37 Both median and mean lifespan were significantly increased by ~15%, a similar increase to that found in Sir2-overexpressing flies and worms, and well within the accepted sirtuin longevity data. A possible explanation for the increased lifespan may be due to a significant decrease in levels and signaling of IGF-1, a check details well-known regulator of aging. Furthermore, this study was performed Inhibitors,research,lifescience,medical in two separate lines of mice, to counteract any site-specific effects of insertion of the SIRT6 transgene. Additionally, to ensure the results were not strain-specific, a mixed CB6
strain was used. Therefore, this study conclusively shows that mammalian sirtuins can extend lifespan in mammals. It is important to note that the lifespan extension was Inhibitors,research,lifescience,medical only observed in males and not females, and more research must be carried out to understand the exact mechanism by which this occurs. These data show for the first time that a mammalian sirtuin can regulate longevity,
and finally resolved the long-standing debate as to whether sirtuins regulate lifespan in multicellular organisms (see Figure 1 for a graphic summary of Inhibitors,research,lifescience,medical the debate’s history). These exciting results in mammals open the way for new aging studies, as there are other mammalian sirtuins similar to SIRT6 which may also be involved in aging, and combining SIRT6 with a different sirtuin may cause a greater increase in lifespan than SIRT6 alone. Figure 1 The history of the debate on the role of sirtuins in regulating lifespan. In the short period since the discovery of sirtuins, Inhibitors,research,lifescience,medical the role they play in regulating lifespan has been highly debated and speculated upon. Results in lower organisms remain uncertain, but the role of mammalian sirtuins in regulating lifespan of
mammals has finally been clarified. Although there is still much research to be done to reveal the true nature of sirtuins and their connection to longevity, it Inhibitors,research,lifescience,medical is clear that mammalian sirtuins, SIRT6 in particular, are critical to a healthy or long life. Will sirtuins regulate longevity in primates as well? Only time will tell. Acknowledgments We thank members of the Cohen lab for their helpful comments on the manuscript. We also thank Avia Cohen for generating Figure 1. This study was supported by grants from the Israeli Academy of Sciences, Koret Foundation, I-Core, 17-DMAG (Alvespimycin) HCl and the ERC: European Research Council for H.Y.C. Abbreviations: DR dietary restriction; ERC extrachromosomal rDNA circle; NA nicotinic acid; NAM nicotinamide; rRNA ribosomal RNA; Sir silent information regulator; SIR2 SIR2 gene; sir2 mutant SIR2 gene; Sir2 Sir2 protein; SIRT sirtuin; TOR target of rapamycin; WAT white adipose tissue. Footnotes Conflict of interest: No potential conflict of interest relevant to this article was reported.
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