew R; Cone-Kimball, Elizabeth; Nguyen, Cathy; Nguyen, Thao D; Pease, Mary E; Chakravarti, Shukti; Oglesby, Ericka N; Quigley, Harry A

    2014-02-01

    The purpose of this research was to study the effects of age and genetic alterations in key connective tissue proteins on susceptibility to experimental glaucoma in mice. We used mice haploinsufficient in the elastin gene (EH) and mice without both alleles of the fibromodulin gene (FM KO) and their wild type (WT) littermates of B6 and CD1 strains, respectively. FM KO mice were tested at two ages: 2 months and 12 months. Intraocular pressure (IOP) was measured by Tonolab tonometer, axial lengths and widths measured by digital caliper post-enucleation, and chronic glaucoma damage was measured using a bead injection model and optic nerve axon counts. IOP in EH mice was not significantly different from WT, but FM KO were slightly lower than their controls (p = 0.04). Loss of retinal ganglion cell (RGC) axons was somewhat, but not significantly greater in young EH and younger or older FM KO strains than in age-matched controls (p = 0.48, 0.34, 0.20, respectively, multivariable regression adjusting for IOP exposure). Older CD1 mice lost significantly more RGC axons than younger CD1 (p = 0.01, multivariable regression). The CD1 mouse strain showed age-dependence of experimental glaucoma damage to RGC in the opposite, and more expected, direction than in B6 mice in which older mice are more resistant to damage. Genetic alteration in two genes that are constituents of sclera, fibromodulin and elastin do not significantly affect RGC loss.

  7. Dietary Tocotrienol/γ-Cyclodextrin Complex Increases Mitochondrial Membrane Potential and ATP Concentrations in the Brains of Aged Mice

    PubMed Central

    Schloesser, Anke; Esatbeyoglu, Tuba; Piegholdt, Stefanie; Dose, Janina; Ikuta, Naoko; Okamoto, Hinako; Ishida, Yoshiyuki; Terao, Keiji; Matsugo, Seiichi; Rimbach, Gerald

    2015-01-01

    Brain aging is accompanied by a decrease in mitochondrial function. In vitro studies suggest that tocotrienols, including γ- and δ-tocotrienol (T3), may exhibit neuroprotective properties. However, little is known about the effect of dietary T3 on mitochondrial function in vivo. In this study, we monitored the effect of a dietary T3/γ-cyclodextrin complex (T3CD) on mitochondrial membrane potential and ATP levels in the brain of 21-month-old mice. Mice were fed either a control diet or a diet enriched with T3CD providing 100 mg T3 per kg diet for 6 months. Dietary T3CD significantly increased mitochondrial membrane potential and ATP levels compared to those of controls. The increase in MMP and ATP due to dietary T3CD was accompanied by an increase in the protein levels of the mitochondrial transcription factor A (TFAM). Furthermore, dietary T3CD slightly increased the mRNA levels of superoxide dismutase, γ-glutamyl cysteinyl synthetase, and heme oxygenase 1 in the brain. Overall, the present data suggest that T3CD increases TFAM, mitochondrial membrane potential, and ATP synthesis in the brains of aged mice. PMID:26301044

  8. Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice.

    PubMed

    Latimer, Caitlin S; Searcy, James L; Bridges, Michael T; Brewer, Lawrence D; Popović, Jelena; Blalock, Eric M; Landfield, Philip W; Thibault, Olivier; Porter, Nada M

    2011-01-01

    Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.

  9. Blueberry supplementation improves memory in middle-aged mice fed a high-fat diet.

    PubMed

    Carey, Amanda N; Gomes, Stacey M; Shukitt-Hale, Barbara

    2014-05-07

    Consuming a high-fat diet may result in behavioral deficits similar to those observed in aging animals. It has been demonstrated that blueberry supplementation can allay age-related behavioral deficits. To determine if supplementation of a high-fat diet with blueberries offers protection against putative high-fat diet-related declines, 9-month-old C57Bl/6 mice were maintained on low-fat (10% fat calories) or high-fat (60% fat calories) diets with and without 4% freeze-dried blueberry powder. Novel object recognition memory was impaired by the high-fat diet; after 4 months on the high-fat diet, mice spent 50% of their time on the novel object in the testing trial, performing no greater than chance performance. Blueberry supplementation prevented recognition memory deficits after 4 months on the diets, as mice on this diet spent 67% of their time on the novel object. After 5 months on the diets, mice consuming the high-fat diet passed through the platform location less often than mice on low-fat diets during probe trials on days 2 and 3 of Morris water maze testing, whereas mice consuming the high-fat blueberry diet passed through the platform location as often as mice on the low-fat diets. This study is a first step in determining if incorporating more nutrient-dense foods into a high-fat diet can allay cognitive dysfunction.

  10. Aged mice receiving caffeine since adulthood show distinct patterns of anxiety-related behavior.

    PubMed

    Botton, Paulo Henrique S; Pochmann, Daniela; Rocha, Andreia S; Nunes, Fernanda; Almeida, Amanda S; Marques, Daniela M; Porciúncula, Lisiane O

    2017-03-01

    Caffeine is the psychostimulant most consumed worldwide. Anxiogenic effects of caffeine have been described in adult animals with controversial findings about its anxiogenic potential. Besides, the effects of caffeine on anxiety with aging are still poorly known. In this study, adult mice (6months old) started to receive caffeine (0.3 and 1.0mg/mL, drinking water) during 12-14months only in the light cycle and at weekdays. The open field (OF) and elevated plus maze (EPM) testing were used to determine the effects of caffeine on anxiety-related behavior in adult and aged mice (18-20months old). Because aging alters synaptic proteins, we also evaluated SNAP-25 (as a nerve terminals marker), GFAP (as an astrocyte marker) and adenosine A1 and A2A receptors levels in the cortex. According to the OF analysis, caffeine did not change both hypolocomotion and anxiety with aging. However, aged mice showed less anxiety behavior in the EPM, but after receiving caffeine (0.3mg/mL) during adulthood they were anxious as adult mice. While SNAP-25 and adenosine A2A receptors increased with aging, both GFAP and adenosine A1 receptors were not affected. Caffeine at moderate dose prevented the age-related increase of the SNAP-25, with no effect on adenosine A2A receptors. The absence of effect for the highest dose suggests that tolerance to caffeine may have developed over time. Aged mice showed high responsiveness to the OF, being difficult to achieve any effect of caffeine. On the other hand this substance sustained the adult anxious behavior over time in a less stressful paradigm, and this effect was coincident with changes in the SNAP-25, suggesting the involvement of this synaptic protein in the ability of caffeine to preserve changes related to emotionality with aging.

  11. Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice.

    PubMed

    Hayashi, Yoshinori; Yoshida, Masayoshi; Yamato, Mayumi; Ide, Tomomi; Wu, Zhou; Ochi-Shindou, Mayumi; Kanki, Tomotake; Kang, Dongchon; Sunagawa, Kenji; Tsutsui, Hiroyuki; Nakanishi, Hiroshi

    2008-08-20

    Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-kappaB (nuclear factor-kappaB) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1beta (IL-1beta) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1beta amount markedly increased in the brain of the TG mice after treatment with lipopolysaccharide (LPS), whereas its mean amount was significantly lower than that of the LPS-treated aged wild-type mice. At the same time, an increased mtDNA damage in microglia and an impaired hippocampal LTP were also observed in the LPS-treated aged TG mice. Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.

  12. Influence of aging on the activity of mice Sca-1+CD31− cardiac stem cells

    PubMed Central

    Pu, Shiming; Qin, Liu; Li, Yun; Zhou, Zuping

    2017-01-01

    Therapeutic application of cardiac resident stem/progenitor cells (CSC/CPCs) is limited due to decline of their regenerative potential with donor age. A variety of studies have shown that the cardiac aging was the problem of the stem cells, but little is known about the impact of age on the subgroups CSC/CPCs, the relationship between subgroups CSC/CPCs ageing and age-related dysfunction. Here, we studied Sca-1+CD31− subgroups of CSCs from younger(2~3months) and older(22~24months) age mice, biological differentiation was realized using specific mediums for 14 days to induce cardiomyocyte, smooth muscle cells or endothelial cells and immunostain analysis of differentiated cell resulting were done. Proliferation and cell cycle were measured by flow cytometry assay, then used microarray to dissect variability from younger and older mice. Although the number of CSCs was higher in older mice, the advanced age significantly reduced the differentiation ability into cardiac cell lineages and the proliferation ability. Transcriptional changes in Sca-1+CD31− subgroups of CSCs during aging are related to Vitamin B6 metabolism, circadian rhythm, Tyrosine metabolism, Complement and coagulation cascades. Taking together these results indicate that Cardiac resident stem/progenitor cells have significant differences in their proliferative, pluripotency and gene profiles and those differences are age depending. PMID:27980224

  13. Aging-related changes in respiratory system mechanics and morphometry in mice.

    PubMed

    Elliott, Jonathan E; Mantilla, Carlos B; Pabelick, Christina M; Roden, Anja C; Sieck, Gary C

    2016-07-01

    Previous work investigating respiratory system mechanics in mice has reported an aging-related increase in compliance and mean linear intercept (Lm). However, these changes were assessed using only a young (2-mo-old) and old (20- and 26-mo-old) group yet were interpreted to reflect a linear evolution across the life span. Therefore, to investigate respiratory system mechanics and lung morphometry across a more complete spectrum of ages, we utilized 2 (100% survival, n = 6)-, 6 (100% survival, n = 12)-, 18 (90% survival, n = 12)-, 24 (75% survival, n = 12)-, and 30 (25% survival, n = 12)-mo-old C57BL/6 mice. We found a nonlinear aging-related decrease in respiratory system resistance and increase in dynamic compliance and hysteresis between 2- and 24-mo-old mice. However, in 30-mo-old mice, respiratory system resistance increased, and dynamic compliance and hysteresis decreased relative to 24-mo-old mice. Respiratory system impedance spectra were measured between 1-20.5 Hz at positive end-expiratory pressures (PEEP) of 1, 3, 5, and 7 cmH2O. Respiratory system resistance and reactance at each level of PEEP were increased and decreased, respectively, only in 2-mo-old animals. No differences in the respiratory system impedance spectra were observed in 6-, 18-, 24-, and 30-mo-old mice. Additionally, lungs were fixed following tracheal instillation of 4% paraformaldehyde at 25 cmH2O and processed for Lm and airway collagen deposition. There was an aging-related increase in Lm consistent with emphysematous-like changes and no evidence of increased airway collagen deposition. Accordingly, we demonstrate nonlinear aging-related changes in lung mechanics and morphometry in C57BL/6 mice.

  14. Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice

    PubMed Central

    Xia, Chenglai; Chen, Ruihong; Chen, Jinman; Qi, Qianqian; Pan, Yanbin; Du, Lanying; Xiao, Guohong; Jiang, Shibo

    2017-01-01

    Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer. PMID:28252027

  15. Effect of Colla corii asini (E'jiao) on D-galactose induced aging mice.

    PubMed

    Wang, Dongliang; Liu, Maoxuan; Cao, Jichao; Cheng, Yanna; Zhuo, Chen; Xu, Hongyan; Tian, Shousheng; Zhang, Yan; Zhang, Jian; Wang, Fengshan

    2012-01-01

    Colla corii asini (E'jiao), donkey-hide gelatin prepared by stewing and concentrating from Equus asinus L. donkey hide, is a traditional Chinese medicine preparation widely used in clinical hematic antanemic therapy in China. The aim of the present study was to investigate potential anti-aging effect of Colla corii asini and explore related mechanisms in D-galactose (gal) induced aging model mice. The mice were artificially induced aging by subcutaneously injection with D-gal at the dose of 100 mg/kg·d for 8 weeks. Colla corii asini was simultaneously treated to them once daily by intragastric gavage. Appetite, mental condition, body weight, and organ index were observed. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as levels of malondialdehyde (MDA) in serum, brain, and liver were determined by according assay kits. Western blotting analysis was used to detect p16 and p21 expression. Results indicated that Colla corii asini could improve appetite, mental condition, body weight, and organ condition of model mice, improve SOD, CAT, and GSH-Px activities, reduce MDA levels, and modulate age-related genes expression in D-gal induced mice. Therefore, Colla corii asini may have effect to suppress the aging process through enhancing antioxidant activity, scavenging free radicals, and modulating aging-related gene expression.

  16. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    PubMed Central

    Li, Li; Xu, Meng; Shen, Bo; Li, Man; Gao, Qian; Wei, Shou-gang

    2016-01-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice. PMID:27335566

  17. Intravenous administration of piceatannol, an arginase inhibitor, improves endothelial dysfunction in aged mice

    PubMed Central

    Nguyen, Minh Cong

    2017-01-01

    Advanced age is one of the risk factors for vascular diseases that are mainly caused by impaired nitric oxide (NO) production. It has been demonstrated that endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) and limits NO generation. Hence, arginase inhibition is suggested to be vasoprotective in aging. In this study, we examined the effects of intravenous injection of Piceatannol, an arginase inhibitor, on aged mice. Our results show that Piceatannol administration reduced the blood pressure in aged mice by inhibiting arginase activity, which was associated with NO production and reactive oxygen species generation. In addition, Piceatannol administration recovered Ca2+/calmodulin-dependent protein kinase II phosphorylation, eNOS phosphorylation and eNOS dimer stability in the aged mice. The improved NO signaling was shown to be effective in attenuating the phenylephrine-dependent contractile response and in enhancing the acetylcholine-dependent vasorelaxation response in aortic rings from the aged mice. These data suggest Piceatannol as a potential treatment for vascular disease. PMID:28066144

  18. Polysaccharide Extracted from Laminaria japonica Delays Intrinsic Skin Aging in Mice

    PubMed Central

    Hu, Longyuan; Tan, Jia; Yang, Xiaomei; Tan, Haitao; Xu, Xiaozhen; You, Manhang; Qin, Wu; Huang, Liangzhao; Li, Siqi; Mo, Manqiu; Wei, Huifen; Li, Jing; Tan, Jiyong

    2016-01-01

    This study aimed to determine the effect of topically applied Laminaria polysaccharide (LP) on skin aging. We applied ointment containing LP (10, 25, and 50 μg/g) or vitamin E (10 μg/g) to the dorsal skin of aging mice for 12 months and young control mice for 4 weeks. Electron microscopy analysis of skin samples revealed that LP increased dermal thickness and skin collagen content. Tissue inhibitor of metalloprotease- (TIMP-) 1 expression was upregulated while that of matrix metalloproteinase- (MMP-) 1 was downregulated in skin tissue of LP-treated as compared to untreated aging mice. Additionally, phosphorylation of c-Jun N-terminal kinase (JNK) and p38 was higher in aging skin than in young skin, while LP treatment suppressed phospho-JNK expression. LP application also enhanced the expression of antioxidative enzymes in skin tissue, causing a decrease in malondialdehyde levels and increases in superoxide dismutase, catalase, and glutathione peroxidase levels relative to those in untreated aging mice. These results indicate that LP inhibits MMP-1 expression by preventing oxidative stress and JNK phosphorylation, thereby delaying skin collagen breakdown during aging. PMID:27143987

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  20. Age-related changes in the bone marrow and spleen of SAS/4 mice.

    PubMed

    Coggle, J E; Gordon, M Y; Proukakis, C; Bogg, C E

    1975-01-01

    The total number of nucleated cells in the bone marrow of SAS/4 mice increase some twofold between 1 and 24 months of age but when related to body weight remains essentially constant over a wide range of ages. The concentration of CFU-S in femoral marrow is also constant with age and since other bones containing marrow appear, at least in young mice, to have the same CFU-S concentration as the femur it is concluded that the CFU-S compartment size of the whole bone marrow is independent of age when expressed on a body weight basis, In contrast, both the absolute number and the concentration of exogenous CFU-S in the spleen decline markedly in old mice. Smilary there is a decline in the number of endogenous colony-forming cells and the spleens of 24-month-old mice seem virtually devoid of such colonies. Not only were older mice less capable of supporting the growth of endogenous colonies, but their spleens also appear to provide a poorer environment for exogenous colony growth when compared with growth in younger recipient spleens.

  1. The nigrostriatal dopamine system of aging GFRalpha-1 heterozygous mice: neurochemistry, morphology and behavior.

    PubMed

    Zaman, Vandana; Boger, Heather A; Granholm, Ann-Charlotte; Rohrer, Baerbel; Moore, Alfred; Buhusi, Mona; Gerhardt, Greg A; Hoffer, Barry J; Middaugh, Lawrence D

    2008-10-01

    Given the established importance of glial cell line-derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high-affinity receptor, GDNF receptor (GFR)alpha-1 (GFRalpha-1(+/-)), were compared with wild-type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRalpha-1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRalpha-1(+/-) mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRalpha-1(+/-) mice. DA in the striatum was reduced in the GFRalpha-1(+/-) mice at both ages, and tyrosine hydroxylase-positive cell numbers in the SN were reduced most substantially in the older GFRalpha-1(+/-) mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRalpha-1(+/-) mice that are indicative of an exacerbated aging-related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRalpha-1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging-related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRalpha-1 can contribute to the degenerative changes observed in this system during the aging process.

  2. Food restriction increases long-term memory persistence in adult or aged mice.

    PubMed

    Talhati, F; Patti, C L; Zanin, K A; Lopes-Silva, L B; Ceccon, L M B; Hollais, A W; Bizerra, C S; Santos, R; Tufik, S; Frussa-Filho, R

    2014-04-03

    Food restriction (FR) seems to be the unique experimental manipulation that leads to a remarkable increase in lifespan in rodents. Evidences have suggested that FR can enhance memory in distinct animal models mainly during aging. However, only few studies systemically evaluated the effects FR on memory formation in both adult (3-month-old) and aged (18-24-month-old) mice. Thus, the aim of the present study was to investigate the effects of acute (12h) or repeated (12h/day for 2days) FR protocols on learning and memory of adult and aged mice evaluated in the plus-maze discriminative avoidance task (PM-DAT), an animal model that concurrently (but independently) evaluates learning and memory, anxiety and locomotion. We also investigated the possible role of FR-induced stress by the corticosterone concentration in adult mice. Male mice were kept at home cage with food ad libitum (CTRL-control condition) or subjected to FR during the dark phase of the cycle for 12h/day or 12h/2days. The FR protocols were applied before training, immediately after it or before testing. Our results demonstrated that only FR for 2days enhanced memory persistence when applied before training in adults and before testing in aged mice. Conversely, FR for 2days impaired consolidation and exerted no effects on retrieval irrespective of age. These effects do not seem to be related to corticosterone concentration. Collectively, these results indicate that FR for 2days can promote promnestic effects not only in aged mice but also in adults.

  3. Characterisation of Age-Dependent Beta Cell Dynamics in the Male db/db Mice

    PubMed Central

    Dalbøge, Louise S.; Almholt, Dorthe L. C.; Neerup, Trine S. R.; Vassiliadis, Efstathios; Vrang, Niels; Pedersen, Lars; Fosgerau, Keld; Jelsing, Jacob

    2013-01-01

    Aim To characterise changes in pancreatic beta cell mass during the development of diabetes in untreated male C57BLKS/J db/db mice. Methods Blood samples were collected from a total of 72 untreated male db/db mice aged 5, 6, 8, 10, 12, 14, 18, 24 and 34 weeks, for measurement of terminal blood glucose, HbA1c, plasma insulin, and C-peptide. Pancreata were removed for quantification of beta cell mass, islet numbers as well as proliferation and apoptosis by immunohistochemistry and stereology. Results Total pancreatic beta cell mass increased significantly from 2.1 ± 0.3 mg in mice aged 5 weeks to a peak value of 4.84 ± 0.26 mg (P < 0.05) in 12-week-old mice, then gradually decreased to 3.27 ± 0.44 mg in mice aged 34 weeks. Analysis of islets in the 5-, 10-, and 24-week age groups showed increased beta cell proliferation in the 10-week-old animals whereas a low proliferation is seen in older animals. The expansion in beta cell mass was driven by an increase in mean islet mass as the total number of islets was unchanged in the three groups. Conclusions/Interpretation The age-dependent beta cell dynamics in male db/db mice has been described from 5-34 weeks of age and at the same time alterations in insulin/glucose homeostasis were assessed. High beta cell proliferation and increased beta cell mass occur in young animals followed by a gradual decline characterised by a low beta cell proliferation in older animals. The expansion of beta cell mass was caused by an increase in mean islet mass and not islet number. PMID:24324833

  4. Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice

    PubMed Central

    Jensen, Cathy Joanna; Demol, Frauke; Bauwens, Romy; Kooijman, Ron; Massie, Ann; Villers, Agnès; Ris, Laurence; De Keyser, Jacques

    2016-01-01

    In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox) and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2). Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment) test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle) administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP) was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function. PMID:27776147

  5. Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development.

    PubMed

    Song, Zhongchen; Liu, Chao; Iwata, Junichi; Gu, Shuping; Suzuki, Akiko; Sun, Cheng; He, Wei; Shu, Rong; Li, Lu; Chai, Yang; Chen, YiPing

    2013-04-12

    Cleft palate represents one of the most common congenital birth defects in humans. TGFβ signaling, which is mediated by Smad-dependent and Smad-independent pathways, plays a crucial role in regulating craniofacial development and patterning, particularly in palate development. However, it remains largely unknown whether the Smad-independent pathway contributes to TGFβ signaling function during palatogenesis. In this study, we investigated the function of TGFβ activated kinase 1 (Tak1), a key regulator of Smad-independent TGFβ signaling in palate development. We show that Tak1 protein is expressed in both the epithelium and mesenchyme of the developing palatal shelves. Whereas deletion of Tak1 in the palatal epithelium or mesenchyme did not give rise to a cleft palate defect, inactivation of Tak1 in the neural crest lineage using the Wnt1-Cre transgenic allele resulted in failed palate elevation and subsequently the cleft palate formation. The failure in palate elevation in Wnt1-Cre;Tak1(F/F) mice results from a malformed tongue and micrognathia, resembling human Pierre Robin sequence cleft of the secondary palate. We found that the abnormal tongue development is associated with Fgf10 overexpression in the neural crest-derived tongue tissue. The failed palate elevation and cleft palate were recapitulated in an Fgf10-overexpressing mouse model. The repressive effect of the Tak1-mediated noncanonical TGFβ signaling on Fgf10 expression was further confirmed by inhibition of p38, a downstream kinase of Tak1, in the primary cell culture of developing tongue. Tak1 thus functions to regulate tongue development by controlling Fgf10 expression and could represent a candidate gene for mutation in human PRS clefting.

  6. Age-dependent effects of UCP2 deficiency on experimental acute pancreatitis in mice.

    PubMed

    Müller, Sarah; Kaiser, Hannah; Krüger, Burkhard; Fitzner, Brit; Lange, Falko; Bock, Cristin N; Nizze, Horst; Ibrahim, Saleh M; Fuellen, Georg; Wolkenhauer, Olaf; Jaster, Robert

    2014-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of acute pancreatitis (AP) for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2)-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively) triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO) in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT) C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively), suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies) and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies) were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.

  7. Mice expressing reduced levels of hepatic glucose-6-phosphatase-α activity do not develop age-related insulin resistance or obesity.

