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Age Oct 1999Loss of proliferative capacity is common in many tissue types during aging. We have shown that mitogenic signaling through the epidermal growth factor (EGF) receptor...
Loss of proliferative capacity is common in many tissue types during aging. We have shown that mitogenic signaling through the epidermal growth factor (EGF) receptor declines in hepatocytes from old rats. Specifically, we showed that in old hepatocytes there is a decrease in autophosphorylation of EGF receptor at Tyr-1173. This results in loss of recruitment of the adapter protein Shc to the membrane and decreased ERK MAP kinase pathway activation. Because EGF receptor signaling also requires intracellular generation of H202, we next questioned whether altering the intracellular GSH/thiol concentration may also affect the age-dependent decline in EGF receptor signaling. Surprisingly, decreased intracellular GSH had no effect on EGF receptor signaling in hepatocytes from either young or old animals. However, increasing the thiol concentration dramatically attenuated EGF receptor signaling in hepatocytes from both young and old animals. Unexpectedly, loss of EGF receptor signaling was due to a specific decrease in EGF receptor number, but not in other components of the EGF receptor signaling pathway such as ERK MAP kinase. These results suggest that age-dependent mechanisms of alteration in EGF receptor signaling are independent of thiol regulation of EGF receptor signaling.
PubMed: 23604425
DOI: 10.1007/s11357-999-0019-y -
Age (Dordrecht, Netherlands) Jun 2014Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related...
Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (ΔYO > 5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.
Topics: Adult; Aged; Aging; Cells, Cultured; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Genome, Human; Healthy Volunteers; Humans; Leukocytes, Mononuclear; Male; Middle Aged; RNA
PubMed: 24789080
DOI: 10.1007/s11357-014-9648-x -
Age (Dordrecht, Netherlands) Sep 2006Common complaints of the elderly involve impaired cognitive abilities, such as loss of memory and inability to attend. Although much research has been devoted to these...
Common complaints of the elderly involve impaired cognitive abilities, such as loss of memory and inability to attend. Although much research has been devoted to these cognitive impairments, other factors such as disrupted sleep patterns and increased daytime drowsiness may contribute indirectly to impaired cognitive abilities. Disrupted sleep-wake cycles may be the result of age-related changes to the internal (circadian) clock. In this article, we review recent research on aging and circadian rhythms with a focus on the senescence-accelerated mouse (SAM) as a model of aging. We explore some of the neurobiological mechanisms that appear to be responsible for our aging clock, and consider implications of this work for age-related changes in cognition.
PubMed: 22253495
DOI: 10.1007/s11357-006-9013-9 -
Age Jul 1998Chloroform-methanol extracts from rat adrenals at five different ages (2, 6, 12, 18 and 24 months), were studied by fluorescence. After obtaining excitation and emission...
Chloroform-methanol extracts from rat adrenals at five different ages (2, 6, 12, 18 and 24 months), were studied by fluorescence. After obtaining excitation and emission spectra, fluorescence intensity was measured at 365 nm excitation and 455 emission for all time points of aging. An additional study of lipid peroxidation employing a thiobarbituric acid reaction was made. Fluorescence intensity increased during aging from 16.39 × 10(3) arbitrary units of fluorescence per gram of tissue at 2 months, to 34.33 × 10(3) units at 24 months. Thiobarbituric acid reaction products expressed in nmol of malondialdehyde per gram of adrenal increased from 172.97 at 2 months to 640.83 at 24 months. One way analysis of variance revealed a statistically significant difference (p<0.05 and p<0.01 respectively). The results show an age-related steady increase in lipid peroxidation products in rat adrenals and suggest their accumulation in lipofuscin granules.
PubMed: 23604369
DOI: 10.1007/s11357-998-0018-4 -
Age (Dordrecht, Netherlands) Dec 2013The musculoskeletal system (muscle-tendon-bone) demonstrates numerous age-related changes, with modifications in tendons the least well studied, although increased...
