Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
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 deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes 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.
Howitz
Konrad T
KT
BIOMOL Research Laboratories, Inc., 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA.
Bitterman
Kevin J
KJ
Cohen
Haim Y
HY
Lamming
Dudley W
DW
Lavu
Siva
S
Wood
Jason G
JG
Zipkin
Robert E
RE
Chung
Phuong
P
Kisielewski
Anne
A
Zhang
Li-Li
LL
Scherer
Brandy
B
Sinclair
David A
DA
D000107:Acetylation / Q000187:drug effects; D031204:Caloric Restriction; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D005419:Flavonoids; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008136:Longevity / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology; D011108:Polymers / Q000494:pharmacology; D059808:Polyphenols; D011995:Recombination, Genetic / Q000187:drug effects; D000077185:Resveratrol; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014920:Wine
D005419:Flavonoids; D010636:Phenols; D011108:Polymers; D059808:Polyphenols; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C087778:SIR2 protein, S cerevisiae; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; D000077185:Resveratrol