Suppression of Transcriptional Drift Extends C. elegans Lifespan by Postponing the Onset of Mortality
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE63528 | GEO | 2016/01/06
SECONDARY ACCESSION(S): PRJNA268148
REPOSITORIES: GEO
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Project description:Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age-dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality. In this study set out to measure aging in the transcriptome by determining drift-variance changes with age in C.elegans. We set up three different cohorts of water or mianserin treated animals. The title of each cohort indicates the treatment (e.g. h2o or mia), the concentration (mia2, mia10, mia50), the day when the treatment was started (e.g. d1= day 1 of adulthood) and the day when the sample was collected (e.g. d10= day 10 of adulthood). cohort #1: Celegans was treated with water or mianserin (50uM) on day 1 and RNA was harvested on day1 (water only), d3, d5 and day 10 (file titles: h2o d1/d1, h2o d1/d3, h2o d1/d5, h2o d1/d10, mia50 d1/d3, mia50 d1/d5, mia50 d1/d10) cohort #2: Celegans was treated with mianserin (50uM) starting on day 3, and day 5, RNA was harvested on day 5 or 10 (file titles: mia50 d3/d10, mia50 d5/d10, mia50 d3/d5) cohort #3: Celegans was treated with mianserin 2 uM and 10 uM Mianserin on day 1 and Rna harvested on day 5 (file titles: mia2 d1/d5, mia10 d1/d5)
2016-01-06 | E-GEOD-63528 | biostudies-arrayexpress
Project description:Functional data indicate that specific histone modification enzymes can be key to longevity in Caenorhabditis elegans, but epigenetic mechanisms of lifespan regulation are not well understood. In this study, we profiled the genome-wide pattern of tri-methylation of lysine 36 on histone 3 (H3K36me3) in the somatic cells of young and old C. elegans. We revealed a new role of H3K36me3 in maintaining gene expression stability through aging with important consequence on longevity. We found that genes with dramatic expression change during aging are marked with low or even undetectable levels of H3K36me3 in their gene-bodies, irrespective of their corresponding mRNA abundance. Importantly, inactivation of the methyltransferase met-1 resulted in a decrease in global H3K36me3 marks, an increase in mRNA expression change with age, and a shortened lifespan, suggesting a causative role of the H3K36me3 marking in modulating age-dependent gene expression stability and longevity. We performed genome-wide mapping of histone H3 and H3K36me3 in young (D2A) and old (D12A) C.elegans somatic cells by ChIP-seq in glp-1(e2141). mRNA-seq was performed in young (D2A) and old (D12A) glp-1(e2141) somatic cells to identify mRNA expression change during aging from D2A to D12A.
2015-04-01 | E-GEOD-62720 | biostudies-arrayexpress
Project description:Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.
2023-10-24 | PXD044118 | Pride
Project description:Skeletal muscle senescence influences whole organism aging, yet little is known on the relay of pro-longevity signals from muscles to other tissues. We performed an RNAi screen in Drosophila for muscle-released cytokines ('myokines') regulating lifespan and identified Myoglianin, the homolog of human Myostatin. Myoglianin is induced in skeletal muscles by the transcription factor Mnt and together they constitute an inter-organ signaling module that regulates lifespan, age-related muscle dysfunction, and protein synthesis across aging tissues. Both Mnt and Myoglianin activate already in young age the protective decline in protein synthesis that is typical of old age, while knock-down of Myoglianin impairs this process. Mechanistically, Mnt decreases the expression of nucleolar components in muscles while also decreasing nucleolar size in distant tissues via Myostatin/p38 MAPK signaling. Our results highlight a myokine-dependent inter-organ longevity pathway that coordinates nucleolar function and protein synthesis across aging tissues. Affymetrix microarrays were used to evaluate genome-wide expression in skeletal muscles of flies with muscle-specific overexpression of FOXO or Mnt (Affymetrix Drosophila Genome 2.0 Array). This design allowed us to identify genes and pathways induced by overexpression of FOXO and/or Mnt, and enabled us to address the degree to which FOXO-induced pathways were independent of those induced by Mnt. Three independent biological replicates from each of three groups (control, UAS-Foxo and UAS-Mnt)
2014-07-02 | E-GEOD-39877 | biostudies-arrayexpress
Project description:One of the most important issues in the study of aging is to discover compounds with longevity-promoting activity and to unravel their underlying mechanisms. Queen honey bees are continuously fed royal jelly (RJ), and they live more than 10 times longer than hive workers, derived from the same diploid genome, which are fed it only for a short period of time during their larval stages. Therefore, RJ is likely to contain longevity-promoting agents for queens. RJ has been reported to possess diverse pharmacological properties. Furthermore, protease-treated RJ (pRJ) has additional beneficial activities. How RJ and pRJ exert these effects and which components in them play a critical role is largely unknown. The evolutionally conserved mechanisms that control lifespan have been indicated. The nematode Caenorhabditis elegans has been widely used for study of aging and longevity, due to its relatively short lifespan and well-established genetic pathways. The purpose of the present study was to elucidate whether RJ and its related substances contain the life span-extending activity in C. elegans and to obtain some insight into the active agents and their mechanisms. We found that both RJ and pRJ extended the lifespan of C. elegans. The life span-extending activity of pRJ was enriched by ODS column chromatography (pRJ-Fraction 5). pRJ-Fr. 5 extended the life span partly by acting through the FOXO transcription factor DAF-16, the activation of which is known to promote longevity in C. elegans by reducing insulin/IGF-1 signaling (IIS). pRJ-Fr. 5 induced changes in the expression of 3 genes encoding insulin-like peptides. Moreover, pRJ-Fr. 5 and reduced IIS shared some common features in terms of their effect on gene expression, such as up-regulation of dod-3 and down-regulation of dod-19, dao-4 and fkb-4. The dod-19 is a previously identified life span determinant in C. elegans, and the fkb-4 encodes a homologue of the mammalian FK506-binding protein. 