Transcriptome profiling of pitp-1 mutant and pitp-1(RNAi)-treated Caenorhabditis elegans
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE309580 | GEO | 2025/10/04
REPOSITORIES: GEO
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Project description:Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived daf-2/insulin receptor mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of daf-2 function, that EIF-2α pS49 potently inhibits protein synthesis and daf-2 longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.
2021-06-10 | PXD020440 |
Project description:Dietary restriction (DR) is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of DR, intermittent fasting (IF) and caloric restriction (CR), have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan, even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that a nutrient-related signalling molecule, the low molecular weight GTPase Cel-Rheb, has a dual role in lifespan regulation; Cel-Rheb is required for the IF-induced longevity, whereas inhibition of Cel-Rheb mimics the CR effects. We also show that Cel-Rheb exerts its effects in part via the insulin/IGF-like signalling effector DAF-16 in IF, and that Cel-Rheb is required for fasting-induced nuclear translocation of DAF-16. We find that HSP-12.6, a DAF-16 target, functions to mediate the IF-induced longevity. Furthermore, our analyses demonstrate that most of fasting-induced upregulated genes require Cel-Rheb function for their induction, and that Cel-Rheb/Cel-TOR signalling is required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling via Cel-Rheb in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway. Experiment Overall Design: We examined fasting-induced changes of the gene expression profiles in Caenorhabditis elegans. We performed the genome-wide analysis by using Affymetrix GeneChip oligonucleotide microarrays, and examined the effect of downregulation of Cel-Rheb and Cel-TOR by RNAi on the expression profiles. Five independent experiments were performed with wild type N2. Synchronized worms under six conditions (control-fed, control-fasting, Rheb RNAi-fed, Rheb RNAi-fasting, TOR RNAi-fed, and TOR RNAi-fasting) were collected and frozen with liquid nitrogen at day 4 of adulthood. Total RNA was extracted with Sepasol(R)-RNA â Super (Nacalai tesque), and purified with RNeasy Mini Kit (Qiagen), according to manufactureâs instructions. Synthesis of cDNA, in vitro transcription and biotin labelling cRNA, and hybridization to the C. elegans Genome Array (Affymetrix) were performed according to Affymetrix protocols. Hybridized arrays were scanned using an Affymetrix GeneChip Scanner. Scanned chip images were analyzed with GeneSpring GX 7.3.1 (Agilent Technologies).
2009-01-13 | E-GEOD-9682 | biostudies-arrayexpress
Project description:Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we investigate the proteomic landscape of Caenorhabditis elegans with severe mitochondrial deficiency in the context of insulin signaling inhibition.
2019-02-13 | PXD011851 | Pride
Project description:Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we investigate the phosphoproteomic landscape of Caenorhabditis elegans with severe mitochondrial deficiency in the context of insulin signaling inhibition.
2019-02-13 | PXD011859 | Pride
Project description:The role of ellagic acid (EA), a natural antioxidant, in regulating anti-aging and its underlying mechanisms remains unclear. In this study, we investigated the anti-aging effects and molecular mechanisms of EA in Caenorhabditis elegans (C. elegans). Our results demonstrate that EA extends the lifespan of C. elegans, enhances motility, reduces lipofuscin accumulation, and improves overall healthspan. Additionally, EA reduces reactive oxygen species (ROS) accumulation in C. elegans under conditions of heat and oxidative stress. The insulin/IGF-1 signaling (IIS) pathway, a key regulator of longevity and stress resistance in C. elegans, was found to mediate EA's effects. EA treatment did not extend the lifespan of mutants defective in daf-2, daf-16, hsf-1, hlh-30, and skn-1, confirming that EA’s lifespan-extending effect operates through the IIS pathway. Furthermore, EA treatment increased the expression of stress response genes downstream of the IIS pathway. Based on RNA sequencing data, we further explored the molecular mechanisms and potential regulatory roles of EA in anti-aging.
2025-05-10 | GSE295741 | GEO
Project description:Dietary restriction (DR) is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of DR, intermittent fasting (IF) and caloric restriction (CR), have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan, even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that a nutrient-related signalling molecule, the low molecular weight GTPase Cel-Rheb, has a dual role in lifespan regulation; Cel-Rheb is required for the IF-induced longevity, whereas inhibition of Cel-Rheb mimics the CR effects. We also show that Cel-Rheb exerts its effects in part via the insulin/IGF-like signalling effector DAF-16 in IF, and that Cel-Rheb is required for fasting-induced nuclear translocation of DAF-16. We find that HSP-12.6, a DAF-16 target, functions to mediate the IF-induced longevity. Furthermore, our analyses demonstrate that most of fasting-induced upregulated genes require Cel-Rheb function for their induction, and that Cel-Rheb/Cel-TOR signalling is required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling via Cel-Rheb in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway.