The musculoskeletal system (muscle-tendon-bone) demonstrates numerous age-related changes, with modifications in tendons the least well studied, although increased predisposition to tendinopathy and rupture have been reported. In order to gain insights into the basis of age-associated increase in tendon injuries, we compared Achilles and tibialis anterior tendons and myotendinous junctions (MTJs) from 3- to 5- and 22- to 25-month-old rats for underlying structure and composition. Significant decreases were observed by qRT-PCR for collagen I, III, and V mRNA expression in tendons of old rats, but immunostaining detected no apparent differences in collagen I and V expression on the protein level. Tendons of old compared with young rats had decreased mRNA expression levels of proteoglycan 4 (PRG4) and elastin (Eln), but no differences in the mRNA expression of connective tissue growth factor, TGF-beta 1, or stromal cell-derived factor 1. For PRG4, immunostaining showed good correlation with qRT-PCR results. This is the first study to show reductions in PRG4 in tendons and MTJs of old rats. Decreased PRG4 expression in tendons could result in increased tendon stiffness and may be associated with decreased activity in the elderly. The diminished collagen mRNA expression in combination with decreased PRG4 and Eln mRNA expression may be associated with increased risk of tendon injury with aging.
Topics: Achilles Tendon; Aging; Animals; Disease Models, Animal; Extracellular Matrix Proteins; Female; Gene Expression Regulation, Developmental; Immunohistochemistry; Male; RNA, Messenger; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Tendon Injuries
PubMed: 23354684
DOI: 10.1007/s11357-013-9514-2 -
Age (Dordrecht, Netherlands) Sep 2011Clinical data from 72 dog breeds of varying size and life expectancy were grouped according to breed body mass and tested for prevalence at ages 4 to 5, ages 7 to 10,...
Clinical data from 72 dog breeds of varying size and life expectancy were grouped according to breed body mass and tested for prevalence at ages 4 to 5, ages 7 to 10, and lifetime incidence of non-hereditary, age-related cataract (ARC). The incidence of ARC was found to be directly related to the relative life expectancies in the breed groups: The smallest dog breeds had a lower ARC prevalence between ages 4 and 5 than mid-size breeds and these, in turn, a lower prevalence than the giant breeds. A similar sequence was evident for ages 7 to 10 and for overall lifetime incidence of ARC. These differences became more significant when comparing small and giant breeds only. We could also confirm the inverse relationship between body size and life expectancy in these same sets of dog breeds. Our results show that body size, life expectancy, and ARC incidence are interrelated in dogs. Given that ARC has been shown to be at least partially caused by oxidative damage to lens epithelial cells and the internal lens, we suggest that it can be considered not only as a general biomarker for life expectancy in the canine and possibly other species, but also for the systemic damages produced by reactive oxygen species. This suggests new approaches to examine the gene expression pathways affecting the above-noted linkages.
Topics: Animals; Biomarkers; Body Size; Cataract; Dogs; Life Expectancy; Longevity
PubMed: 20607428
DOI: 10.1007/s11357-010-9158-4 -
Age (Dordrecht, Netherlands) 2015Neurexin1 (Nrxn1) and Neuroligin3 (Nlgn3) are cell adhesion proteins, which play an important role in synaptic plasticity that declines with advancing age. However, the...
Neurexin1 (Nrxn1) and Neuroligin3 (Nlgn3) are cell adhesion proteins, which play an important role in synaptic plasticity that declines with advancing age. However, the expression of these proteins during aging has not been analyzed. In the present study, we have examined the age-related changes in the expression of these proteins in cerebral cortex and hippocampus of 10-, 30-, 50-, and 80-week-old male mice. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis indicated that messenger RNA (mRNA) level of Nrxn1 and Nlgn3 significantly increased from 10 to 30 weeks and then decreased at 50 weeks in both the regions. However, in 80-week-old mice, Nrxn1 and Nlgn3 were further downregulated in cerebral cortex while Nrxn1 was downregulated and Nlgn3 was upregulated in hippocampus. These findings were corroborated by immunoblotting and immunofluorescence results. When the expression of Nrxn1 and Nlgn3 was correlated with presynaptic density marker synaptophysin, it was found that synaptophysin protein expression in cerebral cortex was high at 10 weeks and decreased gradually up to 80 weeks, whereas in hippocampus, it decreased until 50 weeks and then increased remarkably at 80 weeks. Furthermore, Pearson's correlation analysis showed that synaptophysin had a strong relation with Nrxn1 and Nlgn3 in cerebral cortex and with Nlgn3 in hippocampus. Thus, these findings showed that Nrxn1 and Nlgn3 are differentially expressed in cerebral cortex and hippocampus which might be responsible for alterations in synaptic plasticity during aging.