    PubMed

    Kim, Goo-Young; Lee, Young Mok; Cho, Jun-Ho; Pan, Chi-Jiunn; Jun, Hyun Sik; Springer, Danielle A; Mansfield, Brian C; Chou, Janice Y

    2015-09-15

    Glycogen storage disease type-Ia (GSD-Ia) is caused by a lack of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. We have shown that gene therapy mediated by a recombinant adeno-associated virus (rAAV) vector expressing human G6Pase-α normalizes blood glucose homeostasis in the global G6pc knockout (G6pc(-/-)) mice for 70-90 weeks. The treated G6pc(-/-) mice expressing 3-63% of normal hepatic G6Pase-α activity (AAV mice) produce endogenous hepatic glucose levels 61-68% of wild-type littermates, have a leaner phenotype and exhibit fasting blood insulin levels more typical of young adult mice. We now show that unlike wild-type mice, the lean AAV mice have increased caloric intake and do not develop age-related obesity or insulin resistance. Pathway analysis shows that signaling by hepatic carbohydrate response element binding protein that improves glucose tolerance and insulin signaling is activated in AAV mice. In addition, several longevity factors in the calorie restriction pathway, including the NADH shuttle systems, NAD(+) concentrations and the AMP-activated protein kinase/sirtuin 1/peroxisome proliferator-activated receptor-γ coactivator 1α pathway are upregulated in the livers of AAV mice. The finding that partial restoration of hepatic G6Pase-α activity in GSD-Ia mice not only attenuates the phenotype of hepatic G6Pase-α deficiency but also prevents the development of age-related obesity and insulin resistance seen in wild-type mice may suggest relevance of the G6Pase-α enzyme to obesity and diabetes.

  8. Behavioural Phenotyping of APPswe/PS1δE9 Mice: Age-Rrelated Changes and Effect of Long-Term Paroxetine Treatment.

    PubMed

    Olesen, Louise Ørum; Bouzinova, Elena V; Severino, Maurizio; Sivasaravanaparan, Mithula; Hasselstrøm, Jørgen Bo; Finsen, Bente; Wiborg, Ove

    2016-01-01

    Alzheimer's disease (AD) is a devastating illness characterized by a progressive loss of cognitive, social, and emotional functions, including memory impairments and more global cognitive deficits. Clinical-epidemiological evidence suggests that neuropsychiatric symptoms precede the onset of cognitive symptoms both in humans with early and late onset AD. The behavioural profile promoted by the AD pathology is believed to associate with degeneration of the serotonergic system. Using the APPswe/PS1δE9 model of AD-like pathology starting with 9 months old mice, we characterised long term non-cognitive behavioural changes measured at 9, 12, 15, and 18 months of age and applied principal component analysis on data obtained from open field, elevated plus maze, and social interaction tests. Long-term treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine was applied to assess the role of 5-HT on the behavioural profile; duration of treatment was 9 months, initiated when mice were 9 months of age. Treatment with paroxetine delays the decline in locomotion, in exploration and risk assessment behaviour, found in the APP/PS1 mice. APP/PS1 mice also exhibit low social activity and less aggressiveness, both of which are not affected by treatment with paroxetine. The APP/PS1 behavioural phenotype, demonstrated in this study, only begins to manifest itself from 12 months of age. Our results indicate that treatment with SSRI might ameliorate some of the behavioural deficits found in aged APP/PS1 mice.

  9. Caloric restriction preserves memory and reduces anxiety of aging mice with early enhancement of neurovascular functions

    PubMed Central

    Parikh, Ishita; Guo, Janet; Chuang, Kai-Hsiang; Zhong, Yu; Rempe, Ralf G.; Hoffman, Jared D.; Armstrong, Rachel; Bauer, Björn; Hartz, Anika M.S.; Lin, Ai-Ling

    2016-01-01

    Neurovascular integrity plays an important role in protecting cognitive and mental health in aging. Lifestyle interventions that sustain neurovascular integrity may thus be critical on preserving brain functions in aging and reducing the risk for age-related neurodegenerative disorders. Here we show that caloric restriction (CR) had an early effect on neurovascular enhancements, and played a critical role in preserving vascular, cognitive and mental health in aging. In particular, we found that CR significantly enhanced cerebral blood flow (CBF) and blood-brain barrier function in young mice at 5-6 months of age. The neurovascular enhancements were associated with reduced mammalian target of rapamycin expression, elevated endothelial nitric oxide synthase signaling, and increased ketone bodies utilization. With age, CR decelerated the rate of decline in CBF. The preserved CBF in hippocampus and frontal cortex were highly correlated with preserved memory and learning, and reduced anxiety, of the aging mice treated with CR (18-20 months of age). Our results suggest that dietary intervention started in the early stage (e.g., young adults) may benefit cognitive and mental reserve in aging. Understanding nutritional effects on neurovascular functions may have profound implications in human brain aging and age-related neurodegenerative disorders. PMID:27829242

  10. Voluntary Wheel Running Does not Affect Lipopolysaccharide-Induced Depressive-Like Behavior in Young Adult and Aged Mice

    PubMed Central

    Martin, Stephen A.; Dantzer, Robert; Kelley, Keith W.; Woods, Jeffrey A.

    2014-01-01

    Peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes prolonged depressive-like behavior in aged mice that is dependent on indoleamine 2,3 dioxygenase (IDO) activation. Regular moderate intensity exercise training has been shown to exert neuroprotective effects that might reduce depressive-like behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced depressive-like behavior and brain IDO gene expression in 4-month-old and 22-month-old C57BL/6J mice. Mice were housed with a running wheel (Voluntary Wheel Running, VWR) or no wheel (Standard) for 30 days (young adult mice) or 70 days (aged mice), after which they were intraperitoneally injected with LPS (young adult mice: 0.83 mg/kg; aged mice: 0.33 mg/kg). Young adult VWR mice ran on average 6.9 km/day, while aged VWR mice ran on average 3.4 km/day. Both young adult and aged VWR mice increased their forced exercise tolerance compared to their respective Standard control groups. VWR had no effect on LPS-induced anorexia, weight-loss, increased immobility in the tail suspension test, and decreased sucrose preference in either young adult or aged mice. Four (young adult mice) and twenty-four (aged mice) hours after injection of LPS transcripts for TNF-α, IL-1β, IL-6, and IDO were upregulated in the whole brain independently of VWR. These results indicate that prolonged physical exercise has no effect on the neuroinflammatory response to LPS and its behavioral consequences. PMID:24281669

  11. Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice.

    PubMed

    Sato, Seidai; Kawamata, Yuka; Takahashi, Akiko; Imai, Yoshinori; Hanyu, Aki; Okuma, Atsushi; Takasugi, Masaki; Yamakoshi, Kimi; Sorimachi, Hiroyuki; Kanda, Hiroaki; Ishikawa, Yuichi; Sone, Saburo; Nishioka, Yasuhiko; Ohtani, Naoko; Hara, Eiji

    2015-04-29

    The p16(INK4a) tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing. However, since p16(INK4a) knockout mice die prematurely from cancer, whether p16(INK4a) reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the α-klotho ageing-suppressor gene (kl(kl/kl)), accelerated ageing phenotypes are rescued by p16(INK4a) ablation. Surprisingly, this is due to the restoration of α-klotho expression in kl(kl/kl) mice and does not occur when p16(INK4a) is ablated in α-klotho knockout mice (kl(-/-)), suggesting that p16(INK4a) is an upstream regulator of α-klotho expression. Indeed, p16(INK4a) represses α-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16(INK4a) are inversely correlated with those of α-klotho throughout ageing, indicate that p16(INK4a) plays a previously unrecognized role in downregulating α-klotho expression during ageing.

  12. Regular and Moderate Exercise Counteracts the Decline of Antioxidant Protection but Not Methylglyoxal-Dependent Glycative Burden in the Ovary of Reproductively Aging Mice

    PubMed Central

    Cordone, V.; Grannonico, M.; Cacchio, M.

    2016-01-01

    Population aging results in urgent needs of interventions aimed at ensuring healthy senescence. Exercise often results in healthy aging, yet many molecular mechanisms underlying such effects still need to be identified. We here investigated whether the age-dependent accumulation of oxidative and methylglyoxal- (MG-) related molecular damage could be delayed by moderate exercise in the mouse ovary, an organ that first exhibits impaired function with advancing age in mammals. CD1 female mice underwent two- or four-month treadmill-based running through the transition from adult to middle age, when ovaries show signs of senescence, and markers of protection against reactive oxygen species (ROS) and MG were measured. The long-term exercise reduced the protein oxidative damage in the ovaries (P < 0.01), and this was linked to the preservation of the glutathione peroxidase protection against ROS (P < 0.001), as well as to the increased glutathione availability (P < 0.001). Conversely, even though the age-related deactivation of the MG-targeting systems was partially prevented by the long-term running programme (P < 0.001), exercised mice were not protected from the age-dependent glycative burden. In summary, lately initiated regular and moderate exercise limited some changes occurring in the ovaries of middle-aged mice, and this might help to develop nonpharmacological cointerventions to reduce the vulnerability of mammalian ovaries towards redox dysfunctions. PMID:28116035

  13. Differential peptidomics assessment of strain and age differences in mice in response to acute cocaine administration.

    PubMed

    Romanova, Elena V; Rubakhin, Stanislav S; Ossyra, John R; Zombeck, Jonathan A; Nosek, Michael R; Sweedler, Jonathan V; Rhodes, Justin S

    2015-12-01

    Neurochemical differences in the hypothalamic-pituitary axis between individuals and between ages may contribute to differential susceptibility to cocaine abuse. This study measured peptide levels in the pituitary gland (Pit) and lateral hypothalamus (LH) in adolescent (age 30 days) and adult (age 65 days) mice from four standard inbred strains, FVB/NJ, DBA/2J, C57BL/6J, and BALB/cByJ, which have previously been characterized for acute locomotor responses to cocaine. Individual peptide profiles were analyzed using mass spectrometric profiling and principal component analysis. Sequences of assigned peptides were verified by tandem mass spectrometry. Principal component analysis classified all strains according to their distinct peptide profiles in Pit samples from adolescent mice, but not adults. Select pro-opiomelanocortin-derived peptides were significantly higher in adolescent BALB/cByJ and DBA/2J mice than in FVB/NJ or C57BL/6J mice. A subset of peptides in the LH, but not in the Pit, was altered by cocaine in adolescents. A 15 mg/kg dose of cocaine induced greater peptide alterations than a 30 mg/kg dose, particularly in FVB/NJ animals, with larger differences in adolescents than adults. Neuropeptides in the LH affected by acute cocaine administration included pro-opiomelanocortin-, myelin basic protein-, and glutamate transporter-derived peptides. The observed peptide differences could contribute to differential behavioral sensitivity to cocaine among strains and ages. Peptides were measured using mass spectrometry (MALDI-TOF) in individual lateral hypothalamus and pituitary samples from four strains and two ages of inbred mice in response to acute cocaine administration. Principal component analyses (PCA) classified the strains according to their peptide profiles from adolescent mice, and a subset of peptides in the lateral hypothalamus was altered by cocaine in adolescents.

  14. Sex and age differences in mercury distribution and excretion in methylmercury-administered mice

    SciTech Connect

    Hirayama, K.; Yasutake, A.

    1986-01-01

    Sex differences in mercury distribution and excretion after single administration of methylmercury chloride (MMC, 5 mg/kg were studied in mice. A sex difference in urinary mercury excretion was found in sexually mature mice (age of 7 wk) of C57BL/6N and BALB/cA strains. Males showed higher mercury levels in urine than females, though no significant difference was found in fecal mercury levels 24 h post exposure to MMC. The higher urinary excretion rates in males accounted for significant lowering of mercury levels in the brain, liver, and blood, but not in the kidney, which showed higher values. At 5 min, however, the sex difference was found only in the kidney, showing higher levels in males. Changes in mercury distribution with time were studied in C57BL/6N mice. The brain mercury increased in both sexes up to 3 d, and decreased only in males on d 5. Liver and blood mercury decreased with time in both sexes, and these were constantly higher in females than in males. Renal mercury in males decreased to similar levels to females on d 3. The sex differences at various ages were studied with C57BL/6N mice 24 h after dosing. Two-week-old mice did not show significant sex differences in the mercury distribution and excretion, and their urinary mercury levels were much lower as compared to the older mice. Urinary mercury excretion in both sexes increased at 4 wk of age and then decreased at 45 wk of age. At 4, 7, 10, and 45 wk of age, males showed higher urinary mercury levels than females. From these findings, it has been suggested that urinary mercury excretion may be related to sex hormones, especially androgens.

  15. Lack of exercise leads to significant and reversible loss of scale invariance in both aged and young mice

    PubMed Central

    Gu, Changgui; Coomans, Claudia P.; Hu, Kun; Scheer, Frank A. J. L.; Stanley, H. Eugene; Meijer, Johanna H.

    2015-01-01

    In healthy humans and other animals, behavioral activity exhibits scale invariance over multiple timescales from minutes to 24 h, whereas in aging or diseased conditions, scale invariance is usually reduced significantly. Accordingly, scale invariance can be a potential marker for health. Given compelling indications that exercise is beneficial for mental and physical health, we tested to what extent a lack of exercise affects scale invariance in young and aged animals. We studied six or more mice in each of four age groups (0.5, 1, 1.5, and 2 y) and observed an age-related deterioration of scale invariance in activity fluctuations. We found that limiting the amount of exercise, by removing the running wheels, leads to loss of scale-invariant properties in all age groups. Remarkably, in both young and old animals a lack of exercise reduced the scale invariance in activity fluctuations to the same level. We next showed that scale invariance can be restored by returning the running wheels. Exercise during the active period also improved scale invariance during the resting period, suggesting that activity during the active phase may also be beneficial for the resting phase. Finally, our data showed that exercise had a stronger influence on scale invariance than the effect of age. The data suggest that exercise is beneficial as revealed by scale-invariant parameters and that, even in young animals, a lack of exercise leads to strong deterioration in these parameters. PMID:25675516

  16. Effects of rhein lysinate on D-galactose-induced aging mice

    PubMed Central

    ZHEN, YONG-ZHAN; LIN, YA-JUN; LI, KAI-JI; ZHANG, GUANG-LING; ZHAO, YU-FANG; WANG, MEI-MEI; WEI, JING-BO; WEI, JIE; HU, GANG

    2016-01-01

    The aim of the present study was to investigate the anti-aging effects of rhein lysinate (RHL), and to explore its mechanism of action in a D-galactose-induced aging mouse model. Aging was induced by D-galactose (100 mg/kg/day) that was subcutaneously injected to animals for 8 weeks. RHL was simultaneously administered once a day by intragastric gavage. The appetite, mental condition, body weight and organ index of the mice were monitored. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were determined, and the levels of malondialdehyde (MDA) in the liver, kidney and serum were measured by appropriate assay kits. Western blot analysis was used to detect proteins associated with age. The results indicated that RHL may improve the appetite, mental state and organ conditions of the model mice, improve the activities of SOD and GSH-Px, reduce MDA levels and modulate the expression of age-associated proteins (Sirtuin 1, p21 and p16) in D-galactose-induced mice. Therefore, RHL may be effective at suppressing the aging process through a combination of enhancing antioxidant activity, scavenging free radicals and modulating aging-associated gene expression. PMID:26889258

  17. Mathematical modeling of left ventricular dimensional changes in mice during aging

    PubMed Central

    2012-01-01

    Cardiac aging is characterized by diastolic dysfunction of the left ventricle (LV), which is due in part to increased LV wall stiffness. In the diastolic phase, myocytes are relaxed and extracellular matrix (ECM) is a critical determinant to the changes of LV wall stiffness. To evaluate the effects of ECM composition on cardiac aging, we developed a mathematical model to predict LV dimension and wall stiffness changes in aging mice by integrating mechanical laws and our experimental results. We measured LV dimension, wall thickness, LV mass, and collagen content for wild type (WT) C57/BL6J mice of ages ranging from 7.3 months to those of 34.0 months. The model was established using the thick wall theory and stretch-induced tissue growth to an isotropic and homogeneous elastic composite with mixed constituents. The initial conditions of the simulation were set based on the data from the young mice. Matlab simulations of this mathematical model demonstrated that the model captured the major features of LV remodeling with age and closely approximated experimental results. Specifically, the temporal progression of the LV interior and exterior dimensions demonstrated the same trend and order-of-magnitude change as our experimental results. In conclusion, we present here a validated mathematical model of cardiac aging that applies the thick-wall theory and stretch-induced tissue growth to LV remodeling with age. PMID:23281647

  18. Procognitive effect of AC-3933 in aged mice, and synergistic effect of combination with donepezil in scopolamine-treated mice.

    PubMed

    Hashimoto, Takashi; Hatayama, Yuki; Nakamichi, Keiko; Yoshida, Naoyuki

    2014-12-15

    We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer׳s disease.

  19. Pathobiology of aging mice and GEM: background strains and experimental design.

    PubMed

    Brayton, C F; Treuting, P M; Ward, J M

    2012-01-01

    The use of induced and spontaneous mutant mice and genetically engineered mice (and combinations thereof) to study cancers and other aging phenotypes to advance improved functional human life spans will involve studies of aging mice. Genetic background contributes to pathology phenotypes and to causes of death as well as to longevity. Increased recognition of expected phenotypes, experimental variables that influence phenotypes and research outcomes, and experimental design options and rationales can maximize the utility of genetically engineered mice (GEM) models to translational research on aging. This review aims to provide resources to enhance the design and practice of chronic and longevity studies involving GEM. C57BL6, 129, and FVB/N strains are emphasized because of their widespread use in the generation of knockout, transgenic, and conditional mutant GEM. Resources are included also for pathology of other inbred strain families, including A, AKR, BALB/c, C3H, C57L, C58, CBA, DBA, GR, NOD.scid, SAMP, and SJL/J, and non-inbred mice, including 4WC, AB6F1, Ames dwarf, B6, 129, B6C3F1, BALB/c,129, Het3, nude, SENCAR, and several Swiss stocks. Experimental strategies for long-term cross-sectional and longitudinal studies to assess causes of or contributors to death, disease burden, spectrum of pathology phenotypes, longevity, and functional healthy life spans (health spans) are compared and discussed.

  20. Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice.

    PubMed

    Peferoen, Laura A N; Breur, Marjolein; van de Berg, Sarah; Peferoen-Baert, Regina; Boddeke, Erik H W G M; van der Valk, Paul; Pryce, Gareth; van Noort, Johannes M; Baker, David; Amor, Sandra

    2016-10-01

    Current therapies for multiple sclerosis (MS) reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice recapitulates clinical features of MS including relapsing-remitting episodes and secondary-progressive disability. To address the contribution of recurrent inflammatory events and ageing as factors that amplify progressive neurological disease, we examined EAE in 8- to 12-week-old and 12-month-old ABH mice. Compared with the relapsing-remitting (RREAE) and secondary progressive (SPEAE) EAE observed in young mice, old mice developed progressive disease from onset (PEAE) associated with pronounced axonal damage and increased numbers of CD3(+) T cells and microglia/macrophages, but not B cells. Whereas the clinical neurological features of PEAE and SPEAE were comparable, the pathology was distinct. SPEAE was associated with significantly reduced perivascular infiltrates and T-cell numbers in the central nervous system (CNS) compared with PEAE and the acute phase of RREAE. In contrast to perivascular infiltrates that declined during progression from RREAE into SPEAE, the numbers of microglia clusters remained constant. Similar to what is observed during MS, the microglia clusters emerging during EAE were associated with axonal damage and oligodendrocytes expressing heat-shock protein B5, but not lymphocytes. Taken together, our data reveal that the course of EAE is dependent on the age of the mice. Younger mice show a relapsing-remitting phase followed by progressive disease, whereas old mice immediately show progression. This indicates that recurrent episodes of inflammation in the CNS, as well as age, contribute to progressive neurological disease.

  1. Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy.

    PubMed

    Brown, Karen L; Mabbott, Neil A

    2014-01-01

    The occurrence of variant Creutzfeldt-Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain. Following peripheral exposure, many prions replicate within the lymphoid tissues before infecting the central nervous system. We have shown that the effects of host age on the microarchitecture of the spleen significantly impair susceptibility to mouse-adapted prions after peripheral exposure. The transmission of prions between different mammalian species is considered to be limited by the 'species barrier', which is dependent on several factors, including an intact immune system. Thus, cross-species prion transmission may be much less efficient in aged individuals. To test this hypothesis, we compared prion pathogenesis in groups of young (6-8 weeks old) and aged (600 days old) mice injected with primary BSE brain homogenate. We showed that prion pathogenesis was impaired dramatically in aged mice when compared with young animals. Whereas most young mice succumbed to clinical prion disease, all aged mice failed to develop clinical disease during their lifespans. However, the demonstration that prion accumulation was detected in the lymphoid tissues of some aged mice after injection with primary BSE brain homogenate, in the absence of clinical signs of prion disease, has important implications for human health.

  2. Chronic Oral Estrogen Affects Memory and Neurochemistry in Middle-Aged Female Mice

    PubMed Central

    Fernandez, Stephanie M.; Frick, Karyn M.

    2006-01-01

    This study tested whether chronic oral estrogen could improve memory and alter neural plasticity in the hippocampus and neocortex of middle-aged female mice. Ovariectomized C57BL/6 mice were administered 1,000, 1,500, or 2,500 nM 17β-estradiol in drinking water for 5 weeks prior to and during spatial and object memory testing. Synaptophysin, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels were then measured in hippocampus and neocortex. The medium dose impaired spatial reference memory in the radial-arm maze, whereas all doses improved object recognition. The high dose increased hippocampal synaptophysin and NGF levels, whereas the medium dose decreased these neocortical levels. The high dose decreased neocortical BDNF levels. These data suggest that chronic oral estrogen selectively affects memory and neural function in middle-aged female mice. PMID:15598143

  3. Effect of chronic piracetam on age-related changes of cross-maze exploration in mice.

    PubMed

    Salimov, R; Salimova, N; Shvets, L; Shvets, N

    1995-11-01

    Normal aging is known to deteriorate memory, spatial orientation, and perceptual recognition. Experiment 1 examined behavioral manifestations of aging by using a cross-maze exploration test in 2-, 6-, and 10-month-old hybrid mice (CBA x C57BL). A decrease in explorative patrolling and an increase in arm reentries, a latency to start and a total time of exploration were found in 10-month-old mice. In Experiment 2, administration of the cognition enhancer piracetam (2-oxo-1-pirrolidone acetamide) (400 mg/kg, IP, once a day for 10 days) enhanced arm patrolling and decreased reentries in 10-month-old mice to the level displayed by the 2-month-old animals. The results suggest that the cross-maze test may be useful for a preliminary screening of antisenescent drugs.

  4. Early maternal separation impacts cognitive flexibility at the age of first independence in mice.

    PubMed

    Thomas, A Wren; Caporale, Natalia; Wu, Claudia; Wilbrecht, Linda

    2016-04-01

    Early life adversity is associated with increased risk for mental and physical health problems, including substance abuse. Changes in neural development caused by early life insults could cause or complicate these conditions. Maternal separation (MS) is a model of early adversity for rodents. Clear effects of MS have been shown on behavioral flexibility in rats, but studies of effects of MS on cognition in mice have been mixed. We hypothesized that previous studies focused on adult mice may have overlooked a developmental transition point when juvenile mice exhibit greater flexibility in reversal learning. Here, using a 4-choice reversal learning task we find that early MS leads to decreased flexibility in post-weaning juvenile mice, but no significant effects in adults. In a further study of voluntary ethanol consumption, we found that adult mice that had experienced MS showed greater cumulative 20% ethanol consumption in an intermittent access paradigm compared to controls. Our data confirm that the MS paradigm can reduce cognitive flexibility in mice and may enhance risk for substance abuse. We discuss possible interpretations of these data as stress-related impairment or adaptive earlier maturation in response to an adverse environment.

