Of Red Wine, Diet, and a Long Life

Abstract

Caloric restriction slows aging and extends the life-span of various organisms. In the yeast Saccharomyces cerevisiae , this extension of life-span is mediated through activation of the sirtuin-family deacetylase Sir2 in what may represent a stress response. Sirtuin activity has also been implicated in Caenorhabditis elegans longevity, and the related human enzyme, SIRT1, which deacetylates the tumor suppressor p53, promotes cell survival (see Finkel). Howitz et al. screened small molecule libraries for compounds that affected sirtuin function and discovered that several plant polyphenols stimulated SIRT1 activity in an in vitro fluorescent deacetylation assay. Resveratrol, which is found in red wine and may be implicated in various health benefits associated with moderate wine drinking, was the most potent of these sirtuin-activating compounds (STACs). Low concentrations of resveratrol stimulated yeast Sir2, and resveratrol and other STACs prolonged yeast replicative life-span. The effects of resveratrol on life-span were dependent on Sir2, and, in the presence of resveratrol, glucose deprivation produced no further life-span extension. Low concentrations of resveratrol extended the survival of human embryonic kidney cells (HEK 293 cells) exposed to ionizing radiation and decreased p53 acetylation in irradiated HEK 293 and osteosarcoma cells. (The concentration dependence of resveratrol's effects was complex, and high concentrations of resveratrol increased p53 acetylation in the osteosarcoma cells.) The authors proposed a model in which plants under stress synthesize polyphenols in order to regulate sirtuin-mediated responses, and animals and fungi are able to respond to these plant stress metabolites. K. T. Howitz, K. J. Bitterman, H. Y. Cohen, D. W. Lamming, S. Lavu, J. G. Wood, R. E. Zipkin, P. Chung, A. Kisielewski, L.-L. Zhang, B. Scherer, D. A. Sinclair, Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425 , 191-196 (2003). [Online Journal] T. Finkel, A toast to long life. Nature 425 , 132-133 (2003). [Online Journal]