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Transcriptional Profiling of Aging in Human Muscle Reveals a Common Aging Signature  [PDF]
Jacob M Zahn,Rebecca Sonu,Hannes Vogel,Emily Crane,Krystyna Mazan-Mamczarz,Ralph Rabkin,Ronald W Davis,Kevin G Becker,Art B Owen,Stuart K Kim
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020115
Abstract: We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.
Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program
Michael G Edwards, Rozalyn M Anderson, Ming Yuan, Christina M Kendziorski, Richard Weindruch, Tomas A Prolla
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-80
Abstract: We identified 712 transcripts that are differentially expressed in young (5 month old) and old (25-month old) mouse skeletal muscle. Caloric restriction (CR) completely or partially reversed 87% of the changes in expression. Examination of individual genes revealed a transcriptional profile indicative of increased p53 activity in the older muscle. To determine whether the increase in p53 activity is associated with transcriptional activation of apoptotic targets, we performed RT-PCR on four well known mediators of p53-induced apoptosis: puma, noxa, tnfrsf10b and bok. Expression levels for these proapoptotic genes increased significantly with age (P < 0.05), while CR significantly lowered expression levels for these genes as compared to control fed old mice (P < 0.05). Age-related induction of p53-related genes was observed in multiple tissues, but was not observed in young SOD2+/- and GPX4+/- mice, suggesting that oxidative stress does not induce the expression of these genes. Western blot analysis confirmed that protein levels for both p21 and GADD45a, two established transcriptional targets of p53, were higher in the older muscle tissue.These observations support a role for p53-mediated transcriptional program in mammalian aging and suggest that mechanisms other than reactive oxygen species are involved in the age-related transcriptional activation of p53 targets.Aging in skeletal muscle is characterized by loss of motor neurons, variations in size and type of muscle fibers, infiltration of fat and connective tissue, and a overall decrease in muscle mass (sarcopenia) [1]. Sarcopenia, the leading cause of frailty and disability in the elderly, has also been linked to other age-associated pathology, such as osteoporosis and impaired thermoregulation [2-5]. Several biological processes, such as an increase in inflammatory cytokines and a decrease in sex and growth hormones with age [6-8], have been suggested as contributing factors to the aging of skeletal muscle. At
Sequential Use of Transcriptional Profiling, Expression Quantitative Trait Mapping, and Gene Association Implicates MMP20 in Human Kidney Aging  [PDF]
Heather E. Wheeler,E. Jeffrey Metter,Toshiko Tanaka,Devin Absher,John Higgins,Jacob M. Zahn,Julie Wilhelmy,Ronald W. Davis,Andrew Singleton,Richard M. Myers,Luigi Ferrucci,Stuart K. Kim
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000685
Abstract: Kidneys age at different rates, such that some people show little or no effects of aging whereas others show rapid functional decline. We sequentially used transcriptional profiling and expression quantitative trait loci (eQTL) mapping to narrow down which genes to test for association with kidney aging. We first performed whole-genome transcriptional profiling to find 630 genes that change expression with age in the kidney. Using two methods to detect eQTLs, we found 101 of these age-regulated genes contain expression-associated SNPs. We tested the eQTLs for association with kidney aging, measured by glomerular filtration rate (GFR) using combined data from the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI study. We found a SNP association (rs1711437 in MMP20) with kidney aging (uncorrected p = 3.6×10?5, empirical p = 0.01) that explains 1%–2% of the variance in GFR among individuals. The results of this sequential analysis may provide the first evidence for a gene association with kidney aging in humans.