  5. Identification of morphological markers of sarcopenia at early stage of aging in skeletal muscle of mice.

    PubMed

    Sayed, Ramy K A; de Leonardis, Erika Chacin; Guerrero-Martínez, José A; Rahim, Ibtissem; Mokhtar, Doaa M; Saleh, Abdelmohaimen M; Abdalla, Kamal E H; Pozo, María J; Escames, Germaine; López, Luis C; Acuña-Castroviejo, Darío

    2016-10-01

    The gastrocnemius muscle (GM) of young (3months) and aged (12months) female wild-type C57/BL6 mice was examined by light and electron microscopy, looking for the presence of structural changes at early stage of the aging process. Morphometrical parameters including body and gastrocnemius weights, number and type of muscle fibers, cross section area (CSA), perimeter, and Feret's diameter of single muscle fiber, were measured. Moreover, lengths of the sarcomere, A-band, I-band, H-zone, and number and CSA of intermyofibrillar mitochondria (IFM), were also determined. The results provide evidence that 12month-old mice had significant changes on skeletal muscle structure, beginning with the reduction of gastrocnemius weight to body weight ratio, compatible with an early loss of skeletal muscle function and strength. Moreover, light microscopy revealed increased muscle fibers size, with a significant increase on their CSA, perimeter, and diameter of both type I and type II muscle fibers, and a reduction in the percentage of muscle area occupied by type II fibers. Enhanced connective tissue infiltrations, and the presence of centrally nucleated muscle fibers, were also found in aged mice. These changes may underlie an attempt to compensate the loss of muscle mass and muscle fibers number. Furthermore, electron microscopy discovered a significant age-dependent increase in the length of sarcomeres, I and H bands, and reduction on the overlapped actin/myosin length, supporting contractile force loss with age. Electron microscopy also showed an increased number and CSA of IFM with age, which may reveal more endurance at 12months of age. Together, mice at early stage of aging already show significant changes in gastrocnemius muscle morphology and ultrastructure that are suggestive of the onset of sarcopenia.

  6. A study of axonal degeneration in the optic nerves of aging mice

    NASA Technical Reports Server (NTRS)

    Johnson, J. E., Jr.; Philpott, D. E.; Miquel, J.

    1978-01-01

    The optic nerves of C57BL/6J mice ranging from 3 to 30 months were examined by electron microscopy. At all ages investigated, optic nerve axons contained enlarged mitochondria with abnormal cristae. With increasing age, a large number of necrotic axons were observed and were in the process of being phagocytized. The abnormal mitochondria may represent preliminary changes that eventually lead to necrosis of the axon.

  7. 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

  8. Characteristics of bone marrow-derived endothelial progenitor cells in aged mice

    SciTech Connect

    Zhang Wei; Zhang Guoping; Jin Huiming . E-mail: hmjin@shmu.edu.cn; Hu Renming

    2006-09-29

    Evidence for dysfunction of endothelial repair in aged mice was sought by studying the pattern of induced differentiation, quantity, and function of bone marrow-derived endothelial progenitor cells (EPCs) in aged mice. The CD117-positive stem cell population was separated from bone marrow by magnetic activated cell-sorting system (MACS), and EPCs were defined by demonstrating the expression of CD117{sup +}CD34{sup +}Flk-1{sup +} by flow cytometry. After 7 days of culture, the number of clones formed was counted, and proliferation and migration of EPCs were analyzed by MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and modified Boyden chamber assay. The results demonstrated that compared to the control group, the quantity of bone marrow-derived CD117{sup +} stem cells and EPCs, as well as the proliferation, migration, the number of clones formed, and phagocytotic function of EPCs were significantly reduced in aged mice. There were no significant differences in the morphology and induced differentiation pattern of EPCs between the aged mouse group and the control group. Authors suggest that the dysfunction of EPCs may serve as a surrogate parameter of vascular function in old mice.

  9. Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

    PubMed

    Ali, Amira A H; Schwarz-Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-06-01

    Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (Bmal1(-/-)) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1(-/-) mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1(-/-) mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70 kDa and expression of the cell cycle inhibitor p21(Waf1/CIP1) were increased in adult Bmal1(-/-) mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

  10. Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice

    PubMed Central

    Zhang, Yiqiang; Fischer, Kathleen E.; Soto, Vanessa; Liu, Yuhong; Sosnowska, Danuta; Richardson, Arlan; Salmon, Adam B.

    2015-01-01

    Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality leading some to suggest this represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased in high fat-fed mice as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process. PMID:25558793

  11. Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

    PubMed Central

    Bobkova, Natalia V.; Evgen’ev, Mikhail; Garbuz, David G.; Kulikov, Alexei M.; Morozov, Alexei; Samokhin, Alexander; Velmeshev, Dmitri; Medvinskaya, Natalia; Nesterova, Inna; Pollock, Andrew; Nudler, Evgeny

    2015-01-01

    Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups. Behavioral assessment after 5 and 9 mo of chronic eHsp70 administration demonstrated improved learning and memory in old mice. Likewise, the investigation of locomotor and exploratory activities after eHsp70 treatment demonstrated a significant therapeutic effect of this chaperone. Measurements of synaptophysin show that eHsp70 treatment in old mice resulted in larger synaptophysin-immunopositive areas and higher neuron density compared with control animals. Furthermore, eHsp70 treatment decreased accumulation of lipofuscin, an aging-related marker, in the brain and enhanced proteasome activity. The potential of eHsp70 intranasal treatment to protect synaptic machinery in old animals offers a unique pharmacological approach for various neurodegenerative disorders associated with human aging. PMID:26668376

  12. Exogenous Hsp70 delays senescence and improves cognitive function in aging mice.

    PubMed

    Bobkova, Natalia V; Evgen'ev, Mikhail; Garbuz, David G; Kulikov, Alexei M; Morozov, Alexei; Samokhin, Alexander; Velmeshev, Dmitri; Medvinskaya, Natalia; Nesterova, Inna; Pollock, Andrew; Nudler, Evgeny

    2015-12-29

    Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups. Behavioral assessment after 5 and 9 mo of chronic eHsp70 administration demonstrated improved learning and memory in old mice. Likewise, the investigation of locomotor and exploratory activities after eHsp70 treatment demonstrated a significant therapeutic effect of this chaperone. Measurements of synaptophysin show that eHsp70 treatment in old mice resulted in larger synaptophysin-immunopositive areas and higher neuron density compared with control animals. Furthermore, eHsp70 treatment decreased accumulation of lipofuscin, an aging-related marker, in the brain and enhanced proteasome activity. The potential of eHsp70 intranasal treatment to protect synaptic machinery in old animals offers a unique pharmacological approach for various neurodegenerative disorders associated with human aging.

  13. Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress?

    PubMed

    Cook, Alexandra R; Bardswell, Sonya C; Pretheshan, Subashini; Dighe, Kushal; Kanaganayagam, Gajen S; Jabr, Rita I; Merkle, Sabine; Marber, Michael S; Engelhardt, Stefan; Avkiran, Metin

    2009-02-01

    Sarcolemmal Na(+)/H(+) exchanger (NHE) activity, which is provided by the NHE isoform 1 (NHE1), has been implicated in ischemia/reperfusion-induced myocardial injury in animal models and humans, on the basis of studies with pharmacological NHE1 inhibitors. We generated a transgenic (TG) mouse model with cardiac-specific over-expression of NHE1 to determine whether this would be sufficient to increase myocardial susceptibility to ischemia/reperfusion-induced injury. TG mouse hearts exhibited increased sarcolemmal NHE activity and normal morphology and function. Surprisingly, they also showed reduced susceptibility to ischemia/reperfusion-induced injury, as reflected by improved functional recovery and smaller infarcts. Such protection was sustained in the presence of NHE1 inhibition with zoniporide, indicating a mechanism that is independent of sarcolemmal NHE activity. Immunoblot analysis revealed accumulation of immature NHE1 protein as well as marked upregulation of both cytoprotective (78/94 kDa glucose-regulated proteins, calreticulin, protein disulfide isomerase) and pro-apoptotic (C/EBP homologous protein) components of the endoplasmic reticulum (ER) stress response in TG myocardium. With increasing age, NHE1 TG mice exhibited increased myocyte apoptosis, developed left ventricular contractile dysfunction, underwent cardiac remodelling and died prematurely. Our findings indicate that: (1) Cardiac-specific NHE1 over-expression induces the ER stress response in mouse myocardium, which may afford protection against ischemia/reperfusion-induced injury despite increased NHE activity; (2) Ageing NHE1 TG mice exhibit myocyte apoptosis, cardiac remodelling and failure, likely as a result of sustained ER stress; (3) The pluripotent effects of the ER stress response may confound studies that are based on the chronic over-expression of complex proteins in myocardium.

  14. Age-related changes in core body temperature and activity in triple-transgenic Alzheimer's disease (3xTgAD) mice.

    PubMed

    Knight, Elysse M; Brown, Timothy M; Gümüsgöz, Sarah; Smith, Jennifer C M; Waters, Elizabeth J; Allan, Stuart M; Lawrence, Catherine B

    2013-01-01

    Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

  15. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.

    PubMed

    Jaskelioff, Mariela; Muller, Florian L; Paik, Ji-Hye; Thomas, Emily; Jiang, Shan; Adams, Andrew C; Sahin, Ergun; Kost-Alimova, Maria; Protopopov, Alexei; Cadiñanos, Juan; Horner, James W; Maratos-Flier, Eleftheria; Depinho, Ronald A

    2011-01-06

    An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2(+) neural progenitors, Dcx(+) newborn neurons, and Olig2(+) oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase

  16. Age-Associated Changes in the Vascular Renin-Angiotensin System in Mice

    PubMed Central

    Yoon, Hye Eun; Kim, Eun Nim; Kim, Min Young; Lim, Ji Hee; Jang, In-Ae; Ban, Tae Hyun; Shin, Seok Joon; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-01-01

    Background. This study evaluated whether the change in the renin-angiotensin system (RAS) is associated with arterial aging in mice. Methods. Histologic changes and expressions of transforming growth factor-β (TGF-β), collagen IV, fibronectin, angiotensin II (Ang II), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), prorenin receptor (PRR), Mas receptor (MasR), endothelial nitric oxide synthase (eNOS), NADPH oxidase 2 and oxidase 4 (Nox2 and Nox4), 8-hydroxy-2′-deoxyguanosine (8-OHdG), 3-nitrotyrosine, and superoxide dismutase 1 and dismutase 2 (SOD1 and SOD2) were measured in the thoracic aortas from 2-month-old, 12-month-old, and 24-month-old C57/BL6 mice. Results. Twenty-four-month-old mice showed significantly increased aortic media thickness and expressions of TGF-β, collagen IV, and fibronectin, compared to 2-month-old and 12-month-old mice. The expressions of PRR, ACE, and Ang II, and AT1R-positive area significantly increased, whereas expressions of ACE2 and MasR and AT2R-positive area decreased with age. The expressions of phosphorylated serine1177-eNOS, SOD1, and SOD2 decreased, and the 8-OHdG-positive area and the 3-nitrotyrosine-positive area increased with age. The expression of Nox2 significantly increased with age, but that of Nox4 did not change. Conclusions. The enhanced PRR-ACE-Ang II-AT1R axis and reduced ACE2-MasR axis were associated with arterial aging in mice. PMID:27200147

  17. Age-Associated Changes in the Vascular Renin-Angiotensin System in Mice.

    PubMed

    Yoon, Hye Eun; Kim, Eun Nim; Kim, Min Young; Lim, Ji Hee; Jang, In-Ae; Ban, Tae Hyun; Shin, Seok Joon; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-01-01

    Background. This study evaluated whether the change in the renin-angiotensin system (RAS) is associated with arterial aging in mice. Methods. Histologic changes and expressions of transforming growth factor-β (TGF-β), collagen IV, fibronectin, angiotensin II (Ang II), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), prorenin receptor (PRR), Mas receptor (MasR), endothelial nitric oxide synthase (eNOS), NADPH oxidase 2 and oxidase 4 (Nox2 and Nox4), 8-hydroxy-2'-deoxyguanosine (8-OHdG), 3-nitrotyrosine, and superoxide dismutase 1 and dismutase 2 (SOD1 and SOD2) were measured in the thoracic aortas from 2-month-old, 12-month-old, and 24-month-old C57/BL6 mice. Results. Twenty-four-month-old mice showed significantly increased aortic media thickness and expressions of TGF-β, collagen IV, and fibronectin, compared to 2-month-old and 12-month-old mice. The expressions of PRR, ACE, and Ang II, and AT1R-positive area significantly increased, whereas expressions of ACE2 and MasR and AT2R-positive area decreased with age. The expressions of phosphorylated serine(1177)-eNOS, SOD1, and SOD2 decreased, and the 8-OHdG-positive area and the 3-nitrotyrosine-positive area increased with age. The expression of Nox2 significantly increased with age, but that of Nox4 did not change. Conclusions. The enhanced PRR-ACE-Ang II-AT1R axis and reduced ACE2-MasR axis were associated with arterial aging in mice.

  18. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type.

    PubMed

    Kane, Alice E; Mitchell, Sarah J; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G; de Cabo, Rafael; Hilmer, Sarah N

    2016-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice.

  19. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    SciTech Connect

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-03-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting /sup 3/H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities.

  20. Beneficial behavioral, neurochemical and molecular effects of 1-(R)-aminoindan in aged mice.

    PubMed

    Badinter, Felix; Amit, Tamar; Bar-Am, Orit; Youdim, Moussa B H; Weinreb, Orly

    2015-12-01

    Previous neuroprotective studies demonstrated that 1-(R)-aminoindan (AI), which is the major metabolite of the anti-Parkinsonian drug rasagiline, possesses beneficial pharmacological effects in various cell culture and animal models of neurodegeneration. The present study was aimed at investigating the possible neuroprotective effects of AI on cognitive impairments and neurochemical alterations in aged mice. Our findings provide evidence that following chronic systemic treatment with AI (5 mg/kg; daily; 3 months) of aged mice (24 months old), the compound exerted a significant positive impact on neuropsychiatric functions and cognitive behavior deficits, assessed in a variety of tasks (spatial learning and memory retention, working memory, learning abilities and nest building behavior) and produced an antidepressant-like effect. In addition, chronic AI treatment significantly enhanced expression levels of neurotrophins, including brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), tyrosine kinase- B (Trk-B) receptor and synaptic plasticity markers, such as synapsin-1 and growth-associated protein-43 (GAP-43) in the striatum and hippocampus in aged mice. Our results also indicate that AI treatment up-regulated the expression levels of the pro-survival Bcl-2 mRNA, increased the anti-apoptotic index Bcl-2/Bax and enhanced the activity of the antioxidant enzyme catalase in the brain of aged mice. These effects of AI were also confirmed in aged rats (24 months old). Altogether, the present findings indicate that AI can induce neuroprotective effects on age-related alterations in neurobehavioral functions and exerts neurotrophic up-regulatory and anti-apoptotic properties in aged animals.

  1. Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice.

    PubMed

    Chumak, Tetyana; Bohuslavova, Romana; Macova, Iva; Dodd, Nicole; Buckiova, Daniela; Fritzsch, Bernd; Syka, Josef; Pavlinkova, Gabriela

    2016-05-01

    The development, maturation, and maintenance of the inner ear are governed by temporal and spatial expression cascades of transcription factors that form a gene regulatory network. ISLET1 (ISL1) may be one of the major players in this cascade, and in order to study its role in the regulation of inner ear development, we produced a transgenic mouse overexpressing Isl1 under the Pax2 promoter. Pax2-regulated ISL1 overexpression increases the embryonic ISL1(+) domain and induces accelerated nerve fiber extension and branching in E12.5 embryos. Despite these gains in early development, the overexpression of ISL1 impairs the maintenance and function of hair cells of the organ of Corti. Mutant mice exhibit hyperactivity, circling behavior, and progressive age-related decline in hearing functions, which is reflected in reduced otoacoustic emissions (DPOAEs) followed by elevated hearing thresholds. The reduction of the amplitude of DPOAEs in transgenic mice was first detected at 1 month of age. By 6-9 months of age, DPOAEs completely disappeared, suggesting a functional inefficiency of outer hair cells (OHCs). The timing of DPOAE reduction coincides with the onset of the deterioration of cochlear efferent terminals. In contrast to these effects on efferents, we only found a moderate loss of OHCs and spiral ganglion neurons. For the first time, our results show that the genetic alteration of the medial olivocochlear (MOC) efferent system induces an early onset of age-related hearing loss. Thus, the neurodegeneration of the MOC system could be a contributing factor to the pathology of age-related hearing loss.

  2. Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice

    NASA Astrophysics Data System (ADS)

    Xu, Zhipeng; Dong, Yuanlin; Wang, Hui; Culley, Deborah J.; Marcantonio, Edward R.; Crosby, Gregory; Tanzi, Rudolph E.; Zhang, Yiying; Xie, Zhongcong

    2014-01-01

    Post-operative cognitive dysfunction (POCD) is associated with increased cost of care, morbidity, and mortality. However, its pathogenesis remains largely to be determined. Specifically, it is unknown why elderly patients are more likely to develop POCD and whether POCD is dependent on general anesthesia. We therefore set out to investigate the effects of peripheral surgery on the cognition and Alzheimer-related neuropathology in mice with different ages. Abdominal surgery under local anesthesia was established in the mice. The surgery induced post-operative elevation in brain β-amyloid (Aβ) levels and cognitive impairment in the 18 month-old wild-type and 9 month-old Alzheimer's disease transgenic mice, but not the 9 month-old wild-type mice. The Aβ accumulation likely resulted from elevation of beta-site amyloid precursor protein cleaving enzyme and phosphorylated eukaryotic translation initiation factor 2α. γ-Secretase inhibitor compound E ameliorated the surgery-induced brain Aβ accumulation and cognitive impairment in the 18 month-old mice. These data suggested that the peripheral surgery was able to induce cognitive impairment independent of general anesthesia, and that the combination of peripheral surgery with aging- or Alzheimer gene mutation-associated Aβ accumulation was needed for the POCD to occur. These findings would likely promote more research to investigate the pathogenesis of POCD.

  3. Melanin precursors prevent premature age-related and noise-induced hearing loss in albino mice.

    PubMed

    Murillo-Cuesta, Silvia; Contreras, Julio; Zurita, Esther; Cediel, Rafael; Cantero, Marta; Varela-Nieto, Isabel; Montoliu, Lluís

    2010-02-01

    Strial melanocytes are required for normal development and correct functioning of the cochlea. Hearing deficits have been reported in albino individuals from different species, although melanin appears to be not essential for normal auditory function. We have analyzed the auditory brainstem responses (ABR) of two transgenic mice: YRT2, carrying the entire mouse tyrosinase (Tyr) gene expression-domain and undistinguishable from wild-type pigmented animals; and TyrTH, non-pigmented but ectopically expressing tyrosine hydroxylase (Th) in melanocytes, which generate the precursor metabolite, L-DOPA, but not melanin. We show that young albino mice present a higher prevalence of profound sensorineural deafness and a poorer recovery of auditory thresholds after noise-exposure than transgenic mice. Hearing loss was associated with absence of cochlear melanin or its precursor metabolites and latencies of the central auditory pathway were unaltered. In summary, albino mice show impaired hearing responses during ageing and after noise damage when compared to YRT2 and TyrTH transgenic mice, which do not show the albino-associated ABR alterations. These results demonstrate that melanin precursors, such as L-DOPA, have a protective role in the mammalian cochlea in age-related and noise-induced hearing loss.

  4. Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice

    PubMed Central

    Cummins, Nathan W.; Weaver, Eric A.; May, Shannon M.; Croatt, Anthony J.; Foreman, Oded; Kennedy, Richard B.; Poland, Gregory A.; Barry, Michael A.; Nath, Karl A.; Badley, Andrew D.

    2012-01-01

    Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P=0.016). HO-1-deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P=0.02). One SNP in HO-1 and one SNP in the constitutively expressed isoform HO-2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers (P=0.017 and 0.014, respectively). HO-1 deficient mice were paired with sex- and age-matched WT controls. HO-1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO-1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness.—Cummins, N. W., Weaver, E. A., May, S. M., Croatt, A. J., Foreman, O., Kennedy, R. B., Poland, G. A., Barry, M. A., Nath, K. A., Badley, A. D. Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice. PMID:22490782

  5. Age-Related Changes in Body Composition of Bovine Growth Hormone Transgenic Mice

    PubMed Central

    Palmer, Amanda J.; Chung, Min-Yu; List, Edward O.; Walker, Jennifer; Okada, Shigeru; Kopchick, John J.; Berryman, Darlene E.

    2009-01-01

    GH has a significant impact on body composition due to distinct anabolic and catabolic effects on lean and fat mass, respectively. Several studies have assessed body composition in mice expressing a GH transgene. Whereas all studies report enhanced growth of transgenic mice as compared with littermate controls, there are inconsistencies in terms of the relative proportion of lean mass to fat mass in these animals. The purpose of this study was to characterize the accumulation of adipose and lean mass with age and according to gender in a bovine (b) GH transgenic mouse line. Weight and body composition measurements were assessed in male and female bGH mice with corresponding littermate controls in the C57BL/6J genetic background. Body composition measurements began at 6 wk and continued through 1 yr of age. At the conclusion of the study, tissue weights were determined and triglyceride content was quantified in liver and kidney. Although body weights for bGH mice were significantly greater than their corresponding littermate controls at all time points, body composition measurements revealed an unexpected transition midway through analyses. That is, younger bGH mice had relatively more fat mass than nontransgenic littermates, whereas bGH mice became significantly leaner than controls by 4 months in males and 6 months in females. These results reveal the importance in timing and gender when conducting studies related to body composition or lean and fat tissue in GH transgenic mice or in other genetically manipulated mouse strains in which body composition may be impacted. PMID:18948397

  6. Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice

    PubMed Central

    Toivola, Diana M.; Habtezion, Aida; Misiorek, Julia O.; Zhang, Linxing; Nyström, Joel H.; Sharpe, Orr; Robinson, William H.; Kwan, Raymond; Omary, M. Bishr

    2015-01-01

    Human mutations in keratin 8 (K8) and keratin 18 (K18), the intermediate filament proteins of hepatocytes, predispose to several liver diseases. K8-null mice develop chronic liver injury and fragile hepatocytes, dysfunctional mitochondria, and Th2-type colitis. We tested the hypothesis that autoantibody formation accompanies the liver damage that associates with K8/K18 absence. Sera from wild-type control, K8-null, and K18-null mice were analyzed by immunoblotting and immunofluorescence staining of cell and mouse tissue homogenates. Autoantibodies to several antigens were identified in 81% of K8-null male mice 8 mo or older. Similar autoantibodies were detected in aging K18-null male mice that had a related liver phenotype but normal colon compared with K8-null mice, suggesting that the autoantibodies are linked to liver rather than colonic disease. However, these autoantibodies were not observed in nontransgenic mice subjected to 4 chronic injury models. The autoantigens are ubiquitous and partition with mitochondria. Mass spectrometry and purified protein analysis identified, mitochondrial HMG-CoA synthase, aldehyde dehydrogenase, and catalase as the primary autoantigens, and glutamate dehydrogenase and epoxide hydrolase-2 as additional autoantigens. Therefore, absence of the hepatocyte keratins results in production of anti-mitochondrial autoantibodies (AMA) that recognize proteins involved in energy metabolism and oxidative stress, raising the possibility that AMA may be found in patients with keratin mutations that associate with liver and other diseases.—Toivola, D. M., Habtezion, A., Misiorek, J. O., Zhang, L., Nyström, J. H., Sharpe, O., Robinson, W. H., Kwan, R., Omary, M. B. Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice. PMID:26399787

  7. Aging-induced Seizure-related Changes to the Hippocampal Mossy Fiber Pathway in Forebrain Specific BDNF Overexpressing Mice

    PubMed Central

    Weidner, Kate L.; Goodman, Jeffrey H.; Chadman, Kathryn K.; McCloskey, Daniel P.

