A metabolic signature for long-life in the c. Elegans mit mutants.

Authors: Butler JA; Mishur RJ; Bhaskaran S; Rea SL
Year: 2012
Journal: Aging cell
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 alpha-ketoacids and alpha-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 upon concerted inhibition of three alpha-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 DLD plays a unique role in modulating length of life. Our findings provide novel insight into the origin of the Mit phenotype. (c) 2012 The Authors Aging Cell (c) 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
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Created on Nov. 24, 2012, 9:09 p.m.
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Species: Nematode

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