title: 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, lifespan variation and aging. Despite the role of metabolic enzymes in energy homeostasis and their metabolites as nutrient signals, little is known about how their gene expression impacts lifespan. In this report, we use P-element mutagenesis in Drosophila to study the effect on lifespan of reductions in expression of seven central metabolic enzymes, and contrast the effects on normal diet and dietary restriction. The major observation is that for five of seven genes, the reduction of gene expression extends lifespan on one or both diets. Two genes are involved in redox balance, and we observe that lower activity genotypes significantly extend lifespan. The hexokinases also show extension of lifespan with reduced gene activity. Since both affect the ATP/ADP ratio, this connects with the role of AMP-activated protein kinase as 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 the genes of central metabolism and demonstrate their effect on lifespan.
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Talbert
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Barnett
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hoff
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Amella
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Kuczynski
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Lavington
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Koury
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Brud
authors.affiliation: Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794, USA walter.eanes@stonybrook.edu.
authors.forename: Walter F
authors.initials: WF
authors.lastname: Eanes
mesh_terms: D000375:Aging / Q000235:genetics; D000824:Animal Nutritional Physiological Phenomena / Q000235:genetics; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism*; D004798:Enzymes / Q000378:metabolism*; D005508:Food Deprivation; D015870:Gene Expression; D008136:Longevity / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction
chemical_list: D029721:Drosophila Proteins; D004798:Enzymes
keywords: aging; caloric restriction; energy homeostasis; redox balance