Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases2,3. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast4. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
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We thank S. Parkhurst for the dSir2-pRSETc plasmid, and J. Whetstine, H. Yang and Y. Shi for advice and reagents. C. elegans strain VC199 (sir-2.1(ok434)) was generated by the C. elegans Reverse Genetics Core Facility at the University of British Columbia. This work was supported by the National Institute on Aging, the Harvard-Armenise Foundation, the Donaghue Foundation, and a generous gift from Harmon Rasnow. S.L.H. is an Ellison Medical Research Foundation Senior Investigator, and D.S. and M.T. are Ellison Medical Research Foundation Fellows. J.W. is supported by an NSF Graduate Research Fellowship.
D.S. and K.H. have filed a provisional patent based on this and other studies. D.S. expects that he will own more than $10,000 equity in a company after September 2004; however, this will not exceed 5% equity.
Mortality plots for C. elegans (on dead and live E. coli) and D. melanogaster (males and females) on resveratrol treatment. (PDF 30 kb)
Summary of results from lifespan trials of C. elegans treated with resveratrol on both live and dead E. coli. Wild-type and sir-2.1 mutants are shown. (PDF 21 kb)
Summary of results from lifespan trials of D. melanogaster males and females treated with resveratrol and fisetin. Various strain backgrounds, dSir2 alleles, and dietary conditions are shown. (PDF 31 kb)
Methods for sirtuin purification and sirtuin deacetylation assays. (DOC 22 kb)
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Wood, J., Rogina, B., Lavu, S. et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686–689 (2004). https://doi.org/10.1038/nature02789
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