Project description:We employed large-scale phenotyping to analyze not only a few, but hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study in aging C57BL/6J mice. For each phenotype, we established lifetime profiles to determine at which age age-dependent phenotypic change is first detectable relative to the young adult baseline.
Project description:This dataset consists of hepatic gene expression profiles of mice subjected to 8 different lifespan-extending interventions, together with the corresponding age-, sex- and strain-matched littermate controls: caloric restriction (CR), methionine restriction (MR), growth hormone receptor knockout (GHRKO), Snell dwarf mice (Pit1 -/-), rapamycin, acarbose, 17-alpha-estradiol (17aE2) and Protandim. Both sexes and different age groups are presented within dataset. Using this data, we identified general and specific gene expression patterns associated with lifespan extension. We detected a feminization effect associated with growth hormone regulation and diminution of sex-related differences in response to many interventions at transcriptome and metabolome levels. Combining the dataset with publicly available resources, we found that many interventions exhibited similar transcriptome changes, whereas some, including rapamycin, showed distinct patterns. We identified common hepatic signatures of lifespan extension, e.g. upregulation of oxidative phosphorylation and NRF2-regulated enzymes, and found that many perturbed pathways are shared across tissues. Moreover, the response of genes related to glucose metabolism and immune function represented both qualitative and quantitative associations with longevity. Finally, we used the detected longevity signatures to identify new candidates for lifespan extension and built GENtervention, a tool that visualizes associations of gene expression responses with lifespan extension.
Project description:The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a new therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life. The microarray experiment examines the transcriptional profiles of wild-type (w1118) vs. wild-type (w1118) + Lithium (LiCl, 10mM). Heads and thoraces from once mated females treated with vehicle or 10mM Li were snap frozen after 10d of treatment. RNA was Dnase treated and checked for quality by Biorad Experion. RNA was processed to cRNA, labeled and used for microarray analysis (GeneChip Drosophila Genome 2.0 Array), following manufacturer's protocol.
Project description:The nutrient-sensing Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved regulator of longevity. S6 kinase (S6K) is an essential downstream mediator for the effect of TORC1 on longevity. However, mechanistic insights on how TORC1-S6K signalling promotes lifespan and healthspan are still limited. Here we show that activity of S6K in the Drosophila fat body is essential for rapamycin-mediated longevity. Fat-body-specific activation of S6K blocked lifespan extension upon rapamycin feeding and induced accumulation of multilamellar lysosomal enlargements. Besides, fat body-specific S6K knockdown extended lifespan in files. We performed proteomics for Drosophila fat body to explore the fat body-specific regulation of protein expression by two separate datasets: fat body-specific S6K activation (Lsp2GS>S6KCA) with rapamycin treatment; and fat body-specific S6K inhibition (Lsp2GS>S6KRNAi). To assess if the age-prolonging mechanisms of TORC1-S6K signalling are conserved between flies and mammals, we assessed the impact of rapamycin treatment in the proteome of liver from C3B6F1 mice (F1 hybrids of C3H/HeOuJ females and C57Bl/6N males).
Project description:Rapamycin extends life span in mice, but it remains unclear if this compound also delays mammalian aging. Here, we present results from a comprehensive large-scale assessment of a wide rage of structural and functional aging phenotypes in mice. Rapamycin extended life span but showed few effects on a large number of systemic aging phenotypes, suggesting that rapamycin's effects on aging are largely limited to the regulation of age-related mortality and carcinogenesis.
Project description:Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age-related changes in DNA methylation at the genome scale have been termed epigenetic drift, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age-related epigenetic changes because of its substantial cell-type homogeneity and its well-known age-related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N=108) using array-based profiling of 450,000 methylation marks in various age groups. Data analysis confirmed that age-related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovers an age-related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome. This data set contains data from transcription profiling by array of human epidermis samples. The results of methylation profiling are provided in the ArrayExpress experiment E-MTAB-4385.
Project description:Rapamycin extends life span in mice, but it remains unclear if this compound also delays mammalian aging. Here, we present results from a comprehensive large-scale assessment of a wide rage of structural and functional aging phenotypes in mice. Rapamycin extended life span but showed few effects on a large number of systemic aging phenotypes, suggesting that rapamycin's effects on aging are largely limited to the regulation of age-related mortality and carcinogenesis. Total RNA obtained from 2-4 male mice of each analysed group (25 weeks old controls, 25 month old controls, 25 month old rapamycin treated)
Project description:Aging-associated functional decline and disease susceptibility are believed to be mediated, at least in part, through alterations in the epigenome. To explore epigenetic changes that might influence visual function with advanced age, we performed whole genome bisulfite sequencing of purified mouse rod photoreceptors at four different ages and identified 2054 genomic regions that gain or lose DNA methylation. Differentially methylated regions (DMRs) clustered at chromosomal hotspots, especially on Chromosome 10 that included a longevity interactome. DMRs were preferentially detected at an early stage of aging in long neuronal genes and in rod-specific regulatory regions containing open chromatin domains and H3K27 acetylation. Integration of methylome to age-related transcriptome changes, chromatin signatures and first order protein-protein interactions uncovered an enrichment of DMRs in pathways associated with aging, longevity, synaptic function, and energy homeostasis. In concordance, we detected reduced mitochondrial maximum reserve capacity with retinal age in ex vivo assays. Our study reveals age-dependent genomic and chromatin features susceptible to DNA methylation changes in rod photoreceptors and identifies associations with established and cell type-specific pathways altered in aging.