    2011-01-01

    Aging confers an increased risk for developing seizure activity, especially within brain regions that mediate learning and synaptic plasticity. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has an important role in regulating growth and development of the nervous system. BDNF is upregulated after pharmacological seizure induction and this upregulation contributes to enhanced excitability of the hippocampal mossy fiber–CA3 pathway, which is accompanied by neuropeptide Y (NPY) upregulation. Mice overexpressing a BDNF transgene in forebrain neurons provide an avenue for understanding the role of neurotrophic support in the aged hippocampus. In this study BDNF transgenic (TG) mice were utilized to determine whether increased BDNF expression through genetic manipulation resulted in age-related changes in hippocampal excitability and NPY expression. Spontaneous behavioral seizures were observed in TG mice, but not WT mice, past 5 months of age and the severity of behavioral seizures increased with age. Electrophysiological investigation of hippocampal CA3 activity indicated that slices from aged TG mice (86%), but not age-matched WT mice, or young TG mice, showed epileptiform activity in response to either repeated paired pulse or high frequency (tetanic) stimulation. Electrophysiological results were supported by the observation of robust ectopic NPY immunoreactivity in hippocampal mossy fibers of most aged TG mice (57%), which was absent in age-matched WT mice and young TG mice. The results from this study indicate that forebrain restricted BDNF overexpression produces age-related changes in hyperexcitability and NPY immunoreactivity in mossy fiber–CA3 pathway. Together, these data suggest that the capability for BDNF to promote epileptogenesis is maintained, and may be enhanced, in the aging hippocampus. PMID:22396883

  8. Aging-induced Seizure-related Changes to the Hippocampal Mossy Fiber Pathway in Forebrain Specific BDNF Overexpressing Mice.

    PubMed

    Weidner, Kate L; Goodman, Jeffrey H; Chadman, Kathryn K; McCloskey, Daniel P

    2011-08-01

    Aging confers an increased risk for developing seizure activity, especially within brain regions that mediate learning and synaptic plasticity. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has an important role in regulating growth and development of the nervous system. BDNF is upregulated after pharmacological seizure induction and this upregulation contributes to enhanced excitability of the hippocampal mossy fiber-CA3 pathway, which is accompanied by neuropeptide Y (NPY) upregulation. Mice overexpressing a BDNF transgene in forebrain neurons provide an avenue for understanding the role of neurotrophic support in the aged hippocampus. In this study BDNF transgenic (TG) mice were utilized to determine whether increased BDNF expression through genetic manipulation resulted in age-related changes in hippocampal excitability and NPY expression. Spontaneous behavioral seizures were observed in TG mice, but not WT mice, past 5 months of age and the severity of behavioral seizures increased with age. Electrophysiological investigation of hippocampal CA3 activity indicated that slices from aged TG mice (86%), but not age-matched WT mice, or young TG mice, showed epileptiform activity in response to either repeated paired pulse or high frequency (tetanic) stimulation. Electrophysiological results were supported by the observation of robust ectopic NPY immunoreactivity in hippocampal mossy fibers of most aged TG mice (57%), which was absent in age-matched WT mice and young TG mice. The results from this study indicate that forebrain restricted BDNF overexpression produces age-related changes in hyperexcitability and NPY immunoreactivity in mossy fiber-CA3 pathway. Together, these data suggest that the capability for BDNF to promote epileptogenesis is maintained, and may be enhanced, in the aging hippocampus.

  9. Estradiol reduces anxiety- and depression-like behavior of aged female mice.

    PubMed

    Walf, Alicia A; Frye, Cheryl A

    2010-02-09

    Beneficial effects of the ovarian steroid, 17beta-estradiol (E(2)), for affective behavior have been reported in young individuals, but less is known about the effects of E(2) among older individuals, and the capacity of older individuals to respond to E(2) following its decline. In the present study, the effects of acute E(2) administration to aged mice for anxiety-like and depression-like behaviors were investigated. Intact female C57BL/6 mice (N=18) that were approximately 24 months old were administered vehicle (sesame oil, n=9) or E(2) (10 microg, n=9) subcutaneously 1h prior to behavioral testing. Mice were tested for anxiety-like behavior (open field, elevated plus maze, mirror chamber, light-dark transition task, Vogel conflict task) and depression-like behavior (forced swim task). To assess the role of general motor behavior and coordination in these aged mice, performance in an activity monitor and rotarod task, and total entries made in tasks (open field, elevated plus maze, light-dark transition task) were determined. Mice administered E(2), compared to vehicle, demonstrated anti-anxiety behavior in the open field, mirror chamber, and light-dark transition task, and anti-depressive-like behavior in the forced swim task. E(2) also tended to have anti-anxiety effects in the elevated plus maze and Vogel task compared to vehicle administration, but these effects did not reach statistical significance. E(2) did not alter motor behavior and/or coordination in the activity monitor, open field, or rotarod tasks. Thus, an acute E(2) regimen produced specific anti-anxiety and anti-depressant effects, independent of effects on motor behavior, when administered to aged female C57BL/6 mice.

  10. Estradiol reduces anxiety- and depression-like behavior of aged female mice

    PubMed Central

    Walf, Alicia A.; Frye, Cheryl A.

    2013-01-01

    Beneficial effects of the ovarian steroid, 17β-estradiol (E2), for affective behavior have been reported in young individuals, but less is known about the effects of E2 among older individuals, and the capacity of older individuals to respond to E2 following its decline. In the present study, the effects of acute E2 administration to aged mice for anxiety-like and depression-like behaviors were investigated. Intact female C57BL/6 mice (N=18) that were approximately 24 months old were administered vehicle (sesame oil, n=9) or E2 (10 μg, n=9) subcutaneously 1h prior to behavioral testing. Mice were tested for anxiety-like behavior (open field, elevated plus maze, mirror chamber, light–dark transition task, Vogel conflict task) and depression-like behavior (forced swim task). To assess the role of general motor behavior and coordination in these aged mice, performance in an activity monitor and rotarod task, and total entries made in tasks (open field, elevated plus maze, light–dark transition task) were determined. Mice administered E2, compared to vehicle, demonstrated anti-anxiety behavior in the open field, mirror chamber, and light–dark transition task, and anti-depressive-like behavior in the forced swim task. E2 also tended to have anti-anxiety effects in the elevated plus maze and Vogel task compared to vehicle administration, but these effects did not reach statistical significance. E2 did not alter motor behavior and/or coordination in the activity monitor, open field, or rotarod tasks. Thus, an acute E2 regimen produced specific anti-anxiety and anti-depressant effects, independent of effects on motor behavior, when administered to aged female C57BL/6 mice. PMID:19804793

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

    PubMed

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

    2016-01-01

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

  12. Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice

    PubMed Central

    Hazra, Sudipta; Glaser, Jan; Holzgrabe, Ulrike; Hazra, Banasri; Schurigt, Uta

    2015-01-01

    Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches. PMID:26554591

  13. In vivo expression of the Arf6 Guanine-nucleotide exchange factor cytohesin-1 in mice exhibits enhanced myelin thickness in nerves.

    PubMed

    Torii, Tomohiro; Miyamoto, Yuki; Onami, Naoko; Tsumura, Hideki; Nemoto, Noriko; Kawahara, Katsumasa; Kato, Minoru; Kotera, Jun; Nakamura, Kazuaki; Tanoue, Akito; Yamauchi, Junji

    2013-10-01

    The myelin sheath consists of a unique multiple layer structure that acts as an insulator between neuronal axons to enhance the propagation of the action potential. In neuropathies such as demyelinating or dismyelinating diseases, chronic demyelination and defective remyelination occur repeatedly, leading to more severe neuropathy. As yet, little is known about the possibility of drug target-specific medicine for such diseases. In the developing peripheral nervous system (PNS), myelin sheaths form as Schwann cells wrap individual axons. It is thought that the development of a drug promoting myelination by Schwann cells would provide effective therapy against peripheral nerve disorders: to test such treatment, genetically modified mice overexpressing the drug target molecules are needed. We previously identified an Arf6 activator, the guanine-nucleotide exchange factor cytohesin-1, as the signaling molecule controlling myelination of peripheral axons by Schwann cells; yet, the important issue of whether cytohesin-1 itself promotes myelin thickness in vivo has remained unclear. Herein, we show that, in mouse PNS nerves, Schwann cell-specific expression of wild-type cytohesin-1 exhibits enhanced myelin thickness. Downstream activation of Arf6 is also seen in these transgenic mice, revealing the involvement of the cytohesin-1 and Arf6 signaling unit in promoting myelination. These results suggest that cytohesin-1 may be a candidate for the basis of a therapy for peripheral neuropathies through its enhancement of myelin thickness.

  14. Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice.

    PubMed

    Weindruch, R; Kayo, T; Lee, C K; Prolla, T A

    2001-03-01

    An active research area in biological gerontology concerns the mechanisms by which caloric restriction (CR) retards the aging process in laboratory rodents. We used high density oligonucleotide arrays representing 6347 genes to determine the gene expression profile of the aging process in gastrocnemius muscle of male C57BL/6 mice. Aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were completely or partially prevented by CR. Transcriptional patterns of muscle from calorie-restricted animals suggest that CR retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage. The use of high density oligonucleotide microarrays provides a new tool to measure biological age on a tissue-specific basis and to evaluate at the molecular level the efficacy of nutritional interventions designed to retard the aging process.

  15. Intrinsic stiffness of extracellular matrix increases with age in skeletal muscles of mice.

    PubMed

    Wood, Lauren K; Kayupov, Erdan; Gumucio, Jonathan P; Mendias, Christopher L; Claflin, Dennis R; Brooks, Susan V

    2014-08-15

    Advanced age is associated with increases in muscle passive stiffness, but the contributors to the changes remain unclear. Our purpose was to determine the relative contributions of muscle fibers and extracellular matrix (ECM) to muscle passive stiffness in both adult and old animals. Passive mechanical properties were determined for isolated individual muscle fibers and bundles of muscle fibers that included their associated ECM, obtained from tibialis anterior muscles of adult (8-12 mo old) and old (28-30 mo old) mice. Maximum tangent moduli of individual muscle fibers from adult and old muscles were not different at any sarcomere length tested. In contrast, the moduli of bundles of fibers from old mice was more than twofold greater than that of fiber bundles from adult muscles at sarcomere lengths >2.5 μm. Because ECM mechanical behavior is determined by the composition and arrangement of its molecular constituents, we also examined the effect of aging on ECM collagen characteristics. With aging, muscle ECM hydroxyproline content increased twofold and advanced glycation end-product protein adducts increased threefold, whereas collagen fibril orientation and total ECM area were not different between muscles from adult and old mice. Taken together, these findings indicate that the ECM of tibialis anterior muscles from old mice has a higher modulus than the ECM of adult muscles, likely driven by an accumulation of densely packed extensively crosslinked collagen.

  16. Long-term dantrolene treatment reduced intraneuronal amyloid in aged Alzheimer triple transgenic mice.

    PubMed

    Wu, Zhen; Yang, Bin; Liu, Chunxia; Liang, Ge; Liu, Weixia; Pickup, Stephen; Meng, Qingcheng; Tian, Yuke; Li, Shitong; Eckenhoff, Maryellen F; Wei, Huafeng

    2015-01-01

    In this study, we investigated the long-term treatment of dantrolene on amyloid and tau neuropathology, brain volume, and cognitive function in aged triple transgenic Alzheimer (3xTg-AD) mice. Fifteen-month old 3xTg-AD mice and wild-type controls were treated with oral dantrolene (5 mg/kg) or vehicle control twice a week for 6 months. Learning and memory were examined using the Morris Water Maze at 21 and 22 months of age. After the behavioral testing, hippocampal and cortical brain volumes were calculated with magnetic resonance imaging and motor function was evaluated using the rotorod. The amyloid burden and tau neurofibrillary tangles in the hippocampus were determined using immunohistochemistry. We found that dantrolene significantly decreased the intraneuronal amyloid accumulation by as much as 76% compared with its corresponding vehicle control, together with a trend to reduce phosphorylated tau in the hippocampus. No significant differences could be detected in hippocampal or cortical brain volume, motor function or cognition among all experimental groups, indicating that the mice were still presymptomatic for Alzheimer disease. Thus, presymptomatic and long-term dantrolene treatment significantly decreased the intraneuronal amyloid burden in aged 3xTg-AD mice before significant changes in brain volume, or cognition.

  17. Inhibition of Advanced Glycation End Products (AGEs) Accumulation by Pyridoxamine Modulates Glomerular and Mesangial Cell Estrogen Receptor α Expression in Aged Female Mice.

    PubMed

    Pereira-Simon, Simone; Rubio, Gustavo A; Xia, Xiaomei; Cai, Weijing; Choi, Rhea; Striker, Gary E; Elliot, Sharon J

    2016-01-01

    Age-related increases in oxidant stress (OS) play a role in regulation of estrogen receptor (ER) expression in the kidneys. In this study, we establish that in vivo 17β-estradiol (E2) replacement can no longer upregulate glomerular ER expression by 21 months of age in female mice (anestrous). We hypothesized that advanced glycation end product (AGE) accumulation, an important source of oxidant stress, contributes to these glomerular ER expression alterations. We treated 19-month old ovariectomized female mice with pyridoxamine (Pyr), a potent AGE inhibitor, in the presence or absence of E2 replacement. Glomerular ERα mRNA expression was upregulated in mice treated with both Pyr and E2 replacement and TGFβ mRNA expression decreased compared to controls. Histological sections of kidneys demonstrated decreased type IV collagen deposition in mice receiving Pyr and E2 compared to placebo control mice. In addition, anti-AGE defenses Sirtuin1 (SIRT1) and advanced glycation receptor 1 (AGER1) were also upregulated in glomeruli following treatment with Pyr and E2. Mesangial cells isolated from all groups of mice demonstrated similar ERα, SIRT1, and AGER1 expression changes to those of whole glomeruli. To demonstrate that AGE accumulation contributes to the observed age-related changes in the glomeruli of aged female mice, we treated mesangial cells from young female mice with AGE-BSA and found similar downregulation of ERα, SIRT1, and AGER1 expression. These results suggest that inhibition of intracellular AGE accumulation with pyridoxamine may protect glomeruli against age-related oxidant stress by preventing an increase of TGFβ production and by regulation of the estrogen receptor.

  18. Age and High-Fat Diet Effects on Glutamine Synthetase Immunoreactivity in Liver and Hippocampus and Recognition Memory in Mice

    PubMed Central

    Soontornniyomkij, Virawudh; Kesby, James P.; Soontornniyomkij, Benchawanna; Kim, Jane J.; Kisseleva, Tatiana; Achim, Cristian L.; Semenova, Svetlana; Jeste, Dilip V.

    2016-01-01

    BACKGROUND High-fat diet (HFD)-induced obesity may promote age-related memory impairment via disturbances of ammonia-glutamine metabolism. OBJECTIVE We studied the effects of age and long-term HFD exposure on glutamine synthetase (GS) expression in the liver and hippocampus and recognition memory in mice. METHODS Adult (5-month-old) and aged (15-month-old) male C57BL/6 mice were exposed to control diet (CD, 14% calories from fat) or HFD (60% fat). Novel place recognition testing was conducted and tissue was collected after 4 and 5 months on HFD, respectively. Tissue GS expression levels were assessed using immunohistochemistry and image analysis. RESULTS The obese mice developed moderate/severe hepatic steatosis. GS immunoreactivity was observed in perivenous hepatocytes and in hippocampal astrocytes and neuropil. Hepatic GS immunoreactivity density was higher in aged mice on HFD (n = 8) than CD (n = 13, P = 0.004). In aged mice, hippocampal GS immunoreactivity density was higher with HFD than CD (P = 0.037). In the novel place recognition test, aged mice were classified into impaired (n = 7) and unimpaired (n = 12), relative to adult mice (n = 22). Hippocampal GS immunoreactivity density was higher in impaired than unimpaired aged mice (P < 0.05). CONCLUSION Long-term exposure of aged mice to HFD was associated with increased GS expression in the liver and hippocampus. Novel place recognition impairment in aged mice was associated with increased hippocampal GS expression. These findings suggest that excess ammonia is involved in the age-related effects of HFD exposure and in neurotoxicity. PMID:27071478

  19. Effects of Aging on Current Vocalization Threshold in Mice Measured by a Novel Nociception Assay

    PubMed Central

    Finkel, Julia C.; Besch, Virginia G.; Hergen, Adrienne; Kakareka, John; Pohida, Thomas; Melzer, Jonathan M.; Koziol, Deloris; Wesley, Robert; Quezado, Zenaide M. N.

    2016-01-01

    Background Age-related changes in nociception have been extensively studied in the past decades. However, it remains unclear whether in addition to the increased incidence of chronic illness, age-related changes in nociception contribute to increased prevalence of pain in the elderly. Although a great deal of evidence suggests that nociception thresholds increase with aging, other studies yield disparate results. The aim of this investigation was to longitudinally determine the effect of aging on nociception. Methods The authors developed a nociception assay for mice using electrical stimuli at 2,000, 250, and 5 Hz that reportedly stimulate Aβ, Aδ, and C sensory nerve fibers, respectively. A system was designed to automate a method that elicits and detects pain-avoiding behavior in mice. Using a Latin square design, the authors measured current vocalization thresholds serially over the course of mice’s life span. Results For 2,000-Hz (Aβ), 250-Hz (Aδ), and 5-Hz (C) electrical stimuli, current vocalization thresholds first decreases and then increases with aging following a U-shaped pattern (P < 0.001). In addition, average current vocalization thresholds at youth and senescence are significantly higher than those at middle age for the 250-Hz (Aδ) and 5-Hz (C fiber) electrical stimulus (P < 0.05). Conclusions Using a novel and noninjurious nociception assay, the authors showed that over the life span of mice, current vocalization threshold to electrical stimuli changes in a U-shaped pattern. The findings support the notion that age-related changes in nociception are curvilinear, and to properly study and treat pain, the age of subjects should be considered. PMID:16871071

  20. Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections

    PubMed Central

    CA, Mares; SS, Ojeda; Q, Li; EG, Morris; JJ, Coalson; JM, Teale

    2012-01-01

    Aging is a complex phenomenon that has been shown to affect many organ systems including the innate and adaptive immune systems. The current study was designed to examine the potential effect of immunosenescence on the pulmonary immune response using a Francisella tularensis live vaccine strain (LVS) inhalation infection model. F. tularensis is a gram-negative intracellular pathogen that can cause a severe pneumonia.In this study both young (8-12 week old) and aged (20-24 month old) mice were infected intranasally with LVS. Lung tissues from young and aged mice were used to assess pathology, recruitment of immune cell types and cytokine expression levels at various times post infection. Bacterial burdens were also assessed. Interestingly, the lungs of aged animals harbored fewer organisms at early time points of infection (day 1, day 3) compared with their younger counterparts. In addition, only aged animals displayed small perivascular aggregates at these early time points that appeared mostly mononuclear in nature. However, the kinetics of infiltrating polymorphonuclear neutrophils (PMNs) and increased cytokine levels measured in the bronchial alveolar lavage fluid (BALF) were delayed in infected aged animals relative to young infected animals with neutrophils appearing at day 5 post infection (PI) in the aged animals as opposed to day 3 PI in the young infected animals. Also evident were alterations in the ratios of mononuclear to PMNs at distinct post infection times. The above evidence indicates that aged mice elicit an altered immune response in the lung to respiratory Francisella tularensis LVS infections compared to their younger counterparts. PMID:19825409

  1. Exercise reduces activation of microglia isolated from hippocampus and brain of aged mice

    PubMed Central

    2013-01-01

    Background Aging is associated with low-grade neuroinflammation that includes basal increases in proinflammatory cytokines and expression of inflammatory markers on microglia. Exercise can reduce neuroinflammation following infection in aged animals, but whether exercise modulates basal changes in microglia activation is unknown. Therefore, we evaluated changes in basal microglia activation in cells isolated from the hippocampus and remaining brain following running-wheel access. Methods Adult (4 months) and aged (22 months) male and female BALB/c mice were housed with or without running wheels for 10 weeks. Microglia were isolated from the hippocampus or remaining brain. Flow cytometry was used to determine microglia (CD11b+ and CD45low) that co-labeled with CD86, CD206, and MHC II. Results Aged mice showed a greater proportion of CD86 and MHC II positive microglia. In aged females, access to a running wheel decreased proportion of CD86+ and MHC II+ microglia in the hippocampus whereas aged males in the running group showed a decrease in the proportion of CD86+ microglia in the brain and an increase in the proportion of MHC II+ microglia in hippocampus and brain. Conclusion Overall, these data indicate that running-wheel access modulates microglia activation, but these effects vary by age, sex, and brain region. PMID:24044641

  2. Dietary Polyphenol Supplementation Prevents Alterations of Spatial Navigation in Middle-Aged Mice

    PubMed Central

    Bensalem, Julien; Servant, Laure; Alfos, Serge; Gaudout, David; Layé, Sophie; Pallet, Véronique; Lafenetre, Pauline

    2016-01-01

    Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to their navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal calmodulin kinase II (CaMKII) mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of nerve growth neurotrophic factor (NGF) mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline. PMID:26903826

  3. Effects of Portulaca oleracea ethanolic extract on reproductive system of aging female mice

    PubMed Central

    Ahangarpour, Akram; Lamoochi, Zohreh; Fathi Moghaddam, Hadi; Mansouri, Seyed Mohamad Taghi

    2016-01-01

    Background: Aging contains morphological and functional deterioration in biological systems. D-galactose (D-gal) generates free radicals and accelerates aging. Portulaca oleracea (Purslane) may have protective effect against oxidative stress. Objective: Purslane ethanolic extract effects were evaluated on antioxidant indices and sex hormone in D-gal aging female mice. Materials and Methods: 48 female NMRI mice (25-35 gr) were randomly divided into, 6 groups: 1- control (normal saline for 45 days), 2- Purslane (200 mg/kg for last 3 weeks), 3-D-gal (500 mg/kg for 45 days), 4-D-gal+Purslane, 5- Aging, 6-Aging+Purslane. Sex hormones, antioxidants and malondialdehyde (MDA) level of ovary and uterus were measured. Histological assessment was also done. Results: In D-gal treated and aging animals, LH and FSH levels were significantly increased (p<0.001) while estrogen and progesterone levels were significantly reduced (p<0.001) in comparison with control group. MDA contents were significantly increased in ovaries and uterus of D-gal and aging groups (p<0.01). Superoxide dismutase (SOD) (p<0.001) and catalase (p<0.01) activities were significantly decreased in both aging and D-gal treated animals. Ovarian follicles were degenerated and atrophy on uterine wall and endometrial glands was observed in D-gal and aging groups. Alteration in hormone levels, MDA contents and antioxidant activity were significantly reversed by Purslane (p<0.05). Purslane could also improve histological changes such as atrophy of endometrium. Conclusion: These findings indicate that Purslane can attenuate aging alternations induced by D-gal and aging in female reproductive system. PMID:27294220

  4. The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice

    PubMed Central

    Vercellotti, Gregory M.; Pace, Betty S.; Solovey, Anna N.; Kollander, Rahn; Abanonu, Chine F.; Nguyen, Julia; Vineyard, Julie V.; Belcher, John D.; Abdulla, Fuad; Osifuye, Shadé; Eaton, John W.; Kelm, Robert J.; Slungaard, Arne

    2010-01-01

    The vascular pathobiology of sickle cell anemia involves inflammation, coagulation, vascular stasis, reperfusion injury, iron-based oxidative biochemistry, deficient nitric oxide (NO) bioavailability, and red cell sickling. These disparate pathobiologies intersect and overlap, so it is probable that multimodality therapy will be necessary for this disease. We have, therefore, tested a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), for efficacy in reducing endothelial activation. We found that pulmonary vascular endothelial VCAM-1 and tissue factor (TF) expression (both are indicators of endothelial activation) are powerfully and significantly inhibited by TSA. This is seen both with pretreatment before the inducing stress of hypoxia/reoxygenation (NY1DD sickle transgenic mouse), and upon longer-term therapy after endothelial activation has already occurred (hBERK1 sickle mouse at ambient air). In addition, TSA prevented vascular stasis in sickle mice, it exhibited activity as an iron chelator, and it induced expression of the antisickling hemoglobin, hemoglobin F. Notably, the TSA analog SAHA (suberoylanilide hydroxaminc acid) that is already approved for human clinical use exhibits the same spectrum of biologic effects as TSA. We suggest that SAHA possibly could provide true, multimodality, salubrious effects for prevention and treatment of the chronic vasculopathy of sickle cell anemia. PMID:20053759

  5. The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice.

    PubMed

    Hebbel, Robert P; Vercellotti, Gregory M; Pace, Betty S; Solovey, Anna N; Kollander, Rahn; Abanonu, Chine F; Nguyen, Julia; Vineyard, Julie V; Belcher, John D; Abdulla, Fuad; Osifuye, Shadé; Eaton, John W; Kelm, Robert J; Slungaard, Arne

    2010-03-25

    The vascular pathobiology of sickle cell anemia involves inflammation, coagulation, vascular stasis, reperfusion injury, iron-based oxidative biochemistry, deficient nitric oxide (NO) bioavailability, and red cell sickling. These disparate pathobiologies intersect and overlap, so it is probable that multimodality therapy will be necessary for this disease. We have, therefore, tested a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), for efficacy in reducing endothelial activation. We found that pulmonary vascular endothelial VCAM-1 and tissue factor (TF) expression (both are indicators of endothelial activation) are powerfully and significantly inhibited by TSA. This is seen both with pretreatment before the inducing stress of hypoxia/reoxygenation (NY1DD sickle transgenic mouse), and upon longer-term therapy after endothelial activation has already occurred (hBERK1 sickle mouse at ambient air). In addition, TSA prevented vascular stasis in sickle mice, it exhibited activity as an iron chelator, and it induced expression of the antisickling hemoglobin, hemoglobin F. Notably, the TSA analog SAHA (suberoylanilide hydroxaminc acid) that is already approved for human clinical use exhibits the same spectrum of biologic effects as TSA. We suggest that SAHA possibly could provide true, multimodality, salubrious effects for prevention and treatment of the chronic vasculopathy of sickle cell anemia.

