Reduced ech-6 expression attenuates fat-induced lifespan shortening in C. elegans

Yasmine J Liu,Aldo Jongejan,Louis R Lapierre,Reuben L Smith,Arwen W Gao,Riekelt H Houtkooper,Melissa J Silvestrini,Georges E Janssens,Daan M Panneman,Frédéric M Vaz,Michel Van Weeghel,Alyson W Macinnes

doi:10.1038/s41598-022-07397-9

Abstract

Deregulated energy homeostasis represents a hallmark of aging and results from complex gene-by-environment interactions. Here, we discovered that reducing the expression of the gene ech-6 encoding enoyl-CoA hydratase remitted fat diet-induced deleterious effects on lifespan in Caenorhabditis elegans, while a basal expression of ech-6 was important for survival under normal dietary conditions. Lipidomics revealed that supplementation of fat in ech-6-silenced worms had marginal effects on lipid profiles, suggesting an alternative fat utilization for energy production. Transcriptomics further suggest a causal relation between the lysosomal pathway, energy production, and the longevity effect conferred by the interaction between ech-6 and fat diets. Indeed, enhancing energy production from endogenous fat by overexpressing lysosomal lipase lipl-4 recapitulated the lifespan effects of fat diets on ech-6-silenced worms. Collectively, these results suggest that the gene ech-6 is potential modulator of metabolic flexibility and may be a target for promoting metabolic health and longevity.

Highlights

Deregulated energy homeostasis represents a hallmark of aging and results from complex geneby-environment interactions
We found that worms exposed to polysorbate 80 (P-80) supplementation had a reduced lifespan (Fig. 1b; Supplementary Table S1), in line with the lifespan effect of excess dietary fat in mice[34]
We conducted an RNAi-based small-scale lifespan screen to search for metabolic genes that could alter the susceptibility to the detrimental effects of this fat diet

Summary

Introduction

Deregulated energy homeostasis represents a hallmark of aging and results from complex geneby-environment interactions. Enhancing energy production from endogenous fat by overexpressing lysosomal lipase lipl-4 recapitulated the lifespan effects of fat diets on ech-6-silenced worms These results suggest that the gene ech-6 is potential modulator of metabolic flexibility and may be a target for promoting metabolic health and longevity. A flexible metabolism allows cells to adapt to fuel usage and to switch efficiently between nutrient sources depending on the environmental conditions[2] Gradual loss of this process during aging is a causative factor for increased susceptibility to aging-related metabolic disorders, yet the incidence and severity of these complex diseases vary considerably[10,11]. The findings of this study indicate that the gene ech-6 represents a factor, with the potential to be used to fine-tune the degree of metabolic flexibility in response to excessive dietary fat intake to modulate lifespan

Objectives

Methods

Results

Conclusion