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Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Nature volume 425, pages 191–196 (2003)Cite this article

Abstract

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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Figure 1: Effects of resveratrol on the kinetics of recombinant SIRT1.
Figure 2: Effects of polyphenols on Sir2 and S. cerevisiae lifespan.
Figure 3: Resveratrol extends lifespan by mimicking calorie restriction and suppressing rDNA recombination.
Figure 4: STACs stimulate sirtuin activity in human cells.

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Acknowledgements

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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  1. BIOMOL Research Laboratories, Inc., 5120 Butler Pike, Plymouth Meeting, Pennsylvania, 19462, USA

    Konrad T. Howitz, Robert E. Zipkin, Phuong Chung, Anne Kisielewski, Li-Li Zhang & Brandy Scherer

  2. Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Masachusetts, 02115, USA

    Kevin J. Bitterman, Haim Y. Cohen, Dudley W. Lamming, Siva Lavu, Jason G. Wood & David A. Sinclair

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Correspondence to David A. Sinclair.

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Competing interests

R. Zipkin is co-founder of BIOMOL and owns equity in the company. All other authors affiliated with BIOMOL are employees of BIOMOL. Sales at BIOMOL may increase as a result of this publication. BIOMOL and Harvard Medical School have filed jointly a provisional patent on this work. D. A. Sinclair, K. T. Howitz, R. E. Zipkin, K. J. Bitterman, Haim Y. Chen and Dudley W. Lamming are expected to be inventors.

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Howitz, K., Bitterman, K., Cohen, H. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003). https://doi.org/10.1038/nature01960

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