  6. C-phycocyanin protects against low fertility by inhibiting reactive oxygen species in aging mice.

    PubMed

    Li, Yan-Jiao; Han, Zhe; Ge, Lei; Zhou, Cheng-Jie; Zhao, Yue-Fang; Wang, Dong-Hui; Ren, Jing; Niu, Xin-Xin; Liang, Cheng-Guang

    2016-04-05

    Women over 35 have higher rates of infertility, largely due to deterioration of oocyte quality characterized by fragmentation, abnormal meiotic spindle-chromosome complexes, and oxidative stress. C-phycocyanin (PC) is a biliprotein enriched in Spirulina platensis that is known to possess antioxidant, anti-inflammatory, and radical-scavenging properties. D-galactose-induced aging acceleration in mice has been extensively used to study aging mechanisms and for pharmaceutical screening. In this study, adult female B6D2F/1 mice injected with D-galactose were used as a model to test the age-reversing effects of PC on degenerated reproductive ability. Our results show that PC can prevent oocyte fragmentation and aneuploidy by maintaining cytoskeletal integrity. Moreover, PC can reverse the expression of antioxidant genes, increase superoxide dismutase (SOD) activity and decrease methane dicarboxylic aldehyde (MDA) content, and normalize mitochondria distribution. PC exerts its benefit by inhibiting reactive oxygen species (ROS) production, which decreases apoptosis. Finally, we observe a significant increase in litter size after PC administration to D-galactose-induced aging mice. Our study demonstrates for the first time that D-galactose-induced impaired female reproductive capability can be partially rescued by the antioxidant effects of PC.

  7. Voluntary exercise rescues sevoflurane-induced memory impairment in aged male mice.

    PubMed

    Tian, Dan; Tian, Miao; Ma, Zhiming; Zhang, Leilei; Cui, Yunfeng; Li, Jinlong

    2016-12-01

    Postoperative cognitive impairment is especially common in older patients following major surgery. Although exposure to sevoflurane is known to cause memory deficits, few studies have examined the putative approaches to reduce such impairments. This study tested the hypotheses that sevoflurane exposure can decrease NR2B subunit-containing NMDA receptor activity in hippocampus of aged mice, and voluntary exercise may counteract the declining hippocampal functions. We found that long exposure (3 h/day for 3 days), but not short exposure (1 h/day for 3 days), to 3 % sevoflurane produced a long-lasting spatial memory deficits up to 3 weeks in aged mice, and such an effect was not due to the neuronal loss in the hippocampus, but was correlated with a long-term decrease in Fyn kinase expression and NR2B subunit phosphorylation in the hippocampus. Furthermore, voluntary exercise rescued sevoflurane-induced spatial memory deficits in aged mice and restored Fyn kinase expression and NR2B subunit phosphorylation in the hippocampus to a level comparable to control animals. Generally, our results suggested that Fyn-mediated NR2B subunit phosphorylation may play a critical role in sevoflurane-induced impairment in cognitive functions in aged animals, and voluntary exercise might be an important non-pharmacological approach to treatment of inhaled anesthetics-induced postoperative cognitive impairment in clinical settings.

  8. C-phycocyanin protects against low fertility by inhibiting reactive oxygen species in aging mice

    PubMed Central

    Li, Yan-Jiao; Han, Zhe; Ge, Lei; Zhou, Cheng-Jie; Zhao, Yue-Fang; Wang, Dong-Hui; Ren, Jing; Niu, Xin-Xin; Liang, Cheng-Guang

    2016-01-01

    Women over 35 have higher rates of infertility, largely due to deterioration of oocyte quality characterized by fragmentation, abnormal meiotic spindle-chromosome complexes, and oxidative stress. C-phycocyanin (PC) is a biliprotein enriched in Spirulina platensis that is known to possess antioxidant, anti-inflammatory, and radical-scavenging properties. D-galactose-induced aging acceleration in mice has been extensively used to study aging mechanisms and for pharmaceutical screening. In this study, adult female B6D2F/1 mice injected with D-galactose were used as a model to test the age-reversing effects of PC on degenerated reproductive ability. Our results show that PC can prevent oocyte fragmentation and aneuploidy by maintaining cytoskeletal integrity. Moreover, PC can reverse the expression of antioxidant genes, increase superoxide dismutase (SOD) activity and decrease methane dicarboxylic aldehyde (MDA) content, and normalize mitochondria distribution. PC exerts its benefit by inhibiting reactive oxygen species (ROS) production, which decreases apoptosis. Finally, we observe a significant increase in litter size after PC administration to D-galactose-induced aging mice. Our study demonstrates for the first time that D-galactose-induced impaired female reproductive capability can be partially rescued by the antioxidant effects of PC. PMID:27008700

  9. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

    PubMed

    Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

    2012-01-01

    Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

  10. Restoration of the immune functions in aged mice by supplementation with a new herbal composition, HemoHIM.

    PubMed

    Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae

    2008-01-01

    The effect of a new herbal composition, HemoHIM, on immune functions was examined in aged mice, in which various immune responses had been impaired. The composition HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Supplementation to the aged mice with HemoHIM restored the proliferative response and cytokine production of splenocytes with a response to ConA. Also, HemoHIM recovered the NK cell activity which had been impaired in the aged mice. Meanwhile aging is known to reduce the Th1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. HemoHIM restored the Th1/Th2 balance in the aged mice through enhanced IFN-gamma and IgG2a production, and conversely a reduced IL-4 and IgG1 production. It was found that one factor for the Th1/Th2 imbalance in the aged mice was a lower production of IL-12p70. However, HemoHIM restored the IL-12p70 production in the aged mice. These results suggested that HemoHIM was effective for the restoration of impaired immune functions of the aged mice and therefore could be a good recommendation for immune restoration in elderly humans.

  11. Memory retrieval improvement by Ptychopetalum olacoides in young and aging mice.

    PubMed

    da Silva, Adriana L; Piato, Angelo L S; Bardini, Simone; Netto, Carlos A; Nunes, Domingos S; Elisabetsky, Elaine

    2004-12-01

    Amazonian peoples use traditional remedies prepared with Ptychopetalum olacoides (PO) roots for treating various age-related conditions. This study shows that a single intraperitoneally (i.p.) administration of Ptychopetalum olacoides ethanol extract (POEE, 50 and 100mg/kg) improved memory retrieval in step-down inhibitory avoidance (P mice. Comparable results were obtained with POEE given p.o. at 800 and 1000mg/kg (P aging (14 months) mice presenting memory deficit (14.95 [10.8-41]) as compared to adult (2.5 months) mice (57 [15.7-141.2]), with the extract given acutely i.p. 100 mg/kg (300 [133.1-300] versus control 14.95 [10.8-41]) or p.o. 800 mg/kg (28.4 [15.1-84.6] versus control 11.5 [7.8-23.3]). Indeed, aging mice treated with POEE (800 mg/kg, p.o.) performed as well as adult mice. Consistently with its traditional use, the data suggest that POEE facilitates memory retrieval. Although the antioxidant and acetylcholinesterase inhibitory properties previously described for this extract may be of relevance, the molecular mechanism(s) underlying the improvement in memory retrieval here reported merit further scrutiny.

  12. Brief dark exposure restored ocular dominance plasticity in aging mice and after a cortical stroke.

    PubMed

    Stodieck, Sophia Katharina; Greifzu, Franziska; Goetze, Bianka; Schmidt, Karl-Friedrich; Löwel, Siegrid

    2014-12-01

    In the primary visual cortex (V1), monocular deprivation (MD) induces a shift in the ocular dominance (OD) of binocular neurons towards the open eye (Wiesel and Hubel, 1963; Gordon and Stryker, 1996). In V1 of C57Bl/6J mice, this OD-plasticity is maximal in juveniles, declines in adults and is absent beyond postnatal day (PD) 110 (Lehmann and Löwel, 2008) if mice are raised in standard cages. Since it was recently shown that brief dark exposure (DE) restored OD-plasticity in young adult rats (PD70-100) (He et al., 2006), we wondered whether DE would restore OD-plasticity also in adult and old mice and after a cortical stroke. To this end, we raised mice in standard cages until adulthood and transferred them to a darkroom for 10-14 days. Using intrinsic signal optical imaging we demonstrate that short-term DE can restore OD-plasticity after MD in both adult (PD138) and old mice (PD535), and that OD-shifts were mediated by an increase of open eye responses in V1. Interestingly, restored OD-plasticity after DE was accompanied by a reduction of both parvalbumin expressing cells and perineuronal nets and was prevented by increasing intracortical inhibition with diazepam. DE also maintained OD-plasticity in adult mice (PD150) after a stroke in the primary somatosensory cortex. In contrast, short-term DE did not affect basic visual parameters as measured by optomotry. In conclusion, short-term DE was able to restore OD-plasticity in both adult and aging mice and even preserved plasticity after a cortical stroke, most likely mediated by reducing intracortical inhibition.

  13. Reactive Oxygen Species Limit the Ability of Bone Marrow Stromal Cells to Support Hematopoietic Reconstitution in Aging Mice

    PubMed Central

    Khatri, Rahul; Krishnan, Shyam; Roy, Sushmita; Chattopadhyay, Saborni; Kumar, Vikash

    2016-01-01

    Aging of organ and abnormal tissue regeneration are recurrent problems in physiological and pathophysiological conditions. This is most crucial in case of high-turnover tissues, like bone marrow (BM). Using reciprocal transplantation experiments in mouse, we have shown that self-renewal potential of hematopoietic stem and progenitor cells (HSPCs) and BM cellularity are markedly influenced with the age of the recipient mice rather than donor mice. Moreover, accumulation of excessive reactive oxygen species (ROS) in BM stromal cells compared to HSPC compartment, in time-dependent manner, suggests that oxidative stress is involved in suppression of BM cellularity by affecting microenvironment in aged mice. Treatment of these mice with a polyphenolic antioxidant curcumin is found to partially quench ROS, thereby rescues stromal cells from oxidative stress-dependent cellular injury. This rejuvenation of stromal cells significantly improves hematopoietic reconstitution in 18-month-old mice compared to age control mice. In conclusion, this study implicates the role of ROS in perturbation of stromal cell function upon aging, which in turn affects BM's reconstitution ability in aged mice. Thus, a rejuvenation therapy using curcumin, before HSPC transplantation, is found to be an efficient strategy for successful marrow reconstitution in older mice. PMID:27140293

  14. Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion

    PubMed Central

    Chen, Jichun; Bryant, Mark A.; Dent, James J.; Sun, Yu; Desierto, Marie J.; Young, Neal S.

    2015-01-01

    A deletion of telomerase RNA component (Terc−/−) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b+ myeloid cells and decreased red blood cells and CD45R+ B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit+Sca-1+Lin− (KSL) cells in old Terc−/− mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc−/− donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc−/− mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b+ myeloid cells and a decrease in CD45R+ B cells, similar to those observed in old Terc−/− mice. Treatment of 11–13 month old Terc−/− mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc−/− animals. PMID:26523501

  15. Hematopoietic lineage skewing and intestinal epithelia degeneration in aged mice with telomerase RNA component deletion.

    PubMed

    Chen, Jichun; Bryant, Mark A; Dent, James J; Sun, Yu; Desierto, Marie J; Young, Neal S

    2015-12-01

    A deletion of a telomerase RNA component (Terc(-/-)) in C57BL/6 (B6) mice resulted in hematopoietic lineage skewing with increased neutrophils and CD11b(+) myeloid cells and decreased red blood cells and CD45R(+) B lymphocytes when animals reach ages older than 12 months. There was no decline in bone marrow (BM) c-Kit(+)Sca-1(+)Lin(-) (KSL) cells in old Terc(-/-) mice, and the lineage skewing phenomenon was not transferred when BM cells from old Terc(-/-) donors were transplanted into young B6 recipients. Necropsy and histological examinations found minimal to no change in the lung, spleen and liver but detected severe epithelia degeneration, ulceration and infection in small and large intestines, leading to enteritis, typhlitis and colitis in old Terc(-/-) mice. In a mouse model of dextran-sulfate-sodium-induced typhlitis and colitis, development of intestinal pathology was associated with increases in neutrophils and CD11b(+) myeloid cells and a decrease in CD45R(+) B cells, similar to those observed in old Terc(-/-) mice. Treatment of 11-13 month old Terc(-/-) mice with antibiotic trimethoprim-sulfa water reduced neutrophils and myeloid cells and increased B lymphocytes in the blood, indicating that mitigation of intestinal infection and inflammation could alleviate hematological abnormalities in old Terc(-/-) animals.

  16. Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice

    PubMed Central

    Ali, Amira A. H.; Schwarz‐Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-01-01

    Hippocampal neurogenesis undergoes dramatic age‐related changes. Mice with targeted deletion of the clock gene Bmal1 (Bmal1‐/‐) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1‐/‐ mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1‐/‐ mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70kDa and expression of the cell cycle inhibitor p21 Waf1/CIP1 were increased in adult Bmal1‐/‐ mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age‐dependent decline in adult neurogenesis presumably as a consequence of oxidative stress. PMID:26142744

  17. Elevated intracellular pH appears in aged oocytes and causes oocyte aneuploidy associated with the loss of cohesion in mice.

    PubMed

    Cheng, Jin-Mei; Li, Jian; Tang, Ji-Xin; Chen, Su-Ren; Deng, Shou-Long; Jin, Cheng; Zhang, Yan; Wang, Xiu-Xia; Zhou, Chen-Xi; Liu, Yi-Xun

    2016-09-16

    Increases in the aneuploidy rate caused by the deterioration of cohesion with increasing maternal age have been well documented. However, the molecular mechanism for the loss of cohesion in aged oocytes remains unknown. In this study, we found that intracellular pH (pHi) was elevated in aged oocytes, which might disturb the structure of the cohesin ring to induce aneuploidy. We observed for the first time that full-grown germinal vesicle (GV) oocytes displayed an increase in pHi with advancing age in CD1 mice. Furthermore, during the in vitro oocyte maturation process, the pHi was maintained at a high level, up to ∼7.6, in 12-month-old mice. Normal pHi is necessary to maintain protein localization and function. Thus, we put forward a hypothesis that the elevated oocyte pHi might be related to the loss of cohesion and the increased aneuploidy in aged mice. Through the in vitro alkalinization treatment of young oocytes, we observed that the increased pHi caused an increase in the aneuploidy rate and the sister inter-kinetochore (iKT) distance associated with the strength of cohesion and caused a decline in the cohesin subunit SMC3 protein level. Young oocytes with elevated pHi exhibited substantially the increase in chromosome misalignment.

  18. Decreased c-Jun expression correlates with impaired spinal motoneuron regeneration in aged mice following sciatic nerve crush.

    PubMed

    Yuan, Qiuju; Su, Huanxing; Guo, Jiasong; Tsang, Kwok Yeung; Cheah, Kathryn S E; Chiu, Kin; Yang, Jian; Wong, Wai-Man; So, Kwok-Fai; Huang, Jian-Dong; Wu, Wutian; Lin, Zhi-xiu

    2012-04-01

    Post-injury nerve regeneration of the peripheral nervous system declines with age, but the mechanisms underlying the weakened axonal regeneration are not well understood. Increased synthesis and activity of the AP-1 transcription factor c-Jun have been implicated in efficient motor axonal regeneration. In the present study, we evaluated the hypothesis that the impaired regenerative capacity in the aged is associated with impaired induction of c-Jun. In non-manipulated young adult or aged mice, no c-Jun and its phosphorylated form were detected in the ventral horn of the spinal cord. Following nerve crush, significant c-Jun and phosphorylated c-Jun occurred in the injured motoneurons of young adult mice, but not in aged animals. In accord with the immunohistochemistry, Western blots also showed that sciatic nerve crush induced c-Jun and its phosphorylation expression in the ventral horn of young adult but not in aged mice. Changes in c-Jun mRNA level detected by in situ hybridization are congruent with that in c-Jun protein content, showing an increase at 5 days after crush in young adult but not aged. Moreover, compared with young adult mice, aged mice showed impaired motor axonal regeneration. These results demonstrate that the impaired motor axonal regeneration seen in aged mice is correlated with impaired c-Jun expression and phosphorylation following injury. These data provide a neurobiological explanation for the poor outcome associated with nerve repair in the aged.

  19. Dietary wolfberry supplementation enhances the protective effect of flu vaccine against influenza challenge in aged mice.

    PubMed

    Du, Xiaogang; Wang, Junpeng; Niu, Xinli; Smith, Donald; Wu, Dayong; Meydani, Simin Nikbin

    2014-02-01

    Current vaccines for influenza do not fully protect the aged against influenza infection. Although wolfberry (goji berry) has been shown to improve immune response, including enhanced antibody production, after vaccination in the aged, it is not known if this effect would translate to better protection after influenza infection, nor is its underlying mechanism well understood. To address these issues, we conducted a study using a 2 × 2 design in which aged male mice (20-22 mo) were fed a control or a 5% wolfberry diet for 30 d, then immunized with an influenza vaccine or saline (control) on days 31 and 52 of the dietary intervention, and finally challenged with influenza A/Puerto Rico/8/34 virus. Mice fed wolfberry had higher influenza antibody titers and improved symptoms (less postinfection weight loss) compared with the mice treated by vaccine alone. Furthermore, an in vitro mechanistic study showed that wolfberry supplementation enhanced maturation and activity of antigen-presenting dendritic cells (DCs) in aged mice, as indicated by phenotypic change in expression of DC activation markers major histocompatibility complex class II, cluster of differentiation (CD) 40, CD80, and CD86, and functional change in DC production of cytokines interleukin-12 and tumor necrosis factor-α as well as DC endocytosis. Also, adoptive transfer of wolfberry-treated bone marrow DCs (loaded with ovalbumin(323-339)-peptide) promoted antigen-specific T cell proliferation as well as interleukin-4 and interferon-γ production in CD4(+) T cells. In summary, our data indicate that dietary wolfberry enhances the efficacy of influenza vaccination, resulting in better host protection to prevent subsequent influenza infection; this effect may be partly attributed to improved DC function.

  20. Oxidative stress is involved in age-dependent spermatogenic damage of Immp2l mutant mice.

    PubMed

    George, Sunil K; Jiao, Yan; Bishop, Colin E; Lu, Baisong

    Mitochondrial reactive oxygen species (ROS) have been implicated in spermatogenic damage, although direct in vivo evidence is lacking. We recently generated a mouse in which the inner mitochondrial membrane peptidase 2-like (Immp2l) gene is mutated. This Immp2l mutation impairs the processing of signal peptide sequences from mitochondrial cytochrome c₁ and glycerol phosphate dehydrogenase 2. The mitochondria from mutant mice generate elevated levels of superoxide ion, which causes age-dependent spermatogenic damage. Here we confirm age-dependent spermatogenic damage in a new cohort of mutants, which started at the age of 10.5 months. Compared with age-matched controls, protein carbonyl content was normal in testes of 2- to 5-month-old mutants, but significantly elevated in testes of 13-month-old mutants, indicating elevated oxidative stress in the testes at the time of impaired spermatogenesis. Testicular expression of superoxide dismutases was not different between control and mutant mice, whereas that of catalase was increased in young and old mutants. The expression of cytosolic glutathione peroxidase 4 (phospholipid hydroperoxidase) in testes was significantly reduced in 13-month-old mutants, concomitant with impaired spermatogenesis. Apoptosis of all testicular populations was increased in mutant mice with spermatogenic damage. The mitochondrial DNA (mtDNA) mutation rate in germ cells of mutant mice with impaired spermatogenesis was unchanged, excluding a major role of mtDNA mutation in ROS-mediated spermatogenic damage. Our data show that increased mitochondrial ROS are one of the driving forces for spermatogenic impairment.

  1. Age- and sex-dependent thymic abnormalities in NZB × SJL F1 hybrid mice

    PubMed Central

    Dumont, F.; Robert, F.

