The University of Southampton
University of Southampton Institutional Repository

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

Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans
Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans
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.
1474-9718
39-54
Mouchiroud, Laurent
4495bc23-51a4-4194-b632-a68e2e68d2ca
Molin, Laurent
d5b2179d-0dec-4b92-8ee0-75efa8e5760c
Kasturi, Prasad
901bc0aa-0da4-4b7f-a9e1-126634528195
Triba, Mohamed N.
2e9346b4-d98e-4c94-b9ad-e460b3c43f28
Dumas, Marc Emmanuel
15b9f5b3-0452-465e-8f0a-d9ac2e94da30
Wilson, Marieangela C.
db405af8-ae07-4c68-80b9-d38755214dd6
Halestrap, Andrew P.
5a82be18-2f1d-4f9f-ba60-0cc8892dd2b4
Roussel, Damien
0239e6af-e548-4e26-8310-bace6cba9913
Masse, Ingrid
f7478f5d-e437-4006-8fec-930526903d9b
Dallière, Nicolas
fbefe788-fe69-48fe-8b07-efe4e78b9161
Ségalat, Laurent
aa758bcf-073f-449c-8d3a-3f3ee888be7f
Billaud, Marc
8b839afb-ee1f-4e30-a02c-31c23df895ab
Solari, Florence
8bd42861-08ee-488a-82b9-6d0f363da4aa
Mouchiroud, Laurent
4495bc23-51a4-4194-b632-a68e2e68d2ca
Molin, Laurent
d5b2179d-0dec-4b92-8ee0-75efa8e5760c
Kasturi, Prasad
901bc0aa-0da4-4b7f-a9e1-126634528195
Triba, Mohamed N.
2e9346b4-d98e-4c94-b9ad-e460b3c43f28
Dumas, Marc Emmanuel
15b9f5b3-0452-465e-8f0a-d9ac2e94da30
Wilson, Marieangela C.
db405af8-ae07-4c68-80b9-d38755214dd6
Halestrap, Andrew P.
5a82be18-2f1d-4f9f-ba60-0cc8892dd2b4
Roussel, Damien
0239e6af-e548-4e26-8310-bace6cba9913
Masse, Ingrid
f7478f5d-e437-4006-8fec-930526903d9b
Dallière, Nicolas
fbefe788-fe69-48fe-8b07-efe4e78b9161
Ségalat, Laurent
aa758bcf-073f-449c-8d3a-3f3ee888be7f
Billaud, Marc
8b839afb-ee1f-4e30-a02c-31c23df895ab
Solari, Florence
8bd42861-08ee-488a-82b9-6d0f363da4aa

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 and Solari, Florence (2011) Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans. Aging Cell, 10 (1), 39-54. (doi:10.1111/j.1474-9726.2010.00640.x). (PMID:21040400)

Record type: Article

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.

Full text not available from this repository.

More information

Published date: February 2011
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 362880
URI: http://eprints.soton.ac.uk/id/eprint/362880
ISSN: 1474-9718
PURE UUID: 045c4793-69c4-4714-90f0-dafc07b54719

Catalogue record

Date deposited: 13 Mar 2014 14:04
Last modified: 16 Jul 2019 21:10

Export record

Altmetrics

Contributors

Author: Laurent Mouchiroud
Author: Laurent Molin
Author: Prasad Kasturi
Author: Mohamed N. Triba
Author: Marc Emmanuel Dumas
Author: Marieangela C. Wilson
Author: Andrew P. Halestrap
Author: Damien Roussel
Author: Ingrid Masse
Author: Nicolas Dallière
Author: Laurent Ségalat
Author: Marc Billaud
Author: Florence Solari

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×