Genetic factors that regulate metabolism and lifespan in Caenorhabditis elegans on glucose-rich diets

DoctorGlucose-enriched diets shorten the lifespan of C. elegans. However, genetic factors that mediate the aging-regulatory effects of glucose and related metabolic processes were poorly understood. Here, I sought to identify genes that mediate the effects of dietary glucose on lifespan. I performed a genome-wide RNAi screen using a glucose-responsive GFP transgenic C. elegans. The level of GFP expression was reproducibly increased by 170 RNAi clones and decreased by 43 RNAi clones. I then examined the effects of these RNAi clones on lifespan upon glucose-rich diet feeding. Knockdown of mdt-15/mediator 15 significantly enhanced the life-shortening effect of glucose-rich diets. MDT-15 regulates lipid metabolism and stress resistance by acting as a co-regulator of transcription factors, SREBP/SBP-1, NHR-49, and SKN-1. Genetic inhibition of sbp-1 enhanced the toxic effects of glucose on lifespan but knockdown of nhr-49 or skn-1 did not. Conversely, gain-of-function mutation of mdt-15 (mdt-15gf) or overexpression of sbp-1(sbp-1OE) restored normal lifespan in glucose-fed conditions. These data suggest that MDT-15 and SBP-1 protect worms from the glucose toxicity. Next, I performed mRNA sequencing and qRT-PCR to identify functionally important downstream effectors of MDT-15 and SBP-1. Glucose-rich diet feeding induced several fatty acid desaturases including fat 7 in an mdt-15- and sbp-1-dependent manner. Fatty acid desaturases are enzymes that convert saturated fatty acids (SFAs) to unsaturated fatty acids. By using GC/MS analysis, I found that the levels of SFAs were further increased in glucose-fed mdt-15(RNAi) and sbp-1(RNAi) animals, while being reduced in mdt-15gf or sbp-1OE animals. In addition, the lifespan-shortening effect of glucose diets was greatly enhanced by SFA feeding, but was suppressed by overexpression of fatty acid desaturases. Thus, MDT-15 and SBP-1 appear to moderate the lifespan-shortening effects of glucose by reducing accumulation of SFAs through inducing fatty acid desaturases. This study will lead to better understanding of the crucial role of the relationship between glucose and lipid metabolism in organismal lifespan regulation