    1980-01-01

    The cellular organization of the thymus was investigated in 3- and 12-month-old NZB × SJL F1 hybrid (NS) mice. Age-dependent alterations were demonstrated which differed strikingly according to the sex of the animals. In female mice, marked abnormalities of the thymus developed during ageing. They consisted of a more or less pronounced hypertrophy accompanied by histological changes and modifications in the nature of the lymphocyte populations. Three types of qualitative changes were found at 12 months of age: (1) depletion of cortical thymocytes as evidenced by histology, by the evaluation of peanut-agglutinin (PNA) binding and by cell electrophoresis; (2) hyperplasia of the medullary lymphoid tissue, probably reflecting the expansion of a population of mature T lymphocytes. This was further suggested by a rise (up to 60%) in the frequency of lymphocytes lacking both PNA receptor and B cell markers, by an increased proportion (57%) of high electrophoretic mobility (EPM) lymphocytes and by an augmentation of in vitro reactivities to phytohaemagglutinin (PHA) and, although to a lesser extent, to concanavalin A (Con A). (3) The appearance of significant numbers of B lymphocytes (up to 20%) as assessed by surface immunoglobulin (sIg) and complement receptor (CR) detection which was accompanied by a vigorous responsiveness of thymus cells to lipopolysaccharide (LPS). None of these abnormalities was seen in the male mice. Instead, the thymus of NS males displayed a nearly normal age-related involution without major change in the proportions of its lymphocyte subpopulations. NS mice thus provide an interesting model of thymic disease influenced by sex-linked factors. ImagesFig. 3 PMID:7438550

  2. Developmental and age-related changes in apolipoprotein B mRNA editing in mice.

    PubMed

    Higuchi, K; Kitagawa, K; Kogishi, K; Takeda, T

    1992-12-01

    Apolipoprotein B (apoB) mRNA is modified by a post-transcriptional editing reaction (C to U) changing a glutamine (CAA) to a translational stop codon (UAA) and producing apoB-48 mRNA in mammalian liver and intestine. Developmental and age-related changes in apoB mRNA editing were studied using two mouse strains with different aging processes (SAM-R/1 with a normal aging process and SAM-P/1 with an accelerated aging process). During growth of both strains, the proportion of unedited (apoB-100) mRNA decreased from 80% in the fetal liver at the 17th day of gestation to 30% in the liver of mature 2-month-old mice. Age-associated increase in the proportion of hepatic apoB-100 mRNA was observed from the age of 18 months in the SAM-R/1 strain. In the SAM-P/1 strain, apoB-100 mRNA in the liver continued to increase from the age of 10 months to death. The profiles of developmental and age-related changes in the proportion of two serum apoB isoproteins (apoB-100 and apoB-48) followed the extent of hepatic apoB mRNA editing. Age-related changes in the extent of apoB mRNA editing in the small intestine were not observed in either strain. A slight expression of apoB was detected by reverse transcriptase-polymerase chain reaction in the kidney, stomach, and colon, and age-associated change in the extent of editing was observed in the kidney. These correlated changes in apoB mRNA editing and serum apoB proteins suggest that RNA editing may be one mechanism involved in the regulation of lipoprotein biogenesis in biological development and in senescent mice. An age-associated decrease in the extent of hepatic apoB mRNA editing and increases of the proportion of serum apoB-100 protein were observed in senescent mice.

  3. Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8).

    PubMed

    Cuesta, Sara; Kireev, Roman; García, Cruz; Rancan, Lisa; Vara, Elena; Tresguerres, Jesús A F

    2013-06-01

    The aim of the present study was to investigate the effect of aging on several parameters related to glucose homeostasis and insulin resistance in pancreas and how melatonin administration could affect these parameters. Pancreas samples were obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant mice (SAMR1). Insulin levels in plasma were increased with aging in both SAMP8 and SAMR1 mice, whereas insulin content in pancreas was decreased with aging in SAMP8 and increased in SAMR1 mice. Expressions of glucagon and GLUT2 messenger RNAs (mRNAs) were increased with aging in SAMP8 mice, and no differences were observed in somatostatin and insulin mRNA expressions. Furthermore, aging decreased also the expressions of Pdx-1, FoxO 1, FoxO 3A and Sirt1 in pancreatic SAMP8 samples. Pdx-1 was decreased in SAMR1 mice, but no differences were observed in the rest of parameters on these mice strains. Treatment with melatonin was able to decrease plasma insulin levels and to increase its pancreatic content in SAMP8 mice. In SAMR1, insulin pancreatic content and plasma levels were decreased. HOMA-IR was decreased with melatonin treatment in both strains of animals. On the other hand, in SAMP8 mice, treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin mRNA. Furthermore, it was also able to increase the expression of Sirt1, Pdx-1 and FoxO 3A. According to these results, aging is associated with significant alterations in the relative expression of pancreatic genes associated to glucose metabolism. This has been especially observed in SAMP8 mice. Melatonin administration was able to improve pancreatic function in old SAMP8 mice and to reduce HOMA-IR improving their insulin physiology and glucose metabolism.

  4. Advancing age increases sperm chromatin damage and impairs fertility in peroxiredoxin 6 null mice

    PubMed Central

    Ozkosem, Burak; Feinstein, Sheldon I.; Fisher, Aron B.; O’Flaherty, Cristian

    2015-01-01

    Due to socioeconomic factors, more couples are choosing to delay conception than ever. Increasing average maternal and paternal age in developed countries over the past 40 years has raised the question of how aging affects reproductive success of males and females. Since oxidative stress in the male reproductive tract increases with age, we investigated the impact of advanced paternal age on the integrity of sperm nucleus and reproductive success of males by using a Prdx6−/− mouse model. We compared sperm motility, cytoplasmic droplet retention sperm chromatin quality and reproductive outcomes of young (2-month-old), adult (8-month-old), and old (20-month-old) Prdx6−/− males with their age-matched wild type (WT) controls. Absence of PRDX6 caused age-dependent impairment of sperm motility and sperm maturation and increased sperm DNA fragmentation and oxidation as well as decreased sperm DNA compaction and protamination. Litter size, total number of litters and total number of pups per male were significantly lower in Prdx6−/− males compared to WT controls. These abnormal reproductive outcomes were severely affected by age in Prdx6−/− males. In conclusion, the advanced paternal age affects sperm chromatin integrity and fertility more severely in the absence of PRDX6, suggesting a protective role of PRDX6 in age-associated decline in the sperm quality and fertility in mice. PMID:25796034

  5. Age-associated cardiomyopathy in heterozygous carrier mice of a pathological mutation of carnitine transporter gene, OCTN2.

    PubMed

    Xiaofei, E; Wada, Yasuhiko; Dakeishi, Miwako; Hirasawa, Fujiko; Murata, Katsuyuki; Masuda, Hirotake; Sugiyama, Toshihiro; Nikaido, Hiroko; Koizumi, Akio

    2002-07-01

    The purpose of this study was to test whether heterozygotes of juvenile visceral steatosis mice, a model for systemic carnitine deficiency, may develop age-associated cardiomyopathy. Tissue morphological observations were carried out by light and electron microscopy to compare the heterozygous and age-matched control mice at periods of 1 and 2 years. Possible effects of the pathological mutation on lipid and glucose levels was also evaluated in humans and mice. Except mild increases in serum cholesterol levels in male heterozygous mice and humans, no changes were found in other factors, indicating that none of the confounding factors seems to be profound. Results demonstrated that heterozygous mice had larger left ventriclular myocyte diameters than the control mice. Morphological changes in cardiac muscles by electron microscopy revealed age-associated changes of lipid deposition and abnormal mitochondria in heterozygous mice. Two out of 60 heterozygous cohort and one out of nine heterozygous trim-kill mice had cardiac hypertrophy at ages older than 2 years. The present study and our previous work suggest that the carrier state of OCTN2 pathological mutations might be a risk factor for age-associated cardiomyopathy.

  6. Arginase I expression is upregulated by dietary restriction in the liver of mice as a function of age.

    PubMed

    Majaw, Teikur; Sharma, Ramesh

    2015-09-01

    Arginase is a cytosolic enzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. This reaction comprises the final step of the urea cycle, which provides the principal route for the disposal of nitrogenous waste from protein catabolism. The present study investigates the normal endogenous activity and expression level of arginase I as a function of age in the liver of 2-, 6-, and 18-month-old mice. The effect of dietary restriction (DR) on the expression of arginase I was also investigated in two age groups of mice, 2- and 18-month old. Arginase I activity was assessed spectrophotometrically, and the level of arginase I protein was further confirmed by Western blotting analyses. Arginase I mRNA level was measured using real-time PCR. Our results show that the arginase I activity (U/mg protein) and protein level in liver was higher in 2-month-old mice and decreased gradually with age. In contrast, arginase I mRNA was observed to be higher in the older mice as compared to the younger mice. DR was seen to upregulate the arginase I activity and expression in both 2- and 18-month-old mice. The findings concluded that arginase I is down-regulated with the advancement of age in the liver of mice and is upregulated by DR. This suggests that DR plays an important role in maintaining related metabolic processes as a function of age in mice.

  7. Age-related reduction of structural complexity in spleen hematopoietic tissue architecture in mice.

    PubMed

    Pantic, Igor; Paunovic, Jovana; Basta-Jovanovic, Gordana; Perovic, Milan; Pantic, Senka; Milosevic, Nebojsa T

    2013-09-01

    The effects of aging on structural complexity in hematopoietic tissue are unknown. In this work, in a mouse experimental model, we report the age-related reduction of spleen hematopoietic tissue (SHT) complexity. Spleen tissue was obtained from the total of 64 male Swiss albino mice divided into 8 age groups: newborns (0 days old), 10 days, 20 days, 30 days, 120 days, 210 days, 300 and 390 days old. SHT was stained using conventional hematoxylin/eosin, and DNA-binding toluidine blue dyes. Fractal dimension as an indicator of cellular complexity, and lacunarity as indicator of tissue heterogeneity were determined based on the binarized SHT micrographs. Results indicate that fractal dimension of mice spleen hematopoietic tissue decreases with age, while lacunarity increases. These changes/trends have been detected in SHT stained both with toluidine blue and conventional hematoxylin/eosin. Fractal dimension was negatively correlated with lacunarity. The detected reduction in complexity suggests that age-related structural changes are present in mouse SHT both in general tissue architecture and progenitor cell DNA.

  8. Metabolism and aging: effects of cold exposure on metabolic rate, body composition, and longevity in mice.

    PubMed

    Vaanholt, Lobke M; Daan, Serge; Schubert, Kristin A; Visser, G Henk

    2009-01-01

    The proposition that increased energy expenditure shortens life has a long history. The rate-of-living theory (Pearl 1928 ) states that life span and average mass-specific metabolic rate are inversely proportional. Originally based on interspecific allometric comparisons between species of mammals, the theory was later rejected on the basis of comparisons between taxa (e.g., birds have higher metabolic rates than mammals of the same size and yet live longer). It has rarely been experimentally tested within species. Here, we investigated the effects of increased energy expenditure, induced by cold exposure, on longevity in mice. Longevity was measured in groups of 60 male mice maintained at either 22 degrees C (WW) or 10 degrees C (CC) throughout adult life. Forty additional mice were maintained at both of these temperatures to determine metabolic rate (by stable isotope turnover, gas exchange, and food intake) as well as the mass of body and organs of subsets of animals at four different ages. Because energy expenditure might affect longevity by either accumulating damage or by instantaneously affecting mortality rate, we included a third group of mice exposed to 10 degrees C early in life and to 22 degrees C afterward (CW). Exposure to cold increased mean daily energy expenditure by ca. 48% (from 47.8 kJ d(-1) in WW to 70.6 kJ d(-1) in CC mice, with CW intermediate at 59.9 kJ d(-1)). However, we observed no significant differences in median life span among the groups (WW, 832 d; CC, 834 d; CW, 751 d). CC mice had reduced body mass (lifetime mean 30.7 g) compared with WW mice (33.8 g), and hence their lifetime energy potential (LEP) per gram whole-body mass had an even larger excess than per individual. Greenberg ( 1999 ) has pointed out that the size of the energetically costly organs, rather than that of the whole body, may be relevant for the rate-of-living idea. We therefore expressed LEP also in terms of energy expenditure per gram dry lean mass or per gram

  9. Whey peptides prevent chronic ultraviolet B radiation-induced skin aging in melanin-possessing male hairless mice.

    PubMed

    Kimura, Yoshiyuki; Sumiyoshi, Maho; Kobayashi, Toshiya

    2014-01-01

    Whey proteins or peptides exhibit various actions, including an antioxidant action, an anticancer action, and a protective action against childhood asthma and atopic syndrome. The effects of orally administered whey peptides (WPs) on chronic ultraviolet B (UVB) radiation-induced cutaneous changes, including changes in cutaneous thickness, elasticity, wrinkle formation, etc., have not been examined. In this study, we studied the preventive effects of WPs on cutaneous aging induced by chronic UVB irradiation in melanin-possessing male hairless mice (HRM). UVB (36-180 mJ/cm(2)) was irradiated to the dorsal area for 17 wk in HRM, and the measurements of cutaneous thickness and elasticity in UVB irradiated mice were performed every week. WPs (200 and 400 mg/kg, twice daily) were administered orally for 17 wk. WPs inhibited the increase in cutaneous thickness, wrinkle formation, and melanin granules and the reduction in cutaneous elasticity associated with photoaging. Furthermore, it has been reported that UVB irradiation-induced skin aging is closely associated with the increase in expression of matrix metalloproteinase (MMP), vascular endothelial growth factor (VEGF), Ki-67-, and 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells. WPs also prevented increases in the expression of MMP-2 and pro-MMP-9, VEGF, and Ki-67- and 8-OHdG-positive cells induced by chronic UVB irradiation. It was found that WPs prevent type IV collagen degradation, angiogenesis, proliferation, and DNA damage caused by UVB irradiation. Overall, these results demonstrate the considerable benefit of WPs for protection against solar UV-irradiated skin aging as a supplemental nutrient.

  10. Endogenously determined restriction of food intake overcomes excitation-contraction uncoupling in JP45KO mice with aging.

    PubMed

    Delbono, Osvaldo; Messi, Maria Laura; Wang, Zhong-Min; Treves, Susan; Mosca, Barbara; Bergamelli, Leda; Nishi, Miyuki; Takeshima, Hiroshi; Shi, Hang; Xue, Bingzhong; Zorzato, Francesco

    2012-04-01

    The decline in muscular strength with age is disproportionate to the loss in total muscle mass that causes it. Knocking out JP45, an integral protein of the junctional face membrane of the skeletal muscle sarcoplasmic reticulum (SR), results in decreased expression of the voltage-gated Ca(2+) channel, Ca(v)1.1; excitation-contraction uncoupling (ECU); and loss of muscle force (Delbono et al., 2007). Here, we show that Ca(v)1.1 expression, charge movement, SR Ca(2+) release, in vitro contractile force, and sustained forced running remain stable in male JP45KO mice at 12 and 18 months. They also exhibit the level of ECU reported for 3-4-month mice (Delbono et al., 2007). No further decline at later ages was recorded. Preserved ECC was not related to increased expression of any protein that directly or indirectly interacts with JP45 at the triad junction. However, maintained muscle force and physical performance were associated with ablation of JP45 expression in the brain, spontaneous and significantly diminished food intake and less tendency toward obesity when exposed to a high-fat diet compared to WT. We propose that (1) endogenously generated restriction in food intake overcomes the deleterious effects of JP45 ablation on ECC and skeletal muscle force mainly through downregulation of neuropeptide-Y expression in the hypothalamic arcuate nucleus; and (2) the JP45KO mouse constitutes an invaluable model to examine the mechanisms controlling food intake as well as skeletal muscle function with aging.

  11. Mitochondria in the Aging Muscles of Flies and Mice: New Perspectives for Old Characters.

    PubMed

    Del Campo, Andrea; Jaimovich, Enrique; Tevy, Maria Florencia

    2016-01-01

    Sarcopenia is the loss of muscle mass accompanied by a decrease in muscle strength and resistance and is the main cause of disability among the elderly. Muscle loss begins long before there is any clear physical impact in the senior adult. Despite all this, the molecular mechanisms underlying muscle aging are far from being understood. Recent studies have identified that not only mitochondrial metabolic dysfunction but also mitochondrial dynamics and mitochondrial calcium uptake could be involved in the degeneration of skeletal muscle mass. Mitochondrial homeostasis influences muscle quality which, in turn, could play a triggering role in signaling of systemic aging. Thus, it has become apparent that mitochondrial status in muscle cells could be a driver of whole body physiology and organismal aging. In the present review, we discuss the existing evidence for the mitochondria related mechanisms underlying the appearance of muscle aging and sarcopenia in flies and mice.

  12. Mitochondria in the Aging Muscles of Flies and Mice: New Perspectives for Old Characters

    PubMed Central

    2016-01-01

    Sarcopenia is the loss of muscle mass accompanied by a decrease in muscle strength and resistance and is the main cause of disability among the elderly. Muscle loss begins long before there is any clear physical impact in the senior adult. Despite all this, the molecular mechanisms underlying muscle aging are far from being understood. Recent studies have identified that not only mitochondrial metabolic dysfunction but also mitochondrial dynamics and mitochondrial calcium uptake could be involved in the degeneration of skeletal muscle mass. Mitochondrial homeostasis influences muscle quality which, in turn, could play a triggering role in signaling of systemic aging. Thus, it has become apparent that mitochondrial status in muscle cells could be a driver of whole body physiology and organismal aging. In the present review, we discuss the existing evidence for the mitochondria related mechanisms underlying the appearance of muscle aging and sarcopenia in flies and mice. PMID:27630760

  13. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

    PubMed

    Mitchell, Sarah J; Madrigal-Matute, Julio; Scheibye-Knudsen, Morten; Fang, Evandro; Aon, Miguel; González-Reyes, José A; Cortassa, Sonia; Kaushik, Susmita; Gonzalez-Freire, Marta; Patel, Bindi; Wahl, Devin; Ali, Ahmed; Calvo-Rubio, Miguel; Burón, María I; Guiterrez, Vincent; Ward, Theresa M; Palacios, Hector H; Cai, Huan; Frederick, David W; Hine, Christopher; Broeskamp, Filomena; Habering, Lukas; Dawson, John; Beasley, T Mark; Wan, Junxiang; Ikeno, Yuji; Hubbard, Gene; Becker, Kevin G; Zhang, Yongqing; Bohr, Vilhelm A; Longo, Dan L; Navas, Placido; Ferrucci, Luigi; Sinclair, David A; Cohen, Pinchas; Egan, Josephine M; Mitchell, James R; Baur, Joseph A; Allison, David B; Anson, R Michael; Villalba, José M; Madeo, Frank; Cuervo, Ana Maria; Pearson, Kevin J; Ingram, Donald K; Bernier, Michel; de Cabo, Rafael

    2016-06-14

    Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

  14. Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes

    SciTech Connect

    Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi; Cerasoli, Douglas M.; Bahnson, Brian J.

    2009-09-02

    The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P{sub R} and P{sub S} stereoisomers at the P-chiral center. The tabun complex displayed only the P{sub R} stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

  15. Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice

    PubMed Central

    Zang, Zhi-Jun; Tang, Hong-Feng; Tuo, Ying; Xing, Wei-Jie; Ji, Su-Yun; Gao, Yong; Deng, Chun-Hua

    2016-01-01

    Twenty-four-month-old male C57BL/6 mice with low serum testosterone levels were used as a late-onset hypogonadism (LOH) animal model for examining the effects of velvet antler polypeptide (VAP) on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg−1 body weight per day (n = 10 mice per dose). Control animals (n = 10) received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone (ITT) concentration also increased in the VAP-treated groups. The expression of StAR, P450scc, and 3β-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis (StAR, P450scc, and 3β-HSD) and the following promotion of testosterone synthesis in vivo. PMID:26608944

  16. Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice.

    PubMed

    Zang, Zhi-Jun; Tang, Hong-Feng; Tuo, Ying; Xing, Wei-Jie; Ji, Su-Yun; Gao, Yong; Deng, Chun-Hua

    2016-01-01

    Twenty-four-month-old male C57BL/6 mice with low serum testosterone levels were used as a late-onset hypogonadism (LOH) animal model for examining the effects of velvet antler polypeptide (VAP) on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg-1 body weight per day (n = 10 mice per dose). Control animals (n = 10) received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone (ITT) concentration also increased in the VAP-treated groups. The expression of StAR, P450scc, and 3β-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis (StAR, P450scc, and 3β-HSD) and the following promotion of testosterone synthesis in vivo.

  17. Molecular detection of chromosomal abnormalities in germ and somatic cells of aged male mice

    SciTech Connect

    Lowe, X.; Baulch, J.; Quintana, L.; Ramsey, M.; Breneman, J.; Tucker, J.; Wyrobek, A.; Collins, B.; Allen, J.; Holland, N.

    1994-12-31

    Three cytogenetic methods were applied to eight B6C3F1 male mice aged 22.5 - 30.5mo to determine if advanced age was associated with an elevated risk of producing chromosomally defective germinal and somatic cells; sperm aneuploidy analysis by multi-color fluorescence in situ hybridization for three chromosomes, spermatid micronucleus analysis with anti-kinetochore antibodies, and translocation analysis of somatic metaphases by {open_quotes}painting{close_quotes} for two chromosomes. Eight mice aged 2.4mo served as controls. Sperm aneuploidy was measured by multi-color fluorescence in situ co-hybridization with DNA probes specific for chromosomes X, Y and 8, scoring 10,000 cells per animal. The aged group showed significant 1.5 - 2.0 fold increases in the hyperhaploidy phenotypes X-X-8, Y-Y-8, 8-8-Y, and 8-8-X with the greater effects appearing in animals aged >29mo. The aged group also showed significantly increased frequencies of micronucleated spermatids (2.0 vs 0.4 per 1000; all were kinetochore negative). Analysis of metaphase chromosomes from blood by {open_quotes}painting{close_quotes} of chromosomes 2 and 8 yielded 4 translocation per 858 cell-equivalents in the aged group which was a non-significant elevation over 0/202 in controls. Although interpretation must be cautious due to the small number of animals analyzed, these findings suggest that advanced paternal age may be a risk factor for chromosomal abnormalities of reproductive and somatic importance.

  18. High folic acid intake reduces natural killer cell cytotoxicity in aged mice.

    PubMed

    Sawaengsri, Hathairat; Wang, Junpeng; Reginaldo, Christina; Steluti, Josiane; Wu, Dayong; Meydani, Simin Nikbin; Selhub, Jacob; Paul, Ligi

    2016-04-01

    Presence of unmetabolized folic acid in plasma, which is indicative of folic acid intake beyond the metabolic capacity of the body, is associated with reduced natural killer (NK) cell cytotoxicity in postmenopausal women ≥50years. NK cells are cytotoxic lymphocytes that are part of the innate immune system critical for surveillance and defense against virus-infected and cancer cells. We determined if a high folic acid diet can result in reduced NK cell cytotoxicity in an aged mouse model. Female C57BL/6 mice (16-month-old) were fed an AIN-93M diet with the recommended daily allowance (1× RDA, control) or 20× RDA (high) folic acid for 3months. NK cytotoxicity was lower in splenocytes from mice fed a high folic acid diet when compared to mice on control diet (P<.04). The lower NK cell cytotoxicity in high folic acid fed mice could be due to their lower mature cytotoxic/naïve NK cell ratio (P=.03) when compared to the control mice. Splenocytes from mice on high folic acid diet produced less interleukin (IL)-10 when stimulated with lipopolysaccharide (P<.05). The difference in NK cell cytotoxicity between dietary groups was abolished when the splenocytes were supplemented with exogenous IL-10 prior to assessment of the NK cytotoxicity, suggesting that the reduced NK cell cytotoxicity of the high folic acid group was at least partially due to reduced IL-10 production. This study demonstrates a causal relationship between high folic acid intake and reduced NK cell cytotoxicity and provides some insights into the potential mechanisms behind this relationship.

  19. Dicer Expression Exhibits a Tissue-Specific Diurnal Pattern That Is Lost during Aging and in Diabetes

    PubMed Central

    Yan, Yuanqing; Salazar, Tatiana E.; Dominguez, James M.; Nguyen, Dung V.; Li Calzi, Sergio; Bhatwadekar, Ashay D.; Qi, Xiaoping; Busik, Julia V.

