Genetic mapping of lifespan and mitochondrial stress response in C. elegans
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ABSTRACT:
PROVIDER: PRJNA1278737 | ENA |
REPOSITORIES: ENA
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Project description:The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) analyses and found one novel UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, underscoring its translational relevance. Overall, our findings demonstrate a novel UPRmt modulator across species and provide insights into potential translational research.
2025-07-30 | GSE300044 | GEO
Project description:Despite longstanding scientific interest in the centrality of mitochondria to biological aging, directly controlling mitochondrial function to test causality has eluded researchers. We show that specifically boosting mitochondrial membrane potential through a light-activated proton pump reversed age-associated phenotypes and extended C. elegans lifespan. We show that harnessing the energy of light to experimentally increase mitochondrial membrane potential during adulthood alone is sufficient to slow the rate of aging.
2022-11-11 | PXD033901 | Pride
Project description:The mitochondrial unfolded protein response (UPRmt) has been associated with long lifespan across metazoans. In Caenorhabditis elegans, mild developmental mitochondrial stress activates UPRmt reporters and extends lifespan. We show that similar developmental stress is necessary and sufficient to extend Drosophila lifespan, and identify Phosphoglycerate Mutase 5 (PGAM5) as a mediator of this response. Developmental mitochondrial stress leads to activation of FoxO, via Apoptosis Signal-regulating Kinase 1 (ASK1) and Jun-N-terminal Kinase (JNK). This activation persists into adulthood and induces a select set of chaperones, many of which have been implicated in lifespan extension in flies. Persistent FoxO activation can be reversed by a high- protein diet in adulthood, through mTORC1 and GCN-2 activity. Accordingly, the observed lifespan extension is prevented on a high-protein diet and in FoxO-null flies. The diet-sensitivity of this pathway has important implications for interventions that seek to engage the UPRmt to improve metabolic health and longevity.
2017-10-25 | GSE106105 | GEO
Project description:Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that generates free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. Mammalian NF-E2-related factor 2 (Nrf2) and its C. elegans ortholog SKN-1, mediate protective responses to oxidative stress by promoting target gene expression via antioxidant response elements (ARE). Genetic analyses showed that skn-1 mediates plumbagin’s lifespan-extending effect in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1-dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway.
2012-03-21 | GSE28301 | GEO
Project description:The molecular mechanisms of aging are unsolved and fascinating fundamental biological questions. Caenorhabditis elegans is an ideal model organism for investigating aging. PUF-8, a PUF (Pumilio and FBF) protein in C. elegans, is crucial for germline development through binding to the 3’ untranslated regions (3’ UTR) in the mRNA of target genes. Recently, PUF-8 was reported to alter mitochondrial dynamics and mitophagy by regulating MFF, a mitochondrial fission factor, and subsequently regulate longevity. Here, we determined the crystal structure of the PUF domain of PUF-8 with an RNA substrate. Mutagenesis experiments were performed to alter PUF-8 recognition of its target mRNAs. We generate these mutations in C. elegans, those mutations reduced the fertility and extended the lifespan. We deep sequenced total mRNAs from wild-type and puf-8 mutant worms and conducted in vitro RNA pull-down experiments. Six PUF-8 regulated genes were identified, in which their mRNA 3’ UTRs contain at least one PUF-binding element (PBE). One of the six genes, pqm-1, is crucial for lipid storage and aging process. Knockdown of pqm-1 could revert the lifespan extension of puf-8(-) animals. Therefore, PUF-8 may regulate the lifespan of C. elegans via modulating pqm-1-related pathways
2021-05-01 | GSE165061 | GEO
Project description:Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Apart from the proteostasis response, whether and how other mechanisms contribute to lifespan extension upon mitochondrial translation inhibition is underexplored. Using multi-omics and functional in vivo screening, we identified the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as essential for mitochondrial translation inhibition-induced longevity. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition while mitochondrial unfolded protein response activation is unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Additionally, we discovered that sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the “immuno-metabolic stress responses” in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
2025-04-23 | GSE248642 | GEO
Project description:While screening our in-house 1,072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic and anti-aging effects, and could further lead to promising application prospects.
2022-04-10 | GSE200459 | 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:Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on lifespan itself. We found that adding a small amount of glucose to the medium (0.1-2%) shortened the lifespan of C. elegans. Glucose shortened lifespan by inhibiting the activities of lifespan-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the down-regulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the lifespan-shortening effect of glucose, and that aqp-1 may act cell non-autonomously as a feedback regulator in the insulin/IGF-1 signaling pathway. Insulin down-regulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together these findings raise the possibility that a low-sugar diet might have beneficial effects on lifespan in higher organisms. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE18561: Adult C. elegans: Control daf-2 mutants treated with daf-16 RNAi vs. daf-2 mutants treated with empty vector RNAi GSE18562: Adult C. elegans: Control OP50 culture vs. OP50 + 2% glucose culture
2010-05-16 | E-GEOD-18563 | biostudies-arrayexpress
Project description:To elucidate the molecular mechanism underlying lifespan reduction induced by PM2.5 exposure in Caenorhabditis elegans, we performed global gene expression profiling by RNA-sequencing technology, and compared the gene expression pattern change induced by PM2.5 exposure.
2023-02-22 | GSE214215 | GEO