Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Konrad T. Howitz; Kevin J. Bitterman; Halm Y. Cohen; Dudley W. Lamming; Siva Lavu; Jason G. Wood; Robert E. Zipkin; Phuong Chung; Anne Kisielewski; Li Li Zhang; Brandy Scherer; David A. Sinclair

doi:10.1038/nature01960

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Konrad T. Howitz, Kevin J. Bitterman, Halm Y. Cohen, Dudley W. Lamming, Siva Lavu, Jason G. Wood, Robert E. Zipkin, Phuong Chung, Anne Kisielewski, Li Li Zhang, Brandy Scherer, David A. Sinclair

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Abstract

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast cerevisiae, calorie restriction extends lifespan by the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD⁺-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that cell survival by negatively regulating the p53 tumour suppressor. 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.

Original language	English
Pages (from-to)	191-196
Number of pages	6
Journal	Nature
Volume	425
Issue number	6954
DOIs	https://doi.org/10.1038/nature01960
State	Published - 11 Sep 2003
Externally published	Yes

Bibliographical note

Funding Information:
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.

Funding Information:
Acknowledgements We thank M. Ludwig for technical assistance; R. Viana for construction of the His6-POL30 vector used for the Supplementary Information; M. Hochstrasser for the ulp1ts and ulp2 mutants; C. Hoege and S. Jentsch for the anti-PCNA antibody used for the Supplementary Information; and W. Kramer for comments on the manuscript. R. Kahmann is acknowledged for generous support. H.D.U. is supported by grants from the German Ministry for Education and Research, Deutsche Forschungsgemeinschaft and the German–Israeli Foundation for Scientific Research and Development.

Funding

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. Acknowledgements We thank M. Ludwig for technical assistance; R. Viana for construction of the His6-POL30 vector used for the Supplementary Information; M. Hochstrasser for the ulp1ts and ulp2 mutants; C. Hoege and S. Jentsch for the anti-PCNA antibody used for the Supplementary Information; and W. Kramer for comments on the manuscript. R. Kahmann is acknowledged for generous support. H.D.U. is supported by grants from the German Ministry for Education and Research, Deutsche Forschungsgemeinschaft and the German–Israeli Foundation for Scientific Research and Development.

Funders	Funder number
Harvard-Armenise Foundation
National Science Foundation
National Institute on Aging	P01AG027916
National Eye Institute
AMERICAN FEDERATION FOR AGING RESEARCH
Deutsche Forschungsgemeinschaft
German-Israeli Foundation for Scientific Research and Development
Bundesministerium für Bildung und Forschung

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title = "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan",

abstract = "In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast cerevisiae, calorie restriction extends lifespan by the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that cell survival by negatively regulating the p53 tumour suppressor. 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.",

author = "Howitz, {Konrad T.} and Bitterman, {Kevin J.} and Cohen, {Halm Y.} and Lamming, {Dudley W.} and Siva Lavu and Wood, {Jason G.} and Zipkin, {Robert E.} and Phuong Chung and Anne Kisielewski and Zhang, {Li Li} and Brandy Scherer and Sinclair, {David A.}",

note = "Funding Information: 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. Funding Information: Acknowledgements We thank M. Ludwig for technical assistance; R. Viana for construction of the His6-POL30 vector used for the Supplementary Information; M. Hochstrasser for the ulp1ts and ulp2 mutants; C. Hoege and S. Jentsch for the anti-PCNA antibody used for the Supplementary Information; and W. Kramer for comments on the manuscript. R. Kahmann is acknowledged for generous support. H.D.U. is supported by grants from the German Ministry for Education and Research, Deutsche Forschungsgemeinschaft and the German–Israeli Foundation for Scientific Research and Development.",

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doi = "10.1038/nature01960",

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AU - Howitz, Konrad T.

AU - Bitterman, Kevin J.

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AU - Lamming, Dudley W.

AU - Lavu, Siva

AU - Wood, Jason G.

AU - Zipkin, Robert E.

AU - Chung, Phuong

AU - Kisielewski, Anne

AU - Zhang, Li Li

AU - Scherer, Brandy

AU - Sinclair, David A.

N1 - Funding Information: 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. Funding Information: Acknowledgements We thank M. Ludwig for technical assistance; R. Viana for construction of the His6-POL30 vector used for the Supplementary Information; M. Hochstrasser for the ulp1ts and ulp2 mutants; C. Hoege and S. Jentsch for the anti-PCNA antibody used for the Supplementary Information; and W. Kramer for comments on the manuscript. R. Kahmann is acknowledged for generous support. H.D.U. is supported by grants from the German Ministry for Education and Research, Deutsche Forschungsgemeinschaft and the German–Israeli Foundation for Scientific Research and Development.

PY - 2003/9/11

Y1 - 2003/9/11

N2 - In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast cerevisiae, calorie restriction extends lifespan by the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that cell survival by negatively regulating the p53 tumour suppressor. 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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Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

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