Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.

@article{citeulike:234740, 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 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.}, address = {BIOMOL Research Laboratories, Inc., 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA.}, author = {Howitz, K. T. and Bitterman, K. J. and Cohen, H. Y. and Lamming, D. W. and Lavu, S. and Wood, J. G. and Zipkin, R. E. and Chung, P. and Kisielewski, A. and Zhang, L. L. and Scherer, B. and Sinclair, D. A. }, citeulike-article-id = {234740}, comment = {discovery of sirt1 activator molecules, including resveratrol. resveratrol increased the yeast life span by 70\%, In human cells, treatment with a low concentration of resveratrol increased cell survival following DNA damage. Moreover, a low resveratrol concentration decreased the acetylation of p53 at the lysine residue 382, a known SIRT1 substrate; however, a high concentration caused the opposite}, doi = {http://dx.doi.org/10.1038/nature01960}, issn = {1476-4687}, journal = {Nature}, keywords = {aging, resveratrol, sirt1}, month = {September}, number = {6954}, pages = {191--196}, posted-at = {2007-11-30 23:13:00}, priority = {2}, title = {Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.}, url = {http://dx.doi.org/10.1038/nature01960}, volume = {425}, year = {2003} }

TY - JOUR ID - citeulike:234740 L3 - citeulike-article-id:234740 N2 - 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. IS - 6954 JF - Nature SN - 1476-4687 AD - BIOMOL Research Laboratories, Inc., 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA. EP - 196 TI - Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. VL - 425 SP - 191 KW - aging KW - resveratrol KW - sirt1 N1 - discovery of sirt1 activator molecules, including resveratrol. resveratrol increased the yeast life span by 70%, In human cells, treatment with a low concentration of resveratrol increased cell survival following DNA damage. Moreover, a low resveratrol concentration decreased the acetylation of p53 at the lysine residue 382, a known SIRT1 substrate; however, a high concentration caused the opposite AU - Howitz, KT AU - Bitterman, KJ AU - Cohen, HY AU - Lamming, DW AU - Lavu, S AU - Wood, JG AU - Zipkin, RE AU - Chung, P AU - Kisielewski, A AU - Zhang, LL AU - Scherer, B AU - Sinclair, DA PY - 2003/09/11/ UR - http://dx.doi.org/10.1038/nature01960 ER -