RRC ID 6935
Author Mouchiroud L, Molin L, Kasturi P, Triba MN, Dumas ME, Wilson MC, Halestrap AP, Roussel D, Masse I, Dallière N, Ségalat L, Billaud M, Solari F.
Title Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans.
Journal Aging Cell
Abstract 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.
Volume 10(1)
Pages 39-54
Published 2011-2-1
DOI 10.1111/j.1474-9726.2010.00640.x
PMID 21040400
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism* Caenorhabditis elegans Proteins / physiology Caloric Restriction Epistasis, Genetic / physiology High-Throughput Screening Assays Longevity / genetics* Membrane Transport Proteins / genetics* Membrane Transport Proteins / metabolism* Metabolism / genetics Mitochondria / genetics Mitochondria / metabolism Monocarboxylic Acid Transporters / genetics* Monocarboxylic Acid Transporters / metabolism Mutation / physiology* Oxidative Stress PTEN Phosphohydrolase / physiology Pyruvate Dehydrogenase Complex / metabolism Pyruvic Acid* / metabolism RNA Interference Signal Transduction / genetics Transcription Factors / genetics Transcription Factors / metabolism
IF 7.238
Times Cited 49
WOS Category GERIATRICS & GERONTOLOGY CELL BIOLOGY
Resource
C.elegans tm2258