2008-12-15 | GSE9682 | GEO
Project description:The nuclear chromatin landscape changes with age – a phenomenon observed across many species, including humans. Notably, perturbing this landscape can alter the rate of aging, indicating at least a partial role in controlling this process. This raises the question of whether chromatin alterations also distinguish animals that age at unusual rates. To explore this, we focused on insulin/IGF-like signaling (IIS) in Caenorhabditis elegans, a well-characterized signaling pathway whose impairment drastically slows aging and extends lifespan of these animals. Specifically, we conducted ATAC- and mRNA-seq in animals with reduced IIS (i.e., daf-2 mutants). Interestingly, we found that enhancer regions tend to close and become transcriptionally repressed with age, but under reduced IIS, they tend to open and become transcriptionally active, suggesting their potential relevance for lifespan regulation. By screening transcription factors (TFs) predicted to bind these regions, we identified the HOX gene LIN-39 as a novel aging-preventive TF required for the longevity of daf-2 mutants. LIN-39 performs this role specifically during development and in neurons. Further investigation showed that LIN-39 was acting around the L3 larval stage and in the hermaphrodite-specific VC class of cholinergic motor neurons – at a time when they undergo maturation. Finally, this LIN-39-dependent longevity required DAF-16/FOXO, a well-established aging-preventive TF that acts downstream of DAF-2, which may synergize with LIN-39 in VC neurons to open enhancer the regions. We ultimately propose a model whereby longevity of daf-2 mutant hermaphrodites requires a longevity-promoting signal emitted by VC neurons – a signal that relies on correct VC neuron maturation around the L3 stage, which in turn is assured by the actions of LIN-39 and resulting chromatin and gene expression changes. This renders LIN-39 a rare example of a developmental determinant of longevity. And given the conservation of IIS, HOX and FOXO TFs, and cholinergic neuron function across species, the here described mechanism may reflect a general principle by which developmental transcriptional programs shape adult longevity.
2025-05-29 | GSE271972 | GEO
Project description:The nuclear chromatin landscape changes with age – a phenomenon observed across many species, including humans. Notably, perturbing this landscape can alter the rate of aging, indicating at least a partial role in controlling this process. This raises the question of whether chromatin alterations also distinguish animals that age at unusual rates. To explore this, we focused on insulin/IGF-like signaling (IIS) in Caenorhabditis elegans, a well-characterized signaling pathway whose impairment drastically slows aging and extends lifespan of these animals. Specifically, we conducted ATAC- and mRNA-seq in animals with reduced IIS (i.e., daf-2 mutants). Interestingly, we found that enhancer regions tend to close and become transcriptionally repressed with age, but under reduced IIS, they tend to open and become transcriptionally active, suggesting their potential relevance for lifespan regulation. By screening transcription factors (TFs) predicted to bind these regions, we identified the HOX gene LIN-39 as a novel aging-preventive TF required for the longevity of daf-2 mutants. LIN-39 performs this role specifically during development and in neurons. Further investigation showed that LIN-39 was acting around the L3 larval stage and in the hermaphrodite-specific VC class of cholinergic motor neurons – at a time when they undergo maturation. Finally, this LIN-39-dependent longevity required DAF-16/FOXO, a well-established aging-preventive TF that acts downstream of DAF-2, which may synergize with LIN-39 in VC neurons to open enhancer the regions. We ultimately propose a model whereby longevity of daf-2 mutant hermaphrodites requires a longevity-promoting signal emitted by VC neurons – a signal that relies on correct VC neuron maturation around the L3 stage, which in turn is assured by the actions of LIN-39 and resulting chromatin and gene expression changes. This renders LIN-39 a rare example of a developmental determinant of longevity. And given the conservation of IIS, HOX and FOXO TFs, and cholinergic neuron function across species, the here described mechanism may reflect a general principle by which developmental transcriptional programs shape adult longevity.
2025-05-29 | GSE271970 | GEO
Project description:The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan ofCaenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans.
2023-10-04 | GSE244493 | GEO
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