Dataset Information

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans

ABSTRACT: mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size or neuronal function. Moreover, while somatic degradation of RAGA-1 alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, neuronal degradation of RAGA-1 only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE237060 | GEO | 2023/07/18

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

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).

Dataset Information

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets