title: A metabolic signature for long life in the Caenorhabditis elegans Mit mutants.
abstract: Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong Caenorhabditis elegans lifespan. In this study we use a metabolomics approach to identify an ensemble of mitochondrial-derived α-ketoacids and α-hydroxyacids that are produced by long-lived Mit mutants but not by other long-lived mutants or by short-lived mitochondrial mutants. We show that accumulation of these compounds is dependent on concerted inhibition of three α-ketoacid dehydrogenases that share dihydrolipoamide dehydrogenase (DLD) as a common subunit, a protein previously linked in humans with increased risk of Alzheimer's disease. When the expression of DLD in wild-type animals was reduced using RNA interference we observed an unprecedented effect on lifespan - as RNAi dosage was increased lifespan was significantly shortened, but, at higher doses, it was significantly lengthened, suggesting that DLD plays a unique role in modulating length of life. Our findings provide novel insight into the origin of the Mit phenotype.
authors.affiliation: Barshop Institute for Longevity and Aging Studies and the Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78240, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Butler
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mishur
authors.forename: Shylesh
authors.initials: S
authors.lastname: Bhaskaran
authors.forename: Shane L
authors.initials: SL
authors.lastname: Rea
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D008058:Dihydrolipoamide Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D009154:Mutation
chemical_list: D029742:Caenorhabditis elegans Proteins; D008058:Dihydrolipoamide Dehydrogenase