Original Article

Subject Category: Internal Medicine

Citation: Cell Death and Disease (2010) 1, e10; doi:10.1038/cddis.2009.8
Published online 14 January 2010

Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy

Edited by G Melino

E Morselli1,2,3, M C Maiuri1,2,3,6, M Markaki4, E Megalou4, A Pasparaki4, K Palikaras4, A Criollo1,2,3, L Galluzzi1,2,3, S A Malik1,2,3, I Vitale1,2,3, M Michaud1,2,3, F Madeo5, N Tavernarakis4,6 and G Kroemer1,2,3,6

  1. 1INSERM, U848, Villejuif F-94805, France
  2. 2Institut Gustave Roussy, F-94805 Villejuif, France
  3. 3Université Paris Sud-XI, Villejuif F-94805, France
  4. 4Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Vasilika Vouton, PO Box 1385, Heraklion 71110, Crete, Greece
  5. 5Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria

Correspondence: N Tavernarakis, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Vasilika Vouton, PO Box 1385, Heraklion 71110, Crete, Greece. Tel: +30 2810 391066, Fax: +30 2810 391067; E-mail: tavernarakis@imbb.forth.gr; G Kroemer, INSERM Unit ‘Apoptosis, Cancer and Immunity’, Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, Villejuif F-94805, France. Tel: +33 1 4211 6046, Fax: +33 1 4211 6047; E-mail: kroemer@orange.fr

6These authors contributed equally to this work.

Received 2 November 2009; Accepted 2 November 2009.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

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Abstract

Caloric restriction and autophagy-inducing pharmacological agents can prolong lifespan in model organisms including mice, flies, and nematodes. In this study, we show that transgenic expression of Sirtuin-1 induces autophagy in human cells in vitro and in Caenorhabditis elegans in vivo. The knockdown or knockout of Sirtuin-1 prevented the induction of autophagy by resveratrol and by nutrient deprivation in human cells as well as by dietary restriction in C. elegans. Conversely, Sirtuin-1 was not required for the induction of autophagy by rapamycin or p53 inhibition, neither in human cells nor in C. elegans. The knockdown or pharmacological inhibition of Sirtuin-1 enhanced the vulnerability of human cells to metabolic stress, unless they were stimulated to undergo autophagy by treatment with rapamycin or p53 inhibition. Along similar lines, resveratrol and dietary restriction only prolonged the lifespan of autophagy-proficient nematodes, whereas these beneficial effects on longevity were abolished by the knockdown of the essential autophagic modulator Beclin-1. We conclude that autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.

Keywords:

ATG7, Caenorhabditis elegans, HCT 116, mTOR, rapamycin, senescence

Abbreviations:

DiOC6(3), 3,3′-dihexyloxacarbocyanine iodide; atg, AuTophaGy-related gene; BafA1, bafilomycin A1; Bec-1, Beclin-1; Δψm, mitochondrial transmembrane potential; GFP, green fluorescent protein; HRP, horseradish peroxidase; mTOR, mammalian target of rapamycin; Rapa, rapamycin; Resv, resveratrol; siRNA, small-interfering RNA; Sirt-1, Sirtuin-1; Tun, tunicamycin; WT, wild type