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Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & David A. Sin, 2003. "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan," Nature, Nature, vol. 425(6954), pages 191-196, September.
    • Handle: RePEc:nat:nature:v:425:y:2003:i:6954:d:10.1038_nature01960
    DOI: 10.1038/nature01960
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    Cited by:

    1. Salvador Manzo-Avalos & Alfredo Saavedra-Molina, 2010. "Cellular and Mitochondrial Effects of Alcohol Consumption," IJERPH, MDPI, vol. 7(12), pages 1-24, December.
    2. Mary M. McDermott & Christopher R. Martens & Kathryn J. Domanchuk & Dongxue Zhang & Clara B. Peek & Michael H. Criqui & Luigi Ferrucci & Philip Greenland & Jack M. Guralnik & Karen J. Ho & Melina R. K, 2024. "Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Robin Haunschild & Werner Marx, 2022. "On Health Effects of Resveratrol in Wine," IJERPH, MDPI, vol. 19(5), pages 1-13, March.
    4. Patricia R. Pitrez & Luis M. Monteiro & Oliver Borgogno & Xavier Nissan & Jerome Mertens & Lino Ferreira, 2024. "Cellular reprogramming as a tool to model human aging in a dish," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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