Genetic perturbation of key central metabolic genes extends lifespan in drosophila and affects response to dietary restriction

Abstract

There is a connection between nutrient inputs, energy-sensing pathways, lifespanvariation and aging. Despite the role of metabolic enzymes in energyhomeostasis and their metabolites as nutrient signals, little is known abouthow their gene expression impacts lifespan. In this report, we use P-elementmutagenesis in Drosophila to study the effect on lifespan of reductions inexpression of seven central metabolic enzymes, and contrast the effects onnormal diet and dietary restriction. The major observation is that for five ofseven genes, the reduction of gene expression extends lifespan on one orboth diets. Two genes are involved in redox balance, and we observe thatlower activity genotypes significantly extend lifespan. The hexokinases alsoshow extension of lifespan with reduced gene activity. Since both affect theATP/ADP ratio, this connects with the role of AMP-activated protein kinaseas an energy sensor in regulating lifespan and mediating caloric restriction.These genes possess significant expression variation in natural populations,and our experimental genotypes span this level of natural activity variation.Our studies link the readout of energy state with the perturbation of thegenes of central metabolism and demonstrate their effect on lifespan.