• Open Access

A metabolic signature for long life in the Caenorhabditis elegans Mit mutants

Authors

  • Jeffrey A. Butler,

    1. Barshop Institute for Longevity and Aging Studies and the Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA
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  • Robert J. Mishur,

    1. Barshop Institute for Longevity and Aging Studies and the Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA
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  • Shylesh Bhaskaran,

    1. Barshop Institute for Longevity and Aging Studies and the Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA
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  • Shane L. Rea

    Corresponding author
    • Barshop Institute for Longevity and Aging Studies and the Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA
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Correspondence

Shane L. Rea, Ph.D., Barshop Institute for Longevity and Aging Studies, 15355 Lambda Drive, STCBM Building, Rm. 2.200.04, Texas Research Park, San Antonio, TX 78245-3207, USA. Tel. 210 562 5092; fax: 210 562 5028; e-mail: reas3@uthscsa.edu

Summary

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.

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