Sleep, aging, and lifespan in Drosophila
Daniel Bushey, Kimberly A Hughes, Giulio Tononi, Chiara Cirelli
BMC Neuroscience , 2010, DOI: 10.1186/1471-2202-11-56
Abstract: We compared 3 short sleeping mutant lines (Hk1, HkY and Hk2) carrying a mutation in Hyperkinetic, which codes for the beta subunit of the Shaker channel, to wild-type siblings throughout their entire lifespan (all flies kept at 20°C). Hk1 and HkY mutants were short sleeping relative to wild-type controls from day 3 after eclosure, and Hk2 flies became short sleepers about two weeks later. All 3 Hk mutant lines had reduced lifespan relative to wild-type flies. Total sleep time showed a trend to increase in all lines with age, but the effect was most pronounced in Hk1 and HkY flies. In both mutant and wild-type lines sleep quality did not decay with age, but the strong preference for sleep at night declined starting in "middle age". Using Cox regression analysis we found that in Hk1 and HkY mutants and their control lines there was a negative relationship between total sleep amount during the first 2 and 4 weeks of age and hazard (individual risk of death), while no association was found in Hk2 flies and their wild-type controls. Hk1 and HkY mutants and their control lines also showed an association between total daily wake activity over the first 2 and 4 weeks of age and hazard. However, when both sleep duration and wake activity were used in the same regression, the effects of activity were much reduced, while most of the sleep effects remained significant. Finally, Hk1 flies and wild-type siblings were also tested at 25°C, and results were similar to those at 20°C. Namely, Hk1 mutants were short sleeping, hyperactive, and short lived relative to controls, and sleep quality in both groups did not decrease with age.Different Hk mutations affect the sleep phenotype, and do so in an age-dependent manner. In 4 of the 6 lines tested sleep associates significantly with lifespan variation even after any effect of activity is removed, but activity does not associate significantly with lifespan after the effects of sleep are removed. Thus, in addition to environmental factor
Changes in Expression of Manganese Superoxide Dismutase, Copper and Zinc Superoxide Dismutase and Catalase in Brachionus calyciflorus during the Aging Process  [PDF]
Jianghua Yang, Siming Dong, Qichen Jiang, Tengjiao Kuang, Wenting Huang, Jiaxin Yang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057186
Abstract: Rotifers are useful model organisms for aging research, owing to their small body size (0.1–1 mm), short lifespan (6–14 days) and the relative easy in which aging and senescence phenotypes can be measured. Recent studies have shown that antioxidants can extend the lifespan of rotifers. In this paper, we analyzed changes in the mRNA expression level of genes encoding the antioxidants manganese superoxide dismutase (MnSOD), copper and zinc SOD (CuZnSOD) and catalase (CAT) during rotifer aging to clarify the function of these enzymes in this process. We also investigated the effects of common life-prolonging methods [dietary restriction (DR) and resveratrol] on the mRNA expression level of these genes. The results showed that the mRNA expression level of MnSOD decreased with aging, whereas that of CuZnSOD increased. The mRNA expression of CAT did not change significantly. This suggests that the ability to eliminate reactive oxygen species (ROS) in the mitochondria reduces with aging, thus aggravating the damaging effect of ROS on the mitochondria. DR significantly increased the mRNA expression level of MnSOD, CuZnSOD and CAT, which might explain why DR is able to extend rotifer lifespan. Although resveratrol also increased the mRNA expression level of MnSOD, it had significant inhibitory effects on the mRNA expression of CuZnSOD and CAT. In short, mRNA expression levels of CAT, MnSOD and CuZnSOD are likely to reflect the ability of mitochondria to eliminate ROS and delay the aging process.
Mitochondrial Inverted Repeats Strongly Correlate with Lifespan: mtDNA Inversions and Aging  [PDF]
Jiang-Nan Yang, Andrei Seluanov, Vera Gorbunova
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073318
Abstract: Mitochondrial defects are implicated in aging and in a multitude of age-related diseases, such as cancer, heart failure, Parkinson’s disease, and Huntington’s disease. However, it is still unclear how mitochondrial defects arise under normal physiological conditions. Mitochondrial DNA (mtDNA) deletions caused by direct repeats (DRs) are implicated in the formation of mitochondrial defects, however, mitochondrial DRs show relatively weak (Pearson’s r = ?0.22, p<0.002; Spearman’s ρ = ?0.12, p = 0.1) correlation with maximum lifespan (MLS). Here we report a stronger correlation (Pearson’s r = ?0.55, p<10–16; Spearman’s ρ = ?0.52, p<10–14) between mitochondrial inverted repeats (IRs) and lifespan across 202 species of mammals. We show that, in wild type mice under normal conditions, IRs cause inversions, which arise by replication-dependent mechanism. The inversions accumulate with age in the brain and heart. Our data suggest that IR-mediated inversions are more mutagenic than DR-mediated deletions in mtDNA, and impose stronger constraint on lifespan. Our study identifies IR-induced mitochondrial genome instability during mtDNA replication as a potential cause for mitochondrial defects.
