The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.
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Acknowledgements We thank R. S. Levy-Drummer, C. Wachtel, S. Schwarzbaum and members of the Cohen laboratory for their comments on the manuscript. This study was supported by National Institutes of Health grant 1RO1GM085022 to Z.B.-J. and by grants from the Israeli Academy of Sciences, the United States - Israel Binational Science Foundation, the Israel Cancer Association, the Koret Foundation, the Israel Cancer Research Fund, the Israel Health Ministry, I-CORE program (41/1), the Israel Science Foundation and the European Research Council to H.Y.C.