10-Hydroxy-2-decenoic acid (10-HDA), which was present in high concentration in pRJ-Fr. 5, increased the lifespan independently of DAF-16 activity.These results demonstrate that RJ and its related substances extended the life span in C. elegans, suggesting that RJ may contain longevity-promoting factors common to diverse species across phyla. pRJ-Fr. 5 had higher life span-extending activity than either RJ or pRJ and extended the life span in part through the IIS-DAF-16 pathway. We provide the first evidence that 10-HDA, a defined natural product in RJ, extended organismal lifespan. It is noteworthy that 10-HDA performed its lifespan-extending function through a mechanism totally different from the IIS-DAF-16 pathway. Further search and characterization of the lifespan-extending agents in RJ and pRJ may broaden our understanding of the gene network of longevity regulation in diverse species and provide the possibility for nutraceutical interventions in the aging process. C. elegans N2 hermaphrodites were untreated or treated with pRJ-Fr. 5 (25mg/ml) for 24 h starting at the larval 4 (L4) stage.
2011-07-21 | E-GEOD-26094 | biostudies-arrayexpress
Project description:Protein translation (PT) declines with age in invertebrates, rodents, and humans1-6. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a novel theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.
2023-08-01 | GSE239506 | GEO
Project description:Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPRmt), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPRmt signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. Here we identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction-of-function of the demethylases potently suppresses longevity and UPRmt induction while gain-of-function is sufficient to extend lifespan in an UPRmt-dependent manner. A systems genetics approach in the BXD mouse reference population further indicated conserved roles of the mammalian orthologs in longevity and UPRmt signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations.
2016-05-03 | GSE78990 | GEO
Project description:Background. Juvenile hormone (JH) has been demonstrated to control adult lifespan in a number of non-model insects where surgical removal of the corpora allata eliminates the source of hormone. In contrast, little is known about how juvenile hormone affects adult Drosophila melanogaster. Previous work suggests that insulin signaling may modulate Drosophila aging in part through its impact on juvenile hormone titer, but no data yet addresses whether reduction of juvenile hormone is sufficient to control Drosophila life span. Here we adapt a recent genetic approach to knock out the corpora allata in adult Drosophila melanogaster and characterize adult life history phenotypes produced by reduction of juvenile hormone. With this system we test potential explanations for how juvenile hormone modulates aging. Conclusions. Reduced juvenile hormone alone is sufficient to extend lifespan of Drosophila melanogaster. Reduced juvenile hormone limits reproduction by inhibiting the production of yolked eggs, and this may arise because juvenile hormone is required for the post-eclosion development of vitellogenin-producing adult fat body. Our data do not support a mechanism for juvenile hormone control of longevity simply based on reducing the physiological costs of reproductive. Nor does the longevity benefit appear to function through mechanisms by which dietary restriction extends longevity. We identify transcripts that change in response to juvenile hormone independent of reproductive state and suggest these represent somatically expressed genes that could modulate how juvenile hormone controls persistence and longevity. Four genotypes were analyzed. They are CA knockout (CAKO), wildtype (wDah/w1118 ), CAKO with OvoD1 mutation and control (wDah/w1118) with OvoD1 mutation. Three biological replicates for each genotype.
2013-07-26 | E-GEOD-48145 | biostudies-arrayexpress
Project description:An inverse correlation between circulating thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness in humans. However, hypothyroidism is a serious medical condition associated with reduced health and life expectancy. In this report, we show that severe and even subtle modulations on thyroid hormone levels leading to different forms of hyperthyroidism and hypothyroidism produce an overall unhealthy status and reduced lifespan in mice. A mild reduction in circulating T4 levels (~10%) resulted in hepatic mitochondrial dysfunction, increased ROS production and oxidative damage accumulation. These actions may contribute to the development of metabolic disorders, increased prevalence of hepatocellular carcinomas and early mortality in mice. Our findings raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan extension in mammals.
2020-04-13 | GSE123288 | GEO
Project description:Extending lifespan from yeast to mammals, calorie restriction (CR) is the most conserved longevity intervention. Numerous conserved pathways regulating aging and mediating CR have been identified; however, the overall proteomic changes during these conditions remain largely unexplored. We compared proteomes between young and replicatively aged yeast cells under normal and CR conditions using SILAC quantitative proteomics and discovered distinct signatures in the aging proteome. We found remarkable similarities between aged and CR cells, including induction of stress response pathways, providing evidence that CR pathways are engaged in aged cells. These observations also uncovered aberrant changes in mitochondria membrane proteins as well as a proteolytic cellular state in old cells. These proteomics analyses also help identify potential genes and pathways that have causal effects on longevity.
2022-02-15 | PXD018917 | Pride