Topics: Aging; Animals; Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal; Cerebral Cortex; Cognitive Aging; Hippocampus; Immunoblotting; Male; Membrane Proteins; Mice, Inbred Strains; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Neuronal Plasticity; Presynaptic Terminals; Reverse Transcriptase Polymerase Chain Reaction; Synaptophysin
PubMed: 25693924
DOI: 10.1007/s11357-015-9752-6 -
Age (Dordrecht, Netherlands) Dec 2016Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a... (Comparative Study)
Comparative Study
Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS (n = 1230 for AM and n = 1458 for ANM), a Korean GWAS (n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also evaluated. We identified two suggestive menarcheal age loci tagged by rs79195475 at 10q21.3 (beta = -0.118 years, P = 3.4 × 10) and rs1023935 at 4p15.1 (beta = -0.145 years, P = 4.9 × 10) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = -0.276 years, P = 8.8 × 10). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations.
Topics: Age Factors; Aged; Asian People; China; Cohort Studies; Female; Genetic Loci; Genome-Wide Association Study; Genotype; Humans; Korea; Linear Models; Menarche; Menopause; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 27629107
DOI: 10.1007/s11357-016-9939-5 -
Age (Dordrecht, Netherlands) Feb 2012Aging has been shown to disrupt performance on tasks that require intact visual search and discrimination abilities in human studies. The goal of the present study was...
Aging has been shown to disrupt performance on tasks that require intact visual search and discrimination abilities in human studies. The goal of the present study was to determine if canines show age-related decline in their ability to perform a novel simultaneous visual search task. Three groups of canines were included: a young group (N = 10; 3 to 4.5 years), an old group (N = 10; 8 to 9.5 years), and a senior group (N = 8; 11 to 15.3 years). Subjects were first tested for their ability to learn a simple two-choice discrimination task, followed by the visual search task. Attentional demands in the task were manipulated by varying the number of distracter items; dogs received an equal number of trials with either zero, one, two, or three distracters. Performance on the two-choice discrimination task varied with age, with senior canines making significantly more errors than the young. Performance accuracy on the visual search task also varied with age; senior animals were significantly impaired compared to both the young and old, and old canines were intermediate in performance between young and senior. Accuracy decreased significantly with added distracters in all age groups. These results suggest that aging impairs the ability of canines to discriminate between task-relevant and -irrelevant stimuli. This is likely to be derived from impairments in cognitive domains such as visual memory and learning and selective attention.
Topics: Aging; Animals; Attention; Discrimination Learning; Distance Perception; Dogs; Memory; Models, Animal; Pattern Recognition, Visual; Time Factors; Vision, Ocular
PubMed: 21336566
DOI: 10.1007/s11357-011-9219-3 -
Age (Dordrecht, Netherlands) Aug 2015The sirtuins comprise a highly conserved family proteins present in virtually all species from bacteria to mammals. Sirtuins are members of the highly conserved class... (Review)
Review
The sirtuins comprise a highly conserved family proteins present in virtually all species from bacteria to mammals. Sirtuins are members of the highly conserved class III histone deacetylases, and seven sirtuin genes (sirtuins 1-7) have been identified and characterized in mammals. Sirtuin activity is linked to metabolic control, apoptosis, cell survival, development, inflammation, and healthy aging. In this review, we summarize and discuss the potential mutual relations between each sirtuin and cardiovascular health and the impact of sirtuins on oxidative stress and so age-related cardiovascular disorders, underlining the possibility that sirtuins will be novel targets to contrast cardiovascular risks induced by aging.
Topics: Aging; Animals; Cardiovascular Diseases; Humans; Oxidative Stress; Risk Factors; Sirtuins
PubMed: 26099749
DOI: 10.1007/s11357-015-9804-y