Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Konrad T. Howitz, Kevin J. Bitterman, Haim Y. Cohen, Dudley W. Lamming, Siva Lavu, Jason G. Wood, Robert E. Zipkin, Phuong Chung, Anne Kisielewski, Li-Li Zhang, Brandy Scherer and David A. Sinclair ()
Additional contact information
Konrad T. Howitz: BIOMOL Research Laboratories, Inc.
Kevin J. Bitterman: Harvard Medical School
Haim Y. Cohen: Harvard Medical School
Dudley W. Lamming: Harvard Medical School
Siva Lavu: Harvard Medical School
Jason G. Wood: Harvard Medical School
Robert E. Zipkin: BIOMOL Research Laboratories, Inc.
Phuong Chung: BIOMOL Research Laboratories, Inc.
Anne Kisielewski: BIOMOL Research Laboratories, Inc.
Li-Li Zhang: BIOMOL Research Laboratories, Inc.
Brandy Scherer: BIOMOL Research Laboratories, Inc.
David A. Sinclair: Harvard Medical School

Nature, 2003, vol. 425, issue 6954, 191-196

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01960

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