    2013-01-01

    Dysregulation of circadian rhythmicity is identified as a key factor in disease pathogenesis. Circadian rhythmicity is controlled at both a transcriptional and post-transcriptional level suggesting the role of microRNA (miRNA) and double-stranded RNA (dsRNA) in this process. Endonuclease Dicer controls miRNA and dsRNA processing, however the role of Dicer in circadian regulation is not known. Here we demonstrate robust diurnal oscillations of Dicer expression in central and peripheral clock control systems including suprachiasmatic nucleolus (SCN), retina, liver, and bone marrow (BM). The Dicer oscillations were either reduced or phase shifted with aging and Type 2 diabetes. The decrease and phase shift of Dicer expression was associated with a similar decrease and phase shift of miRNAs 146a and 125a-5p and with an increase in toxic Alu RNA. Restoring Dicer levels and the diurnal patterns of Dicer-controlled miRNA and RNA expression may provide new therapeutic strategies for metabolic disease and aging-associated complications. PMID:24244599

  20. Humulus japonicus extract exhibits antioxidative and anti-aging effects via modulation of the AMPK-SIRT1 pathway.

    PubMed

    Sung, Bokyung; Chung, Ji Won; Bae, Ha Ram; Choi, Jae Sue; Kim, Cheol Min; Kim, Nam Deuk

    2015-05-01

    The perennial herb, Humulus japonicus, has been previously described as possessing potential antituberculosis and anti-inflammatory properties. In the present study, the anti-aging activity of ethanol extracts from the leaves of H. japonicus (HJE) was evaluated in yeast and human fibroblast cells. In addition, the antioxidant activity of HJE was analyzed using free radical scavenging assays. Furthermore, the mechanism underlying the hypothesized HJE-associated extension of lifespan was investigated, and the results indicated that HJE was able to extend the lifespan of yeast cells. Further experiments demonstrated that HJE upregulated the longevity-associated proteins, sirtuin 1 and AMP-activated protein kinase, and effectively inhibited the generation of reactive oxygen species (ROS). In addition, the antioxidative potential of the active constituents of HJE, including luteolin, luteolin 7-glycoside, quercetin and quercitrin, was evaluated and the results demonstrated that these flavonoids were able to scavenge ROS in cell-free and intracellular systems. In summary, the results revealed that HJE possessed the potential for antioxidative activity; however, further in vivo investigations are required with the aim of developing safe, high-efficacy anti-aging agents.

  1. Humulus japonicus extract exhibits antioxidative and anti-aging effects via modulation of the AMPK-SIRT1 pathway

    PubMed Central

    SUNG, BOKYUNG; CHUNG, JI WON; BAE, HA RAM; CHOI, JAE SUE; KIM, CHEOL MIN; KIM, NAM DEUK

    2015-01-01

    The perennial herb, Humulus japonicus, has been previously described as possessing potential antituberculosis and anti-inflammatory properties. In the present study, the anti-aging activity of ethanol extracts from the leaves of H. japonicus (HJE) was evaluated in yeast and human fibroblast cells. In addition, the antioxidant activity of HJE was analyzed using free radical scavenging assays. Furthermore, the mechanism underlying the hypothesized HJE-associated extension of lifespan was investigated, and the results indicated that HJE was able to extend the lifespan of yeast cells. Further experiments demonstrated that HJE upregulated the longevity-associated proteins, sirtuin 1 and AMP-activated protein kinase, and effectively inhibited the generation of reactive oxygen species (ROS). In addition, the antioxidative potential of the active constituents of HJE, including luteolin, luteolin 7-glycoside, quercetin and quercitrin, was evaluated and the results demonstrated that these flavonoids were able to scavenge ROS in cell-free and intracellular systems. In summary, the results revealed that HJE possessed the potential for antioxidative activity; however, further in vivo investigations are required with the aim of developing safe, high-efficacy anti-aging agents. PMID:26136899

  2. A Novel Bufalin Derivative Exhibited Stronger Apoptosis-Inducing Effect than Bufalin in A549 Lung Cancer Cells and Lower Acute Toxicity in Mice

    PubMed Central

    Liu, Miao; Feng, Li-Xing; Sun, Peng; Liu, Wang; Wu, Wan-Ying; Jiang, Bao-Hong; Yang, Min; Hu, Li-Hong; Guo, De-An; Liu, Xuan

    2016-01-01

    BF211 is a synthetic molecule derived from bufalin (BF). The apoptosis-inducing effect of BF211 was stronger than that of BF while the acute toxicity of BF211 was much lower than that of BF. BF211 exhibited promising concentration-dependent anti-cancer effects in nude mice inoculated with A549 cells in vivo. The growth of A549 tumor xenografts was almost totally blocked by treatment with BF211 at 6 mg/kg. Notably, BF and BF211 exhibited differences in their binding affinity and kinetics to recombinant proteins of the α subunits of Na+/K+-ATPase. Furthermore, there was a difference in the effects of BF or BF211 on inhibiting the activity of porcine cortex Na+/K+-ATPase and in their time-dependent effects on intracellular Ca2+ levels in A549 cells. The time-dependent effects of BF or BF211 on the activation of Src, which was mediated by the Na+/K+-ATPase signalosome, in A549 cells were also different. Both BF and BF211 could induce apoptosis-related cascades, such as activation of caspase-3 and the cleavage of PARP (poly ADP-ribose polymerase) in A549 cells, in a concentration-dependent manner; however, the effects of BF211 on apoptosis-related cascades was stronger than that of BF. The results of the present study supported the importance of binding to the Na+/K+-ATPase α subunits in the mechanism of cardiac steroids and also suggested the possibility of developing new cardiac steroids with a stronger anti-cancer activity and lower toxicity as new anti-cancer agents. PMID:27459387

  3. Aging has small effects on initial ischemic acute kidney injury development despite changing intrarenal immunologic micromilieu in mice.

    PubMed

    Jang, Hye Ryoun; Park, Ji Hyeon; Kwon, Ghee Young; Park, Jae Berm; Lee, Jung Eun; Kim, Dae Joong; Kim, Yoon-Goo; Kim, Sung Joo; Oh, Ha Young; Huh, Wooseong

    2016-02-15

    Inflammatory process mediated by innate and adaptive immune systems is a major pathogenic mechanism of renal ischemia-reperfusion injury (IRI). There are concerns that organ recipients may be at increased risk of developing IRI after receiving kidneys from elder donors. To reveal the effects of aging on the development of renal IRI, we compared the immunologic micromilieu of normal and postischemic kidneys from mice of three different ages (9 wk, 6 mo, and 12 mo). There was a higher number of total T cells, especially effector memory CD4/CD8 T cells, and regulatory T cells in the normal kidneys of old mice. On day 2 after IRI, the proportion of necrotic tubules and renal functional changes were comparable between groups although old mice had a higher proportion of damaged tubule compared with young mice. More T cells, but less B cells, trafficked into the postischemic kidneys of old mice. The infiltration of NK T cells was similar across the groups. Macrophages and neutrophils were comparable between groups in both normal kidneys and postischemic kidneys. The intrarenal expressions of TNF-α and VEGF were decreased in normal and postischemic kidneys of aged mice. These mixed effects of aging on lymphocytes and cytokines/chemokines were not different between the two groups of old mice. Our study demonstrates that aging alters the intrarenal micromilieu but has small effects on the development of initial renal injury after IRI. Further study investigating aging-dependent differences in the repair process of renal IRI may be required.

  4. Autoimmune manifestations in aged mice arise from early-life immune dysregulation

    PubMed Central

    Mahmoud, Tamer I.; Wang, Jingya; Karnell, Jodi L.; Wang, Qiming; Wang, Shu; Naiman, Brian; Gross, Phillip; Brohawn, Philip Z.; Morehouse, Chris; Aoyama, Jordan; Wasserfall, Clive; Carter, Laura; Atkinson, Mark A.; Serreze, David V.; Braley-Mullen, Helen; Mustelin, Tomas; Kolbeck, Roland; Herbst, Ronald; Ettinger, Rachel

    2017-01-01

    Autoantibodies can be present years to decades prior to the onset of disease manifestations in autoimmunity. This suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. Here we show Sjögren’s Syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren’s pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks-of-age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed early anti-CD40L greatly repressed B cell function, while having a broader effect on multiple biological pathways including IL-12 and interferon signaling. Importantly, a single, prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and NOD mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest early peripheral immune dysregulation gives rise to autoimmune manifestations later in life and for diseases pre-dated by autoantibodies, early prophylactic intervention with biologics may prove efficacious. PMID:27798262

  5. Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer's disease.

    PubMed

    Duncan, Marilyn J; Smith, J Tyler; Franklin, Kathleen M; Beckett, Tina L; Murphy, M Paul; St Clair, Daret K; Donohue, Kevin D; Striz, Martin; O'Hara, Bruce F

    2012-08-01

    Profound disruptions of circadian rhythms and sleep/wake cycles constitute a major cause of institutionalization of AD patients. This study investigated whether a rodent model of AD, APP(NLH/NLH)/PS-1(P264L/264L) (APPxPS1) mice, exhibits circadian alterations. The APPxPS1 mice were generated using CD-1/129 mice and Cre-lox knock-in technology to "humanize" the mouse amyloid (A)β sequence and create a presenilin-1 mutation identified in familial early-onset AD patients. APPxPS1 and WT mice of several ages (~4, 11, and 15 months) were monitored for circadian rhythms in wheel running, cage activity, and sleep:wake behavior. After rhythm assessment, the mice were euthanized at zeitgeber time (ZT) 2 or 10 (i.e., 2 or 10 h after lights-on) and brains were dissected. Amyloidβ levels were measured in cortical samples and brain sections of the hypothalamus and hippocampus were prepared and used for in situ hybridization of circadian or neuropeptide genes. The most significant effects of the APPxPS1 transgenes were phase delays of ~2 h in the onset of daytime wakefulness bouts (P<0.005) and peak wakefulness (P<0.02), potentially relevant to phase delays previously reported in AD patients. However, genotype did not affect the major activity peaks or phases of wheel running, wake, or general movement, which were bimodal with dominant dawn and dusk activity. Expression of Period 2 in the suprachiasmatic nucleus was affected by ZT (P<0.0001) with a marginal interaction effect of age, genotype, and ZT (P<0.08). A separate analysis of the old animals indicated a robust interaction between ZT and genotype, as well as main effects of these parameters. Aging also altered sleep (e.g., bout length and amount of daytime sleep) and the amount of wheel running and cage activity. In conclusion, the APPxPS1 knock-in mice exhibit some alterations in their sleep:wake rhythm and clock gene expression, but do not show robust, genotype-related changes in activity rhythms. The prominent daytime

  6. 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

  7. Supplemental nitric oxide augments satellite cell activity on cultured myofibers from aged mice.

    PubMed

    Betters, Jenna L; Lira, Vitor A; Soltow, Quinlyn A; Drenning, Jason A; Criswell, David S

    2008-12-01

    Skeletal muscle regenerative potential is reduced with aging. We hypothesized that in vitro activation of muscle satellite cells would be compromised, and that nitric oxide (NO) supplementation would improve satellite cell activity in old muscle. Single intact myofibers were isolated from the gastrocnemius muscles of young (2 mo), adult (10 mo), and aged (22 mo) mice. Fibers were centrifuged to stimulate satellite cells and incubated with L-arginine (2mM), the NO donor, diethylenetriamine NONOate (DETA-NO; 10 microM), or control media for 48 h. The number of activated satellite cells after centrifugation was reduced in aged fibers compared to young and adult. L-arginine or DETA-NO treatment increased satellite cell activation in all age groups. However, an age-dependent deficit in satellite cell activity persisted within treatment groups. In separate fibers, exogenous HGF was equally effective in activating satellite cells across age groups, indicating that events downstream of HGF release are intact in aged muscle. These data suggest that l-arginine bioavailability and NO production limit muscle satellite cell activity in response to a submaximal mechanical stimulus, regardless of age. Further, the decline in satellite cell activity in early senescence can be partially abrogated by exogenous L-arginine or an NO donor.

  8. Plasmacytoid DC from Aged Mice Down-Regulate CD8 T Cell Responses by Inhibiting cDC Maturation after Encephalitozoon cuniculi Infection

    PubMed Central

    Gigley, Jason P.; Khan, Imtiaz A.

    2011-01-01

    Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations. PMID:21695169

  9. Plasmacytoid DC from aged mice down-regulate CD8 T cell responses by inhibiting cDC maturation after Encephalitozoon cuniculi infection.

    PubMed

    Gigley, Jason P; Khan, Imtiaz A

    2011-01-01

    Age associated impairment of immune function results in inefficient vaccination, tumor surveillance and increased severity of infections. Several alterations in adaptive immunity have been observed and recent studies report age related declines in innate immune responses to opportunistic pathogens including Encephalitozoon cuniculi. We previously demonstrated that conventional dendritic cells (cDC) from 9-month-old animals exhibit sub-optimal response to E. cuniculi infection, suggesting that age associated immune senescence begins earlier than expected. We focused this study on how age affects plasmacytoid DC (pDC) function. More specifically how aged pDC affect cDC function as we observed that the latter are the predominant activators of CD8 T cells during this infection. Our present study demonstrates that pDC from middle-aged mice (12 months) suppress young (8 week old) cDC driven CD8 T cell priming against E. cuniculi infection. The suppressive effect of pDC from older mice decreased maturation of young cDC via cell contact. Aged mouse pDC exhibited higher expression of PD-L1 and blockade of their interaction with cDC via this molecule restored cDC maturation and T cell priming. Furthermore, the PD-L1 dependent suppression of cDC T cell priming was restricted to effector function of antigen-specific CD8 T cells not their expansion. To the best of our knowledge, the data presented here is the first report highlighting a cell contact dependent, PD-L1 regulated, age associated defect in a DC subpopulation that results in a sub-optimal immune response against E. cuniculi infection. These results have broad implications for design of immunotherapeutic approaches to enhance immunity for aging populations.

  10. Survival of irradiated recipient mice after transplantation of bone marrow from young, old and "early aging" mice.

    PubMed

    Guest, Ian; Ilic, Zoran; Scrable, Heidi; Sell, Stewart

    2015-12-01

    Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16-18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors. In the p44-based model, short term survival/engraftment is significantly reduced in recipients of 11 month-old p44 donor cells compared to 4 week-old p44 or wild type donor cells of either age; mid-life survival at 40 weeks is also significantly less in recipients of p44 cells. BMDSCs are readily detectable within recipient bone marrow, lymph node, intestinal villi and liver sinusoids, but not in epithelial derived cells. These results indicate that recipients of young BMDSCs may survive longer than recipients of old bone marrow, but the difference is marginal at best.

  11. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice.

    PubMed

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M; Schrøder, Henrik Daa

    2007-11-01

    Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed effect of ADAM12 was suggested to be mediated via a membrane-stabilizing up-regulation of utrophin, alpha7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also improved regeneration after freeze injury, presumably by the same mechanism. Hence, it was suggested that ADAM12 could be a candidate for nonreplacement gene therapy of Duchenne muscular dystrophy. We therefore evaluated the long-term effect of ADAM12 overexpression in muscle. Surprisingly, we observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically overexpressing ADAM12 (ADAM12(+)/mdx mice), even though their utrophin levels were mildly elevated compared with age-matched controls. Thus, membrane stabilization was not sufficient to provide protection during prolonged disease. Consequently, we reinvestigated skeletal muscle regeneration in ADAM12 transgenic mice (ADAM12(+)) after a knife cut lesion and observed that the regeneration process was significantly impaired. ADAM12 seemed to inhibit the satellite cell response and delay myoblast differentiation. These results discourage long-term therapeutic use of ADAM12. They also point to impaired regeneration as a possible factor in development of muscular dystrophy.

  12. Global gene profiling of aging lungs in Atp8b1 mutant mice

    PubMed Central

    Soundararajan, Ramani; Stearns, Timothy M.; Czachor, Alexander; Fukumoto, Jutaro; Turn, Christina; Westermann-Clark, Emma; Breitzig, Mason; Tan, Lee; Lockey, Richard F.; King, Benjamin L.; Kolliputi, Narasaiah

    2016-01-01

    Objective Recent studies implicate cardiolipin oxidation in several age-related diseases. Atp8b1 encoding Type 4 P-type ATPases is a cardiolipin transporter. Mutation in Atp8b1 gene or inflammation of the lungs impairs the capacity of Atp8b1 to clear cardiolipin from lung fluid. However, the link between Atp8b1 mutation and age-related gene alteration is unknown. Therefore, we investigated how Atp8b1 mutation alters age-related genes. Methods We performed Affymetrix gene profiling of lungs isolated from young (7-9 wks, n=6) and aged (14 months, 14 M, n=6) C57BL/6 and Atp8b1 mutant mice. In addition, Ingenuity Pathway Analysis (IPA) was performed. Differentially expressed genes were validated by quantitative real-time PCR (qRT-PCR). Results Global transcriptome analysis revealed 532 differentially expressed genes in Atp8b1 lungs, 157 differentially expressed genes in C57BL/6 lungs, and 37 overlapping genes. IPA of age-related genes in Atp8b1 lungs showed enrichment of Xenobiotic metabolism and Nrf2-mediated signaling pathways. The increase in Adamts2 and Mmp13 transcripts in aged Atp8b1 lungs was validated by qRT-PCR. Similarly, the decrease in Col1a1 and increase in Cxcr6 transcripts was confirmed in both Atp8b1 mutant and C57BL/6 lungs. Conclusion Based on transcriptome profiling, our study indicates that Atp8b1 mutant mice may be susceptible to age-related lung diseases. PMID:27689529

  13. Royal jelly prevents the progression of sarcopenia in aged mice in vivo and in vitro.

    PubMed

    Niu, Kaijun; Guo, Hui; Guo, Yinting; Ebihara, Satoru; Asada, Masanori; Ohrui, Takashi; Furukawa, Katsutoshi; Ichinose, Masakazu; Yanai, Kazuhiko; Kudo, Yukitsuka; Arai, Hiroyuki; Okazaki, Tatsuma; Nagatomi, Ryoichi

    2013-12-01

    Sarcopenia is characterized by the age-related loss of muscle mass and strength. One of the mechanisms of sarcopenia is the loss in the function and number of muscle satellite cells. Royal jelly (RJ) is a health food used worldwide. To obtain better digestion and absorption than RJ, protease-treated RJ (pRJ) has been developed. RJ and pRJ have been suggested to have potential pharmacological benefits such as prolonging the life span and reducing fatigue. Because these effects may improve sarcopenia and the functions of satellite cells, we examined the effects of RJ or pRJ treatment on the skeletal muscles in an animal model using aged mice. In vivo, RJ/pRJ treatment attenuated the decrease in the muscle weight and grip strength and increased the regenerating capacity of injured muscles and the serum insulin-like growth factor-1 levels compared with controls. In vitro, using isolated satellite cells from aged mice, pRJ treatment increased the cell proliferation rate, promoted cell differentiation, and activated Akt intracellular signaling pathway compared with controls. These findings suggest that RJ/pRJ treatment had a beneficial effect on age-related sarcopenia.

  14. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

    PubMed Central

    Bitto, Alessandro; Ito, Takashi K; Pineda, Victor V; LeTexier, Nicolas J; Huang, Heather Z; Sutlief, Elissa; Tung, Herman; Vizzini, Nicholas; Chen, Belle; Smith, Kaleb; Meza, Daniel; Yajima, Masanao; Beyer, Richard P; Kerr, Kathleen F; Davis, Daniel J; Gillespie, Catherine H; Snyder, Jessica M; Treuting, Piper M; Kaeberlein, Matt

    2016-01-01

    The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome. DOI: http://dx.doi.org/10.7554/eLife.16351.001 PMID:27549339

  15. Behavioural Phenotyping of APPswe/PS1δE9 Mice: Age-Rrelated Changes and Effect of Long-Term Paroxetine Treatment

    PubMed Central

    Olesen, Louise Ørum; Bouzinova, Elena V.; Severino, Maurizio; Sivasaravanaparan, Mithula; Hasselstrøm, Jørgen Bo

    2016-01-01

    Alzheimer’s disease (AD) is a devastating illness characterized by a progressive loss of cognitive, social, and emotional functions, including memory impairments and more global cognitive deficits. Clinical-epidemiological evidence suggests that neuropsychiatric symptoms precede the onset of cognitive symptoms both in humans with early and late onset AD. The behavioural profile promoted by the AD pathology is believed to associate with degeneration of the serotonergic system. Using the APPswe/PS1δE9 model of AD-like pathology starting with 9 months old mice, we characterised long term non-cognitive behavioural changes measured at 9, 12, 15, and 18 months of age and applied principal component analysis on data obtained from open field, elevated plus maze, and social interaction tests. Long-term treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine was applied to assess the role of 5-HT on the behavioural profile; duration of treatment was 9 months, initiated when mice were 9 months of age. Treatment with paroxetine delays the decline in locomotion, in exploration and risk assessment behaviour, found in the APP/PS1 mice. APP/PS1 mice also exhibit low social activity and less aggressiveness, both of which are not affected by treatment with paroxetine. The APP/PS1 behavioural phenotype, demonstrated in this study, only begins to manifest itself from 12 months of age. Our results indicate that treatment with SSRI might ameliorate some of the behavioural deficits found in aged APP/PS1 mice. PMID:27814403

  16. Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

    PubMed Central

    Ohshima, Toshio; Schiffmann, Raphael; Murray, Gary J.; Kopp, Jeffrey; Quirk, Jane M.; Stahl, Stefanie; Chan, Chi-Chao; Zerfas, Patricia; Tao-Cheng, Jung-Hwa; Ward, J. M.; Brady, Roscoe O.; Kulkarni, Ashok B.

    1999-01-01

    Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease. PMID:10339603

  17. Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder

    PubMed Central

    DeLorey, Timothy M.; Sahbaie, Peyman; Hashemi, Ezzat; Homanics, Gregg E.; Clark, J. David

    2009-01-01

    Objective GABAA receptors play an important regulatory role in the developmental events leading to the formation of complex neuronal networks and to the behaviors they govern. The primary aim of this study was to assess whether gabrb3 gene deficient (gabrb3-/-) mice exhibit abnormal social behavior, a core deficit associated with autism spectrum disorder. Methods Social and exploratory behaviors along with non-selective attention were assessed in gabrb3-/-, littermates (gabrb3+/+) and progenitor strains, C57BL/6J and 129/SvJ. In addition, semi-quantitative assessments of the size of cerebellar vermal lobules were performed on gabrb3+/+ and gabrb3-/- mice. Results Relative to controls, gabrb3-/- mice exhibited significant deficits in activities related to social behavior including sociability, social novelty and nesting. In addition, gabrb3-/- mice also exhibited differences in exploratory behavior compared to controls, as well as reductions in the frequency and duration of rearing episodes, suggested as being an index of non-selective attention. Gabrb3-/- mice also displayed significant hypoplasia of the cerebellar vermis compared to gabrb3+/+ mice. Conclusions The observed behavioral deficits, especially regarding social behaviors, strengthens the face validity of the gabrb3 gene deficient mouse as being a model of autism spectrum disorder. PMID:17983671

  18. Maintenance of muscle mass and load-induced growth in Muscle RING Finger 1 null mice with age.

    PubMed

    Hwee, Darren T; Baehr, Leslie M; Philp, Andrew; Baar, Keith; Bodine, Sue C

    2014-02-01

    Age-related loss of muscle mass occurs to varying degrees in all individuals and has a detrimental effect on morbidity and mortality. Muscle RING Finger 1 (MuRF1), a muscle-specific E3 ubiquitin ligase, is believed to mediate muscle atrophy through the ubiquitin proteasome system (UPS). Deletion of MuRF1 (KO) in mice attenuates the loss of muscle mass following denervation, disuse, and glucocorticoid treatment; however, its role in age-related muscle loss is unknown. In this study, skeletal muscle from male wild-type (WT) and MuRF1 KO mice was studied up to the age of 24 months. Muscle mass and fiber cross-sectional area decreased significantly with age in WT, but not in KO mice. In aged WT muscle, significant decreases in proteasome activities, especially 20S and 26S β5 (20-40% decrease), were measured and were associated with significant increases in the maladaptive endoplasmic reticulum (ER) stress marker, CHOP. Conversely, in aged MuRF1 KO mice, 20S or 26S β5 proteasome activity was maintained or decreased to a lesser extent than in WT mice, and no increase in CHOP expression was measured. Examination of the growth response of older (18 months) mice to functional overload revealed that old WT mice had significantly less growth relative to young mice (1.37- vs. 1.83-fold), whereas old MuRF1 KO mice had a normal growth response (1.74- vs. 1.90-fold). These data collectively suggest that with age, MuRF1 plays an important role in the control of skeletal muscle mass and growth capacity through the regulation of cellular stress.

