Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity (RNA-seq)
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE149944 | GEO | 2021/07/06
REPOSITORIES: GEO
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Project description:Aging is a major risk factor for disease, and developing effective pharmaceutical interventions to improve healthspan and promote longevity has become a high priority for society. One of the molecular pathways that has emerged from research in various model organisms revolves around lowering AKT1 levels. This prompted our in silico drug screen for small molecules capable of mimicking the transcriptional effects of AKT1 knockdown. We found topoisomerase inhibitors as a top candidate longevity-drug class. Evaluating multiple compounds from this class in C. elegans revealed that the topoisomerase inhibitor amonafide has the greatest benefit on healthspan and lifespan. Intriguingly, the longevity effect of amonafide was not solely dependent on DAF-16/FOXO, the canonical pathway for lifespan extension via AKT1 inhibition. We performed RNA-seq on amonafide-treated worms and revealed a more youthful transcriptional signature, along with the activation of diverse molecular and cellular defense pathways. We found the mitochondrial unfolded protein response (UPRmt) regulator afts-1 to be crucial for both improved healthspan and extended lifespan upon amonafide treatment. Moreover, healthspan was partially dependent on the immune response transcription factor zip-2 and the integrated stress response transcription factor atf-4. We further examined the potential of amonafide in age-related disease. Treating a C. elegans model for Parkinson's disease with amonafide improved mobility. In conclusion, we identified amonafide as a novel geroprotector, activating mitochondrial- pathogenic- and xenobiotic-associated defense responses and may serve as a candidate for Parkinson's disease therapy.
2025-03-30 | GSE254627 | GEO
Project description:FoxO transcription factors can promote longevity in invertebrates and mammals. In C.elegans, the FoxO family member DAF-16 is required for lifespan extension in the contexts of daf-2/IGFR mutation and germline ablation. The daf-16 genomic locus encodes three distinct groups of transcripts (a,b, and d/f/h). In animals with reduced insulin signaling or ablated germlines, mutations that reduce daf-16a and d/f/h levels without affecting daf-16b reduce lifespan to the same extent as daf-16 null mutations. We reasoned that identifying a set of targets of the daf-16a and d/f/h isoforms that are differentially regulated in two contexts of reduced insulin signaling and in germline ablated animals would enrich for the daf-16 transcriptional targets that are required for longevity. We identified targets that were differentially regulated in daf-2(e1368) and daf-2(e1370) mutants relative to wild-type, and differentially regulated in the opposite direction from WT in compound mutants with both daf-16(mg54), which eliminates the a and d/f/h isoforms, and daf-16(mu86) which is a predicted null allele. We performed a similar analysis in glp-1(e2141) germline ablated animals (omitting the wild-type comparison). We then identified daf-16 targets associated with longevity (dal genes) which were found in all three sets of comparisons.
2019-03-01 | GSE111338 | GEO
Project description:Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity (RNA-seq)
| PRJNA630672 | ENA
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: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.
2018-02-26 | GSE93724 | GEO
Project description:FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these data sets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals. Whole-transcriptome profiling of daf-16/FoxO isoform-specific deletion mutants in the long-lived daf-2(e1370) background. Included are daf-16 wild-type, daf-16 null mutation, daf-16a/f mutation, two independent daf-16a mutations, and daf-16f mutation. N2 wild-type controls are also included.
2015-08-27 | E-GEOD-72426 | biostudies-arrayexpress
Project description:FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these data sets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals.
2015-08-27 | GSE72426 | 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
Project description:Dietary restriction extends lifespan and delays the age-related physiological decline in many species. Intermittent fasting (IF) is one of the most effective dietary restriction regimens that extends lifespan in C. elegans and mammals1,2. In C. elegans, the FOXO transcription factor DAF-16 is implicated in fasting-induced gene expression changes and the longevity response to IF3; however, the mechanisms that sense and transduce fasting-stress stimuli have remained largely unknown. Here we show that a KGB-1/AP1 (activator protein 1) module is a key signalling pathway that mediates fasting-induced transcriptional changes and IF-induced longevity. Our promoter analysis coupled to genome-wide microarray results has shown that the AP-1-binding site, together with the FOXO-binding site, is highly over-represented in the promoter regions of fasting-induced genes. We find that JUN-1 (C. elegans c-Jun) and FOS-1 (C. elegans c-Fos), which constitute the AP-1 transcription factor complex, are required for IF-induced longevity. We also find that KGB-1 acts as a direct activator of JUN-1 and FOS-1, is activated in response to fasting, and, among the three C. elegans JNKs, is specifically required for IF-induced longevity. Our results demonstrate that most fasting-induced upregulated genes, including almost all of the DAF-16-dependent genes, require KGB-1 and JUN-1 function for their induction, and that the loss of kgb-1 suppresses the fasting-induced upregulation of DAF-16 target genes without affecting fasting-induced DAF-16 nuclear translocation. These findings identify the evolutionarily conserved JNK/AP-1 module as a key mediator of fasting-stress responses, and suggest a model in which two fasting-induced signalling pathways leading to DAF-16 nuclear translocation and KGB-1/AP-1 activation, respectively, integrate in the nucleus to coordinately mediate fasting-induced transcriptional changes and IF-induced longevity. To delineate the whole picture of transcriptional changes in response to fasting, we performed genome-wide gene expression analyses during 2 days (48 h) fasting. Two and three independent experiments were performed in the time course and mutants, respectively.
2013-03-15 | E-GEOD-27677 | biostudies-arrayexpress