Activated SKN-1 alters the longevity trajectory of long-lived C. elegans mutants
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PROVIDER: PRJNA1128548 | ENA |
REPOSITORIES: ENA
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Project description:In the presence of stressful environments, the SKN-1 cytoprotective transcription factor is activated to induce the expression of gene targets that can restore homeostasis. However, constitutive activation of SKN-1 results in diminished health and a reduction of lifespan. Here we demonstrate the necessity to regulate the activity of SKN-1 for maintaining the longevity promoting responses associated with impaired daf-2/insulin receptor signaling, the eat-2 model of caloric restriction, and glp-1-dependent loss of germ cell proliferation. A hallmark of animals with constitutive SKN-1 activation is the age-dependent loss of somatic lipids and this phenotype is linked to the general reduction in survival in animals harboring the skn-1gf allele, but surprisingly, daf-2lf; skn-1gf double mutant animals do not redistribute somatic lipids which suggests the insulin signaling pathway functions downstream of SKN-1 in the maintenance of lipid distribution. As expected, eat-2lf; skn-1gf double mutant animals, which independently activate SKN-1, continue to display somatic lipid depletion in older ages with and without the skn-1gf activating mutation but animals lacking a proliferating germline do not redistribute somatic lipids, which supports a genetic model where SKN-1 activity is an important regulator of lipid mobilization in response to food availability to fuel the developing germline by engaging the daf-2/insulin receptor pathway.
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Project description:Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants (clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2. We show that DAF-16 and multiple DAF-16 interacting proteins (MATH-33, IMB-2, CST-1/2, BAR-1) are required for the longevity of all three mitochondrial mutants. Our results suggest that the activation of DAF-16 in these mutants results from elevated levels of reactive oxygen species. Overall, this work reveals an overlapping genetic pathway required for longevity in three mitochondrial mutants, and, combined with previous work, demonstrates that DAF-16 is a downstream mediator of lifespan extension in multiple pathways of longevity.
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Project description:Analysis of gene expression in two long-lived daf-2 mutant (mutation in the insulin/IGF-1 receptor) and eat-2 mutant (caloric restriction model), comparison of gene expression profiles of two long-lived mutants provide novel insight into longevity Impaired insulin/IGF-1 signaling (IIS) pathway and caloric restriction (CR) are two well-established interventions to prolong lifespan in worm C. elegans. Although many studies using “-omics” approaches have gained informative knowledges on key longevity regulators in either IIS or CR models, few of those investigated the shared regulators between these two longevity interventions and integrated the messages from different –omics studies. In this study, we aimed to identify key pathways and metabolite fingerprints of longevity shared between the two interventions in worms using a multi-omics integration approach. We collected transcriptomics and metabolomics data from two long-lived mutant worm strains, i.e. daf-2 (impaired IIS pathway) and eat-2 (CR model) and compared with N2 strain. We detected many key pathways that were upregulated at the gene expression level in both long-lived mutants, such as defense response and lipid storage, while synthesis of macromolecules and developmental processes were downregulated at the transcript level. From our polar metabolite analysis, we discovered several shared metabolic features between the two long-lived mutants, including glycerol-3P, adenine, xanthine and AMP. In addition, we detected a lowered amino acid pool and two fatty acid species, C18:0 and C17:1, that behaved similarly in both long-lived mutants. After we integrated transcriptomics and metabolomics data based on the annotations in KEGG, our results highlighted a downregulation of pyrimidine metabolism and upregulation of purine metabolism in both long-lived mutants compared to N2 worms. Overall, our findings point towards the existence of shared metabolic pathways that are important for lifespan extension and provide novel insight of potential regulators and metabolic fingerprints for longevity.
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Project description:A major goal of healthy aging is to prevent declining resilience and increasing frailty, which are associated with many chronic diseases and deterioration of stress response. We have successfully used loss-or-gain model of stress survival to quantify organismal resilience. As a proof of concept, this is demonstrated in C. elegans exposed to increasing oxidative stress induced by exogenous paraquat and with proteotoxic stress caused by endogenous polyQ and Aβ aggregation, respectively. Based on this, we reveal that abalone peptide AbaPep#07 (SETYELRK) not only promotes survival resilience against paraquat-induced oxidative stress but also confers protection against polyQ- or Aβ-mediated behavioral dysfunction in C. elegans, indicating its capacity against stress and neurodegeneration. Importantly, we further show that the peptide increases physical fitness of aged C. elegans and extends life span without compromise of growth and reproduction, demonstrating its cost-free prolongevity activity. Moreover, we reveal that the peptide induces differential expression of a number of genes, including innate immune, lipid metabolism and metabolic detoxification genes, which are associated with the SKN-1/Nrf transcription factor. Collectively, our findings demonstrate that the novel abalone cryptide AbaPep#07 increases stress survival resilience and cost-free longevity via SKN-1/Nrf-governed transcriptional reprogramming and provide an insight into the neuroprotective and health-promoting potential of cryptides as proteostasis regulators.
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Project description:Mammals display wide range of variation in their lifespan. Investigating the molecular networks that distinguish long- from short-lived species has proven useful to identify determinants of longevity. Here, we compared the liver of long-lived naked mole-rats (NMRs) and the phylogenetically closely related, shorter-lived, guinea pigs using an integrated omic approach. We found that NMRs livers display a unique expression pattern of mitochondrial proteins that result in distinct metabolic features of their mitochondria. For instance, we observed a generally reduced respiration rate associated with lower protein levels of respiratory chain components, particularly complex I, and increased capacity to utilize fatty acids. Interestingly, we show that the same molecular networks are affected during aging in both NMR and humans, supporting a direct link to the extraordinary longevity of both species. Finally, we identified a novel longevity pathway and validated it experimentally in the nematode C. elegans.
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