  19. Aging does not affect spermatogenic recovery after experimentally induced injury in mice.

    PubMed

    Ehmcke, Jens; Joshi, Bhavika; Hergenrother, Scott D; Schlatt, Stefan

    2007-01-01

    Testes in aging mammals undergo a variety of age-related changes, such as reduction of size, lower sperm output, an increase in abnormal forms of sperm, and endocrine malfunctions. It has been suggested that the spermatogenic defects are due to loss and dysfunction of spermatogonial stem cells as well as deterioration of the tubule microenvironment. In the present study, we explore the depletion and recovery of spermatogenesis in young (3 month) and old (12 month) mice exposed to cooling, X-irradiation (5 Gy) or cytotoxic treatment using Busulfan (40 mg/kg). We aim to determine a potential age-related change of vulnerability to gonadotoxic treatments by describing the intensity of spermatogenic depletion and the degree of spermatogenic recolonization with qualitative and quantitative parameters on organ weights and histological parameters at two time points (2 weeks, depletion; 6 weeks, recovery). Our data reveal specific acute effects of cooling on multinucleation of germ cells but no other severe injury. Irradiation and Busulfan-treatment exerted the expected depletional wave of germ cells leading to severe testicular injury and spermatogenic failure. The recovery of spermatogenesis occurred in both treatment groups and both age groups to a similar extent. We therefore noted no prominent age-related differences in spermatogenic depletion and recovery in any treatment group. We conclude that in both age groups, the remaining spermatogonial stem cells are capable to induce spermatogenic recovery and the aging tubule microenvironment at 1 year has not become more vulnerable to irradiation, Busulfan-treatment or testicular cooling.

  20. Age-related transcriptional changes in gene expression in different organs of mice support the metabolic stability theory of aging.

    PubMed

    Brink, Thore C; Demetrius, Lloyd; Lehrach, Hans; Adjaye, James

    2009-10-01

    Individual differences in the rate of aging are determined by the efficiency with which an organism transforms resources into metabolic energy thus maintaining the homeostatic condition of its cells and tissues. This observation has been integrated with analytical studies of the metabolic process to derive the following principle: The metabolic stability of regulatory networks, that is the ability of cells to maintain stable concentrations of reactive oxygen species (ROS) and other critical metabolites is the prime determinant of life span. The metabolic stability of a regulatory network is determined by the diversity of the metabolic pathways or the degree of connectivity of genes in the network. These properties can be empirically evaluated in terms of transcriptional changes in gene expression. We use microarrays to investigate the age-dependence of transcriptional changes of genes in the insulin signaling, oxidative phosphorylation and glutathione metabolism pathways in mice. Our studies delineate age and tissue specific patterns of transcriptional changes which are consistent with the metabolic stability-longevity principle. This study, in addition, rejects the free radical hypothesis which postulates that the production rate of ROS, and not its stability, determines life span.

  1. Sex and age mortality responses in zinc acetate-treated mice

    SciTech Connect

    Hogan, G.R.; Cole, B.S.; Lovelace, J.M.

    1987-07-01

    In regard to trace metal treatment or exposure, a number of variables are known to affect the expression of toxicity concerning its time course and degree. For example, known variables are route of administration, anionic component of the test substance, and sex and age of the recipient animal. Concerning the latter, little, if any, data have been reported dealing with sex- and age-related responses to excess zinc in mammalian systems. The primary purpose of the short communication presented here focuses on the determination of median lethal dose in sexually immature, i.e., juvenile, and adult female and male mice following a single zinc acetate insult. In addition, variation of lethality responses was examined with the age and sex groups to a divided treatment of a lethal dosage of zinc acetate, the injections of which were separated by various intervals.

  2. Proteome wide reduction in AGE modification in streptozotocin induced diabetic mice by hydralazine mediated transglycation

    PubMed Central

    Kesavan, Suresh K.; Bhat, Shweta; Golegaonkar, Sandeep B.; Jagadeeshaprasad, Mashanipalya G.; Deshmukh, Arati B.; Patil, Harshal S.; Bhosale, Santosh D.; Shaikh, Mahemud L.; Thulasiram, Hirekodathakallu V.; Boppana, Ramanamurthy; Kulkarni, Mahesh J.

    2013-01-01

    The non-enzymatic reaction between glucose and protein can be chemically reversed by transglycation. Here we report the transglycation activity of hydralazine using a newly developed MALDI-TOF-MS based assay. Hydralazine mediated transglycation of HbA1c, plasma proteins and kidney proteins was demonstrated in streptozotocin (STZ) induced diabetic mice, as evidenced by decrease in protein glycation, as well as presence of hydralazine-glucose conjugate in urine of diabetic mice treated with hydralazine. Hydralazine down regulated the expression of Receptor for Advanced Glycation End products (RAGE), NADPH oxidase (NOX), and super oxide dismutase (SOD). These findings will provide a new dimension for developing intervention strategies for the treatment of glycation associated diseases such as diabetes complications, atherosclerosis, and aging. PMID:24126953

  3. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans.

    PubMed

    Donato, Anthony J; Magerko, Katherine A; Lawson, Brooke R; Durrant, Jessica R; Lesniewski, Lisa A; Seals, Douglas R

    2011-09-15

    We tested the hypothesis that reductions in the cellular deacetylase, sirtuin-1 (SIRT-1), contribute to vascular endothelial dysfunction with ageing via modulation of endothelial nitric oxide synthase (eNOS) acetylation/activation-associated nitric oxide (NO) production. In older (30 months, n = 14) vs. young (5-7 months, n = 16) B6D2F1 mice, aortic protein expression of SIRT-1 and eNOS phosphorylated at serine 1177 were lower (both P < 0.05), and acetylated eNOS was 6-fold higher (P < 0.05), whereas total eNOS did not differ (P = 0.65). Acetylcholine (ACh)-induced peak endothelium-dependent dilatation (EDD) was lower in isolated femoral arteries with ageing (P < 0.001). Incubation with sirtinol, a SIRT-1 inhibitor, reduced EDD in both young and older mice, abolishing age-related differences, whereas co-administration with l-NAME, an eNOS inhibitor, further reduced EDD similarly in both groups. Endothelium-independent dilatation to sodium nitroprusside (EID), was not altered by age or sirtinol treatment. In older (64 ± 1 years, n = 22) vs. young (25 ± 1 years, n = 16) healthy humans, ACh-induced forearm EDD was impaired (P = 0.01) and SIRT-1 protein expression was 37% lower in endothelial cells obtained from the brachial artery (P < 0.05), whereas EID did not differ. In the overall group, EDD was positively related to endothelial cell SIRT-1 protein expression (r = 0.44, P < 0.01). Reductions in SIRT-1 may play an important role in vascular endothelial dysfunction with ageing. SIRT-1 may be a key therapeutic target to treat arterial ageing.

  4. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans

    PubMed Central

    Donato, Anthony J; Magerko, Katherine A; Lawson, Brooke R; Durrant, Jessica R; Lesniewski, Lisa A; Seals, Douglas R

    2011-01-01

    Abstract We tested the hypothesis that reductions in the cellular deacetylase, sirtuin-1 (SIRT-1), contribute to vascular endothelial dysfunction with ageing via modulation of endothelial nitric oxide synthase (eNOS) acetylation/activation-associated nitric oxide (NO) production. In older (30 months, n = 14) vs. young (5–7 months, n = 16) B6D2F1 mice, aortic protein expression of SIRT-1 and eNOS phosphorylated at serine 1177 were lower (both P < 0.05), and acetylated eNOS was 6-fold higher (P < 0.05), whereas total eNOS did not differ (P = 0.65). Acetylcholine (ACh)-induced peak endothelium-dependent dilatation (EDD) was lower in isolated femoral arteries with ageing (P < 0.001). Incubation with sirtinol, a SIRT-1 inhibitor, reduced EDD in both young and older mice, abolishing age-related differences, whereas co-administration with l-NAME, an eNOS inhibitor, further reduced EDD similarly in both groups. Endothelium-independent dilatation to sodium nitroprusside (EID), was not altered by age or sirtinol treatment. In older (64 ± 1 years, n = 22) vs. young (25 ± 1 years, n = 16) healthy humans, ACh-induced forearm EDD was impaired (P = 0.01) and SIRT-1 protein expression was 37% lower in endothelial cells obtained from the brachial artery (P < 0.05), whereas EID did not differ. In the overall group, EDD was positively related to endothelial cell SIRT-1 protein expression (r = 0.44, P < 0.01). Reductions in SIRT-1 may play an important role in vascular endothelial dysfunction with ageing. SIRT-1 may be a key therapeutic target to treat arterial ageing. PMID:21746786

  5. A human apolipoprotein E mimetic peptide reduces atherosclerosis in aged apolipoprotein E null mice

    PubMed Central

    Xu, Yanyong; Liu, Hongmei; Liu, Mengting; Li, Feifei; Liu, Liangchen; Du, Fen; Fan, Daping; Yu, Hong

    2016-01-01

    Apolipoprotein E (apoE) is well known as an antiatherogenic protein via regulating lipid metabolism and inflammation. We previously reported that a human apoE mimetic peptide, EpK, reduced atherosclerosis in apoE null (apoE-/-) mice through reducing inflammation without affecting plasma lipid levels. Here, we construct another human apoE mimetic peptide, named hEp, and investigate whether expression of hEp can reduce atherosclerotic lesion development in aged female apoE-/- mice with pre-existing lesions. We found that chemically synthesized hEp significantly decreased cholesterol accumulation induced by oxidized low density lipoprotein and the expression of inflammatory cytokines TNFα and IL-6 induced by lipopolysaccharide in macrophages. In an in vivo study, Lv-hEp-GFP lentiviruses were intravenously injected into 9 month-old apoE-/- mice. Mice were then fed a chow diet for 18 weeks. Results showed that in comparison to the Lv-GFP lentivirus injection (Lv-GFP) group, Lv-hEp-GFP lentivirus injection achieved hepatic hEp expression and secretion in apoE-/- mice. It was observed that hEp expression significantly reduced plasma VLDL and LDL cholesterol levels and decreased aortic atherosclerotic lesions. This was accompanied by an increase of LDL receptor expression and a reduction of TNFα and IL-6 mRNA levels in the liver. Moreover, expression of hEp increased plasma paraoxonase-1 activity and decreased plasma myeloperoxidase activity and serum amyloid A levels. Our study provides evidence that hEp may be developed as a promising therapeutic apoE mimetic peptide for atherosclerosis-related cardiovascular diseases through its induction of plasma VLDL/LDL cholesterol clearance as well as its anti-oxidative and anti-inflammatory activities. PMID:27648138

  6. Effect of Erabu sea snake (Laticauda semifasciata) lipids on the swimming endurance of aged mice.

    PubMed

    Zhang, Guihua; Shirai, Nobuya; Higuchi, Tomoyuki; Suzuki, Hiramitsu; Shimizu, Eiji

    2007-12-01

    The effect of Erabu sea snake (Laticauda semifasciata) lipids on the swimming endurance was investigated in aged mice. Fifty three-week-old male Crlj:CD-1 (ICR) mice were fed one of three experimental diets containing either 6% lard, 6% fish oil, or 6% sea snake lipids for 16 wk. The swimming exercise was carried out in an acrylic plastic tank filled with 25 cm of water maintained at 23(o)C. Swimming times to exhaustion were measured with a load of 2% of their body weights attached to the tails of the mice. The swimming times to exhaustion of the group that were fed the sea snake lipid diet tended to be longer than those of the lard diet group, and were significantly improved compared with the fish oil diet group (p<0.05). The plasma and muscle lactate levels were significantly lower in the sea snake lipid diet group than in the lard and fish oil diet groups (p<0.05). The liver glycogen and plasma glucose levels of the sea snake lipid diet group did not differ markedly from those of the lard diet group (p>0.05), and were significantly higher than those of the fish oil diet group (p<0.05). These results suggest that an intake of sea snake lipids but not the fish oil, which is also rich in n-3 polyunsaturated fatty acids (n-3 PUFAs), is useful for improving the swimming endurance of aged mice by attenuating lactate production and/or enhancing lactate clearance during swimming exercise, and the n-3 PUFAs contained in the sea snake lipids did little or nothing for this improved endurance.

  7. Combined Anti-Inflammatory and Anti-AGE Drug Treatments Have a Protective Effect on Intervertebral Discs in Mice with Diabetes

    PubMed Central

    Illien-Junger, Svenja; Grosjean, Fabrizio; Laudier, Damien M.; Vlassara, Helen; Striker, Gary E.; Iatridis, James C.

    2013-01-01

    Objective Diabetes and low back pain are debilitating diseases and modern epidemics. Diabetes and obesity are also highly correlated with intervertebral disc (IVD) degeneration and back pain. Advanced-glycation-end-products (AGEs) increase reactive-oxygen-species (ROS) and inflammation, and are one cause for early development of diabetes mellitus. We hypothesize that diabetes results in accumulation of AGEs in spines and associated spinal pathology via increased catabolism. We present a mouse model showing that: 1) diabetes induces pathological changes to structure and composition of IVDs and vertebrae; 2) diabetes is associated with accumulation of AGEs, TNFα, and increased catabolism spinal structures; and 3) oral-treatments with a combination of anti-inflammatory and anti-AGE drugs mitigate these diabetes-induced degenerative changes to the spine. Methods Three age-matched groups of ROP-Os mice were compared: non-diabetic, diabetic (streptozotocin (STZ)-induced), or diabetic mice treated with pentosan-polysulfate (anti-inflammatory) and pyridoxamine (AGE-inhibitor). Mice were euthanized and vertebra-IVD segments were analyzed by μCT, histology and Immunohistochemistry. Results Diabetic mice exhibited several pathological changes including loss in IVD height, decreased vertebral bone mass, decreased glycosaminoglycan content and morphologically altered IVDs with focal deposition of tissues highly expressing TNFα, MMP-13 and ADAMTS-5. Accumulation of larger amounts of methylglyoxal suggested that AGE accumulation was associated with these diabetic degenerative changes. However, treatment prevented or reduced these pathological effects on vertebrae and IVD. Conclusion This is the first study to demonstrate specific degenerative changes to nucleus pulposus (NP) morphology and their association with AGE accumulation in a diabetic mouse model. Furthermore, this is the first study to demonstrate that oral-treatments can inhibit AGE-induced ROS and inflammation in

  8. Gender differences between hypocretin/orexin knockout and wild type mice: age, body weight, body composition, metabolic markers, leptin and insulin resistance.

    PubMed

    Ramanathan, Lalini; Siegel, Jerome M

    2014-12-01

    Female hypocretin knockout (Hcrt KO) mice have increased body weight despite decreased food intake compared to wild type (WT) mice. In order to understand the nature of the increased body weight, we carried out a detailed study of Hcrt KO and WT, male, and female mice. Female KO mice showed consistently higher body weight than WT mice, from 4 to 20 months (20-60%). Fat, muscle, and free fluid levels were all significantly higher in adult (7-9 months) as well as old (18-20 months) female KO mice compared to age-matched WT mice. Old male KO mice showed significantly higher fat content (150%) compared to age-matched WT mice, but no significant change in body weight. Respiratory quotient (-19%) and metabolic rates (-14%) were significantly lower in KO mice compared to WT mice, regardless of gender or age. Female KO mice had significantly higher serum leptin levels (191%) than WT mice at 18-20 months, but no difference between male mice were observed. Conversely, insulin resistance was significantly higher in both male (73%) and female (93%) KO mice compared to age- and sex-matched WT mice. We conclude that absence of the Hcrt peptide has gender-specific effects. In contrast, Hcrt-ataxin mice and human narcoleptics, with loss of the whole Hcrt cell, show weight gain in both sexes.

  9. Aging reduces the high-frequency and short-term adaptation of the vestibulo-ocular reflex in mice.

    PubMed

    Khan, Serajul I; Hübner, Patrick P; Brichta, Alan M; Smith, Doug W; Migliaccio, Americo A

    2017-03-01

    Prevailing evidence indicates a relatively late life decline in human vestibulo-ocular reflex (VOR) function. Although mice are commonly used in mechanistic studies of vestibular function, it remains unclear whether aging produces a corresponding decline in VOR function in mice. We sought to determine how the baseline VOR and its short-term adaptation were affected by aging. We tested 8 young (3-month old) and 8 aged (30-month old-equivalent to a ∼80-year old human) C57BL/6 mice. We measured their VOR response to whole-body static tilts and during 0.1-10 Hz whole-body sinusoidal and transient rotations before and after VOR adaptation training. Our data revealed minimal differences in static counter-tilt response between young and aged mice, but a significant deficit in baseline VOR gain in aged mice during transient rotations. Moreover, aged mice had a significant decrease in short-term VOR adaptation, particularly for training that sought to decrease the VOR response.

  10. Phenotype screening for genetically deermined age-onset disorders and increased longevity in ENU-mutagenized mice

    SciTech Connect

    Johnson, Dabney K; Rinchik, Eugene M; Moustaid-Moussa, Naima; Miller, Darla R; Williams, Robert; Michaud III, Edward J; Jablonski, Monica M.; Elberger, Andrea; Hamre, Kristin M.; Smeyne, Richard; Chesler, Elissa J; Goldowitz, Daniel

    2005-01-01

    With the goal of discovering genes that contribute to late-onset neurological and ocular disorders and also genes that extend the healthy life span in mammals, we are phenotyping mice carrying new mutations induced by the chemical N-ethyl-N-nitrosourea (ENU). The phenotyping plan includes basic behavioral, neurohistological, and vision testing in sibling cohorts of mice aged to 18 months, and then evaluation for markers of growth trajectory and stress response in these same cohorts aged up to 28 months. Statistical outliers are identified by comparison to test results of similar aged cohorts, and potential mutants are recovered for re-aging to confirm heritability of the phenotype.

  11. Dietary Fat and Aging Modulate Apoptotic Signaling in Liver of Calorie-Restricted Mice

    PubMed Central

    López-Domínguez, José Alberto; Khraiwesh, Husam; González-Reyes, José Antonio; López-Lluch, Guillermo; Navas, Plácido; Ramsey, Jon Jay; de Cabo, Rafael; Burón, María Isabel

    2015-01-01

    Imbalance between proliferation and cell death accounts for several age-linked diseases. Aging, calorie restriction (CR), and fat source are all factors that may influence apoptotic signaling in liver, an organ that plays a central metabolic role in the organism. Here, we have studied the combined effect of these factors on a number of apoptosis regulators and effectors. For this purpose, animals were fed diets containing different fat sources (lard, soybean oil, or fish oil) under CR for 6 or 18 months. An age-linked increase in the mitochondrial apoptotic pathway was detected with CR, including a decrease in Bcl-2/Bax ratio, an enhanced release of cytochrome c to the cytosol and higher caspase-9 activity. However, these changes were not fully transmitted to the effectors apoptosis-inducing factor and caspase-3. CR (which abated aging-related inflammatory responses) and dietary fat altered the activities of caspases-8, -9, and -3. Apoptotic index (DNA fragmentation) and mean nuclear area were increased in aged animals with the exception of calorie-restricted mice fed a lard-based fat source. These results suggest possible protective changes in hepatic homeostasis with aging in the calorie-restricted lard group. PMID:24691092

  12. Impaired phagocytosis of apoptotic cells causes accumulation of bone marrow-derived macrophages in aged mice

    PubMed Central

    Kim, Ok-Hee; Kim, Hyojung; Kang, Jinku; Yang, Dongki; Kang, Yu-Hoi; Lee, Dae Ho; Cheon, Gi Jeong; Park, Sang Chul; Oh, Byung-Chul

    2017-01-01

    Accumulation of tissue macrophages is a significant characteristic of disease-associated chronic inflammation, and facilitates the progression of disease pathology. However, the functional roles of these bone marrow-derived macrophages (BMDMs) in aging are unclear. Here, we identified age-dependent macrophage accumulation in the bone marrow, showing that aging significantly increases the number of M1 macrophages and impairs polarization of BMDMs. We found that age-related dysregulation of BMDMs is associated with abnormal overexpression of the anti-inflammatory interleukin-10. BMDM dysregulation in aging impairs the expression levels of pro-inflammatory cytokines and genes involved in B-cell maturation and activation. Phagocytosis of apoptotic Jurkat cells by BMDMs was reduced because of low expression of phagocytic receptor CD14, indicating that increased apoptotic cells may result from defective phagocytosis of apoptotic cells in the BM of aged mice. Therefore, CD14 may represent a promising target for preventing BMDM dysregulation, and macrophage accumulation may provide diagnostic and therapeutic clues. PMID:27866511

  13. Modified forelimb grip strength test detects aging-associated physiological decline in skeletal muscle function in male mice.

    PubMed

    Takeshita, Hikari; Yamamoto, Koichi; Nozato, Satoko; Inagaki, Tadakatsu; Tsuchimochi, Hirotsugu; Shirai, Mikiyasu; Yamamoto, Ryohei; Imaizumi, Yuki; Hongyo, Kazuhiro; Yokoyama, Serina; Takeda, Masao; Oguro, Ryosuke; Takami, Yoichi; Itoh, Norihisa; Takeya, Yasushi; Sugimoto, Ken; Fukada, So-Ichiro; Rakugi, Hiromi

    2017-02-08

    The conventional forelimb grip strength test is a widely used method to assess skeletal muscle function in rodents; in this study, we modified this method to improve its variability and consistency. The modified test had lower variability among trials and days than the conventional test in young C57BL6 mice, especially by improving the variabilities in male. The modified test was more sensitive than the conventional test to detect a difference in motor function between female and male mice, or between young and old male mice. When the modified test was performed on male mice during the aging process, reduction of grip strength manifested between 18 and 24 months of age at the group level and at the individual level. The modified test was similar to the conventional test in detecting skeletal muscle dysfunction in young male dystrophic mice. Thus, the modified forelimb grip strength test, with its improved validity and reliability may be an ideal substitute for the conventional method.

  14. Voluntary aerobic exercise increases arterial resilience and mitochondrial health with aging in mice

    PubMed Central

    Gioscia-Ryan, Rachel A.; Battson, Micah L.; Cuevas, Lauren M.; Zigler, Melanie C.; Sindler, Amy L.; Seals, Douglas R.

    2016-01-01

    Mitochondrial dysregulation and associated excessive reactive oxygen species (mtROS) production is a key source of oxidative stress in aging arteries that reduces baseline function and may influence resilience (ability to withstand stress). We hypothesized that voluntary aerobic exercise would increase arterial resilience in old mice. An acute mitochondrial stressor (rotenone) caused greater (further) impairment in peak carotid EDD in old (~27 mo., OC, n=12;−32.5±-10.5%) versus young (~7 mo., YC n=11;−5.4±- 3.7%) control male mice, whereas arteries from young and old exercising (YVR n=10 and OVR n=11, 10-wk voluntary running;−0.8±-2.1% and −8.0±4.9%, respectively) mice were protected. Ex-vivo simulated Western diet (WD, high glucose and palmitate) caused greater impairment in EDD in OC (-28.5±8.6%) versus YC (-16.9±5.2%) and YVR (-15.3±2.3%), whereas OVR (-8.9±3.9%) were more resilient (not different versus YC). Simultaneous ex-vivo treatment with mitochondria-specific antioxidant MitoQ attenuated WD-induced impairments in YC and OC, but not YVR or OVR, suggesting that exercise improved resilience to mtROS-mediated stress. Exercise normalized age-related alterations in aortic mitochondrial protein markers PGC-1α, SIRT-3 and Fis1 and augmented cellular antioxidant and stress response proteins. Our results indicate that arterial aging is accompanied by reduced resilience and mitochondrial health, which are restored by voluntary aerobic exercise. PMID:27875805

  15. Longevity and