In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases2,3,4,5,6. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan7, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor8,9,10. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
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Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000)
Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807–5811 (2000)
Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)
Smith, J. S. et al. A phylogenetically conserved NAD + -dependent protein deacetylase activity in the Sir2 protein family. Proc. Natl Acad. Sci. USA 97, 6658–6663 (2000)
Tanner, K. G., Landry, J., Sternglanz, R. & Denu, J. M. Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc. Natl Acad. Sci. USA 97, 14178–14182 (2000)
Tanny, J. C., Dowd, G. J., Huang, J., Hilz, H. & Moazed, D. An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 99, 735–745 (1999)
Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001)
Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001)
Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001)
Langley, E. P. M. et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 21, 2383–2396 (2002)
Kenyon, C. A conserved regulatory mechanism for ageing. Cell 105, 165–168 (2001)
Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and Pnc1 govern lifespan extension by calorie restriction in S. cerevisiae. Nature 423, 181–185 (2003)
Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated ageing by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002)
Masoro, E. J. Caloric restriction and ageing: an update. Exp. Gerontol. 35, 299–305 (2000)
Glossmann, H., Presek, P. & Eigenbrodt, E. Quercetin inhibits tyrosine phosphorylation by the cyclic nucleotide-independent, transforming protein kinase, pp60src. Naunyn Schmiedebergs Arch. Pharmacol. 317, 100–102 (1981)
Oliver, J. M., Burg, D. L., Wilson, B. S., McLaughlin, J. L. & Geahlen, R. L. Inhibition of mast cell Fc epsilon R1-mediated signaling and effector function by the Syk-selective inhibitor, piceatannol. J. Biol. Chem. 269, 29697–29703 (1994)
Ferguson, L. R. Role of plant polyphenols in genomic stability. Mutat. Res. 475, 89–111 (2001)
Middleton, E. Jr, Kandaswami, C. & Theoharides, T. C. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 52, 673–751 (2000)
Jang, M. et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218–220 (1997)
Stojanovic, S., Sprinz, H. & Brede, O. Efficiency and mechanism of the antioxidant action of trans-resveratrol and its analogues in the radical liposome oxidation. Arch. Biochem. Biophys. 391, 79–89 (2001)
Monod, J., Wyman, J. & Changeux, J.-P. On the nature of allosteric transitions. J. Mol. Biol. 12, 88–118 (1965)
Sinclair, D. A. Paradigms and pitfalls of yeast longevity research. Mech. Ageing Dev. 123, 857–867 (2002)
Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles-a cause of ageing in yeast. Cell 91, 1033–1042 (1997)
Defossez, P. A. et al. Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol. Cell 3, 447–455 (1999)
Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999)
Jazwinski, S. M. Metabolic control and gene dysregulation in yeast ageing. Ann. NY Acad. Sci. 908, 21–30 (2000)
Dong, Z. Molecular mechanism of the chemopreventive effect of resveratrol. Mutat. Res. 523–524, 145–150 (2003)
Nicolini, G., Rigolio, R., Miloso, M., Bertelli, A. A. & Tredici, G. Anti-apoptotic effect of trans-resveratrol on paclitaxel-induced apoptosis in the human neuroblastoma SH-SY5Y cell line. Neurosci. Lett. 302, 41–44 (2001)
Pandey, R. et al. Analysis of histone acetyltransferase and histone deacetylase families of Arabidopsis thaliana suggests functional diversification of chromatin modification among multicellular eukaryotes. Nucleic Acids Res. 30, 5036–5055 (2002)
Soleas, G. J., Diamandis, E. P. & Goldberg, D. M. Resveratrol: a molecule whose time has come? And gone? Clin. Biochem. 30, 91–113 (1997)
We wish to thank members of the Sinclair and BIOMOL laboratories for discussions and manuscript preparation, S. Luikenhuis and J. Fox for critical reading of the manuscript, and R. Frye for reagents. This work was supported by the National Institute on Aging and the Harvard-Armenise Foundation. D.S. is an Ellison Medical Research Foundation New Research Scholar. K.B. is a Harvard Medical School Pathology Department MPM Scholar. H.C. is supported by the American Federation of Aging Research, D.L. by a National Eye Institute training grant, and J.W. by an NSF Fellowship.
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Plant Cell Reports (2019)