Reproductive Aging Drives Protein Accumulation in the Uterus and Limits Lifespan in C. elegans  [PDF]
Stephanie M. Zimmerman?,Izumi V. Hinkson?,Joshua E. Elias?,Stuart K. Kim
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005725
Abstract: Aging in Caenorhabditis elegans is characterized by widespread physiological and molecular changes, but the mechanisms that determine the rate at which these changes occur are not well understood. In this study, we identify a novel link between reproductive aging and somatic aging in C. elegans. By measuring global age-related changes in the proteome, we identify a previously uncharacterized group of secreted proteins in the adult uterus that dramatically increase in abundance with age. This accumulation is blunted in animals with an extended reproductive period and accelerated in sterile animals lacking a germline. Uterine proteins are not removed in old post-reproductive animals or in young vulvaless worms, indicating that egg-laying is necessary for their rapid removal in wild-type young animals. Together, these results suggest that age-induced infertility contributes to extracellular protein accumulation in the uterus with age. Finally, we show that knocking down multiple age-increased proteins simultaneously extends lifespan. These results provide a mechanistic example of how the cessation of reproduction contributes to detrimental changes in the soma, and demonstrate how the timing of reproductive decline can influence the rate of aging.
OASIS: Online Application for the Survival Analysis of Lifespan Assays Performed in Aging Research  [PDF]
Jae-Seong Yang, Hyun-Jun Nam, Mihwa Seo, Seong Kyu Han, Yonghwan Choi, Hong Gil Nam, Seung-Jae Lee, Sanguk Kim
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023525
Abstract: Background Aging is a fundamental biological process. Characterization of genetic and environmental factors that influence lifespan is a crucial step toward understanding the mechanisms of aging at the organism level. To capture the different effects of genetic and environmental factors on lifespan, appropriate statistical analyses are needed. Methodology/Principal Findings We developed an online application for survival analysis (OASIS) that helps conduct various novel statistical tasks involved in analyzing survival data in a user-friendly manner. OASIS provides standard survival analysis results including Kaplan-Meier estimates and mean/median survival time by taking censored survival data. OASIS also provides various statistical tests including comparison of mean survival time, overall survival curve, and survival rate at specific time point. To visualize survival data, OASIS generates survival and log cumulative hazard plots that enable researchers to easily interpret their experimental results. Furthermore, we provide statistical methods that can analyze variances among survival datasets. In addition, users can analyze proportional effects of risk factors on survival. Conclusions/Significance OASIS provides a platform that is essential to facilitate efficient statistical analyses of survival data in the field of aging research. Web application and a detailed description of algorithms are accessible from http://sbi.postech.ac.kr/oasis.
Transcriptional (dys)regulation and aging in Caenorhabditis elegans
Zachary Pincus, Frank J Slack
Genome Biology , 2008, DOI: 10.1186/gb-2008-9-9-233
Abstract: The fact that single-gene mutations can prolong an organism's lifespan might seem unlikely, but many 'gerontogenes' have been identified in model organisms that, when knocked out or over- or underexpressed, increase or decrease lifespan in the laboratory environment. These genes largely assort into several now-familiar pathways [1,2], many of which converge on the insulin/insulin-like growth factor I (IGF-I) signaling pathway, which in Caenorhabditis elegans includes daf-2, an insulin/IGF-I receptor homolog; age-1, which encodes a phosphatidylinositol 3-OH kinase (PI3K) at the top of the DAF-2-activated signaling cascade; and daf-16, a forkhead-family transcription factor that is inactivated by this cascade. Nevertheless, it is unclear whether the activities of these 'longevity pathways' are modulated during normal aging, and as such, their role in the process of senescent decline in wild-type individuals is uncertain. Several pathways with longevity phenotypes in knockout animals may not be relevant to normal aging; these include the insulin/IGF-1 pathway, the endoplasmic reticulum stress response mediated by the sirtuin SIR-2.1, and mitochondrial electron transport [3]. Because of this, many researchers in the field suspect that aging is primarily driven by accumulation of cellular damage and not age-related gene (dys)regulation.In a recent paper in Cell [3], however, Yelena Budovskaya and colleagues in the labs of Stuart Kim and Tom Johnson have identified a circuit of GATA transcription factors that alters C. elegans longevity when knocked out or knocked down, and which also plays a role in regulating the changes in gene expression observed during normal aging. Moreover, this circuit helps determine lifespan. One of these factors, ELT-3, is required for the pro-longevity effects of reduced insulin/IGF-I-like signaling and dietary restriction, providing at last a potential link between these longevity pathways and the normal process of aging.Budovskaya et al. [3]
Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila  [PDF]
Beno?t Biteau equal contributor,Jason Karpac equal contributor,Stephen Supoyo,Matthew DeGennaro,Ruth Lehmann,Heinrich Jasper
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001159
Abstract: Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected to be critical for longevity in metazoans. The intestinal epithelium of Drosophila provides an accessible model in which to test this prediction. In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs) and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. Here we show that conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. Our results highlight the importance of the balance between regenerative processes and strategies to prevent hyperproliferative disorders and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan.
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