The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Nature. 2012 Feb 22;483(7388):218-21. doi: 10.1038/nature10815.
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.
在过去的一个世纪中，人类寿命的显著延长给我们带来了巨大的医学挑战。为了应对这些挑战，必须了解和控制决定健康衰老的机制。Sirtuins 是高度保守的去乙酰化酶，已被证明可以调节酵母、线虫和果蝇的寿命。然而，Sirtuins 在调节蠕虫和苍蝇寿命中的作用最近引起了争议。此外，七种哺乳动物 Sirtuins（SIRT1 到 SIRT7，是酵母 Sirtuin Sir2 的同源物）在调节寿命中的作用尚不清楚。在这里，我们发现过表达 Sirt6（参考文献 4）的雄性而非雌性转基因小鼠的寿命比野生型小鼠显著延长。基因表达分析显示，Sirt6 转基因雄性小鼠与雄性野生型小鼠之间存在显著差异：转基因雄性小鼠的血清胰岛素样生长因子 1（IGF1）水平较低，IGF 结合蛋白 1 水平较高，并且 IGF1 信号通路的主要成分的磷酸化水平发生改变，IGF1 信号通路是调节寿命的关键途径。这项研究表明 Sirtuins 家族成员可以调节哺乳动物的寿命，并对与年龄相关的疾病具有重要的治疗意义。
