Identification of key pathways and metabolic fingerprints of longevity in C. elegans

Abstract

Impaired insulin/IGF-1 signaling (IIS) pathway and caloric restriction (CR) are two wellestablished interventions to prolong lifespan in worm C. elegans. However, a cross comparison of these longevity pathways using a multi-omics integration approach is lacking.In this study, we aimed to identify key pathways and metabolite fingerprints of longevity that are shared between IIS and CR worm models using a multi-omics integration approach. We generated 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 them with the N2 strain. Transcriptional profiling identified shared longevity signatures between the two strains, such as an upregulation of lipid storage and defense responses and downregulation of macromolecule synthesis and developmental processes. The shared longevity signatures revealed by metabolomics profiling included an increase in the levels of glycerol-3P, ademine, xanthine, and AMP, and a decrease in the levels of the amino acid pool, the C18:0 and C17:1 fatty acids. 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 as a commonality between the two longevity mechanisms. Overall, our findings point towards the existence of shared metabolic pathways that are likely important for lifespan extension and provide novel insights into potential regulators and metabolic fingerprints for longevity.

The role of Rsv1 in the transcriptional regulation of genes involved in sugar metabolism for long‐term survival

“…The gluconate shunt, the first reaction of which is mediated by Gcd1, provides NADPH and ribose 5‐phosphate through the pentose phosphate pathway . Although the genetic regulation of the NADPH‐generating pathways has not been well‐studied under nutrient starvation, some studies have described the relationship between genes involved in the pentose phosphate pathway and lifespan, suggesting that the transcription levels of pentose phosphate pathway genes are actively adjusted to maintain cell viability . Based on our additional ChIP‐Seq and RNA‐Seq results, we found that Rsv1 directly represses the transcription of idn1 , gnd1 , hxk2 , and gcd1 , a set of genes involved in the glucose shunt and pentose phosphate pathway, for up to 6 h of glucose starvation (Fig.…”

Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction

“…Given this and in the hope of finding alternative compounds and/or targets for therapeutic interventions, we investigated how genetic inhibition of the IIS has lifespan-extending properties in OXPHOS-deficient organisms. Previously, xanthine along with adenine has been found to be slightly, yet significantly reduced in IIS-deficient nematodes within a larger context of metabolic flexibility (Gao et al, 2018). As part of our target validation, we then defined the epistatic relationship between the IIS cascade and novel molecular components predicted to participate in the metabolic reprogramming of mitochondrial mutant nematodes.…”

Differential microRNAs expression profiles in liver from three different lifestyle modification mice models

“…PPARδ has also been observed in response to exercise [41]. The changes of the pathways, such as lipid metabolism, fatty acid degradation and metabolic pathways, have also been reported in CR [42,43]. Studies have reported that HF has an important impact on the lipid metabolism process in rat liver [44].…”