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Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP–mediated feedforward loop

ABSTRACT: A hallmark of aging is immunosenescence, a decline in immune functions, which appeared to be inevitable in living organisms, includingCaenorhabditis elegans. Here, we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically enhances immunocompetence in old age inC. elegans. We demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in olddaf-2(−)animals. In contrast, p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunity, is only partially required for this rejuvenated immunity. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of thezip-10/bZIP transcription factor, which in turn down-regulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS prevents immune aging via the up-regulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a feedforward mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies against immune aging in humans.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE244494 | GEO | 2023/10/04

REPOSITORIES: GEO

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FOXO and HSF1 rejuvenate immunity via positive feedback regulation of insulin/IGF-1 signaling

Project description:A hallmark of aging is immunosenescence, a decline in immune function that appeared to be inevitable. Surprisingly, here we show that genetic inhibition of DAF-2/insulin/IGF-1 receptor drastically delays immunosenescence and even rejuvenates immunity in C. elegans. We find that p38 mitogen activated protein kinase (PMK-1), a key determinant of immunosenescence in wild-type, is dispensable for this rejuvenated immunity. Instead, we demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of zip-10/bZip transcription factor, which in turn down-regulates ins-7, an agonistic insulin-like peptide, for further reduction in insulin/IGF-1 signaling (IIS). Thus, reduced IIS bypasses immunosenescence and rejuvenates immunity via up-regulating anti-aging transcription factors that regulate an endocrine insulin-like peptide through a positive feedback mechanism. Because many functions of IIS are conserved across phyla, our study may lead to developing strategies for immune rejuvenation in humans.

2021-02-26 | GSE137861 | GEO

Prefoldin 6 mediates longevity response from heat shock factor 1 to FOXO in C. elegans

Project description:Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. InCaenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.

2023-10-04 | GSE244495 | GEO

RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

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

Insulin Signaling Regulates Longevity Through Protein Phosphorylation in Caenorhabditis elegans

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 | iProX

Histone Demethylase UTX-1 Regulates the Caenorhabditis elegans Lifespan by Targeting the Insulin/IGF-1 Signaling Pathway

Project description:Epigenetic modifications are thought to be important for gene expression changes during development and aging. However, besides the Sir2 histone deacetylase in somatic tissues and H3K4 trimethylation in germlines, there is scant evidence implicating epigenetic regulations in aging. The insulin/IGF-1 signaling (IIS) pathway is a major lifespan regulatory pathway. Here we show that progressive increases in gene expression and loss of H3K27me3 on IIS components are due, at least in part, to increased activity of the H3K27 demethylase UTX-1 during aging. RNAi of the utx-1 gene extended the mean lifespan of C. elegans by ~30%, dependent on DAF-16 activity and not additive in daf-2 mutants. The loss of utx-1 increased H3K27me3 on the Igf1r/daf-2 gene and decreased IIS activity leading to a more "naive" epigenetic state. Like stem cell reprogramming, our results suggest that reestablishing epigenetic marks lost during aging might help "reset" the developmental age of animal cells. Examination of H3K27me3 in young and old worms without or with Utx-1 RNAi.

2011-11-22 | E-GEOD-29896 | biostudies-arrayexpress

A PTEN variant uncouples longevity from impaired fitness in C. elegans via tuning the activity of FOXO and NRF

Project description:Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in many species. In C. elegans, mutations in daf-2/insulin/IGF-1 receptor dramatically increase lifespan and pathogen resistance, but generally impair motility, development, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in the IIS pathway remains unknown. Here we show that a single amino acid change in DAF-18, PTEN phosphatase, allows worms to maintain longevity and enhanced immunity in daf-2 mutants compared to wild-type, without defects in growth and motility. Through performing a mutagenesis screen, we identified a missense mutation in daf-18 [daf-18(yh1)], which suppressed developmental defects in daf-2 mutants with small effects on pathogen resistance. We showed that the daf-18(yh1) caused a reduction in its function, but maintained long lifespan, motility span, and resistance against various stresses in daf-2 mutants. We further showed that daf-18(yh1) retained the activity of DAF-16/FOXO but restricted detrimental upregulation of SKN-1/NRF, for exerting beneficial physiological consequences. Our study will provide important insights into how one evolutionarily conserved component, PTEN coordinates healthy longevity and fitness.

2021-08-13 | GSE154338 | GEO

Histone Demethylase UTX-1 Regulates the Caenorhabditis elegans Lifespan by Targeting the Insulin/IGF-1 Signaling Pathway

2011-11-22 | GSE29896 | GEO

RNA sequencing analysis of DAF-16 target gene expression when math-33 function is genetically inactivated

Project description:In this study we have investigated the effect of loss of math-33 activity on DAF-16-mediated target gene regulation in C. elegans under conditions of reduced Insulin/IGF-1 signaling (IIS). Using whole nematode RNA sequencing experiments we found that the daf-2(e1370)-mediated induction and repression of DAF-16 target genes was decreased in daf-2(e1370); math-33(tm3561) mutant animals. Our data suggest that the downregulation of endogenous DAF-16 isoforms in the absence of a functional MATH-33 severely affects the global expression of DAF-16 targets when IIS activity is reduced. Therefore, MATH-33 is essential for DAF-16-mediated target gene activation and repression in the context of IIS.

2016-06-22 | GSE70117 | GEO

Glucose Shortens the Lifespan of Caenorhabditis elegans by Down-Regulating Aquaporin Gene Expression

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

RNA sequencing analysis of DAF-16 target gene expression when math-33 function is genetically inactivated

2016-06-22 | E-GEOD-70117 | biostudies-arrayexpress

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