X-Message-Number: 22440
Date: Sat, 30 Aug 2003 20:58:01 -0700 (PDT)
From: Doug Skrecky <>
Subject: Small molecule activators of sirtuins extend Saccharomyces cerevisiae

Nature. 2003 Aug 24 [Epub ahead of print].

	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.

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