Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans

Summary Dietary restriction (DR) is the most universal intervention known to extend animal lifespan. DR also prevents tumor development in mammals, and this effect requires the tumor suppressor PTEN. However, the metabolic and cellular processes that underly the beneficial effects of DR are poorly u...

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Published in:	Aging cell Vol. 10; no. 1; pp. 39 - 54
Main Authors:	Mouchiroud, Laurent, Molin, Laurent, Kasturi, Prasad, Triba, Mohamed N., Dumas, Marc Emmanuel, Wilson, Marieangela C., Halestrap, Andrew P., Roussel, Damien, Masse, Ingrid, Dallière, Nicolas, Ségalat, Laurent, Billaud, Marc, Solari, Florence
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01.02.2011 John Wiley & Sons, Inc Wiley Open Access
Subjects:	Animals Biochemistry, Molecular Biology Caenorhabditis elegans Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Caenorhabditis elegans Proteins Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Caenorhabditis elegans Proteins - physiology Caloric Restriction dietary restriction Epistasis, Genetic Epistasis, Genetic - physiology High-Throughput Screening Assays hormesis Life Sciences Longevity Longevity - genetics Membrane Transport Proteins Membrane Transport Proteins - genetics Membrane Transport Proteins - metabolism Metabolic Phenomena Metabolism - genetics Mitochondria Mitochondria - genetics Mitochondria - metabolism Molecular biology Monocarboxylic Acid Transporters Monocarboxylic Acid Transporters - genetics Monocarboxylic Acid Transporters - metabolism Mutation Mutation - physiology Oxidative Stress PTEN Phosphohydrolase PTEN Phosphohydrolase - physiology PTEN/daf‐18 pyruvate Pyruvate Dehydrogenase Complex Pyruvate Dehydrogenase Complex - metabolism Pyruvic Acid Pyruvic Acid - metabolism RNA Interference Signal Transduction Signal Transduction - genetics Transcription Factors Transcription Factors - genetics Transcription Factors - metabolism daf-18 OXIDATIVE STRESS TRANSPORTERS PTEN pyruvate Caenorhabditis elegans INSULIN-RECEPTOR INDUCED LONGEVITY GROWTH DISEASE CALORIC RESTRICTION DAF-16/FOXO MICE C-ELEGANS hormesis dietary restriction
ISSN:	1474-9718, 1474-9726, 1474-9726, 1474-9728
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Summary:	Summary Dietary restriction (DR) is the most universal intervention known to extend animal lifespan. DR also prevents tumor development in mammals, and this effect requires the tumor suppressor PTEN. However, the metabolic and cellular processes that underly the beneficial effects of DR are poorly understood. We identified slcf‐1 in an RNAi screen for genes that extend Caenorhabditis elegans lifespan in a PTEN/daf‐18‐dependent manner. We showed that slcf‐1 mutation, which increases average lifespan by 40%, mimics DR in worms fed ad libitum. An NMR‐based metabolomic characterization of slcf‐1 mutants revealed lower lipid levels compared to wild‐type animals, as expected for dietary‐restricted animals, but also higher pyruvate content. Epistasis experiments and metabolic measurements support a model in which the long lifespan of slcf‐1 mutants relies on increased mitochondrial pyruvate metabolism coupled to an adaptive response to oxidative stress. This response requires DAF‐18/PTEN and the previously identified DR effectors PHA‐4/FOXA, HSF‐1/HSF1, SIR‐2.1/SIRT‐1, and AMPK/AAK‐2. Overall, our data show that pyruvate homeostasis plays a central role in lifespan control in C. elegans and that the beneficial effects of DR results from a hormetic mechanism involving the mitochondria. Analysis of the SLCF‐1 protein sequence predicts that slcf‐1 encodes a plasma membrane transporter belonging to the conserved monocarboxylate transporter family. These findings suggest that inhibition of this transporter homolog in mammals might also promote a DR response.
Bibliography:	Present address: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D‐82152 Martinsried, Germany. Present address: Université de Lyon, CNRS, UMR5534, 43 boulevard du 11 novembre 1918, Villeurbanne Cedex, 69622, France. ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	1474-9718 1474-9726 1474-9726 1474-9728
DOI:	10.1111/j.1474-9726.2010.00640.x