Guarente Leonard
Glenn Lab for the Science of Aging and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Methods Mol Biol. 2013;1077:3-10. doi: 10.1007/978-1-62703-637-5_1.
Over the past 15 years, the number of papers published on sirtuins has exploded. The initial link between sirtuins and aging comes from studies in yeast, in which it was shown that the life span of yeast mother cells (replicative aging) was proportional to the SIR2 gene dosage. Subsequent studies have shown that SIR2 homologs also slow aging in C. elegans, Drosophila, and mice. An important insight into the function of sirtuins came from the finding that yeast Sir2p and mammalian SIRT1 are NAD(+)-dependent protein deacetylases. In mammals, there are seven sirtuins (SIRT1-7). Their functions do not appear to be redundant, in part because three are primarily nuclear (SIRT1, 6, and 7), three are mitochondrial (SIRT3, 4, and 5), and one is cytoplasmic (SIRT2). The past decade has provided an avalanche of data showing deacetylation of many key transcription factors. In this chapter, I will address the evidence that sirtuins mediate the effects of CR on physiology and will then turn to the evidence of a relationship between sirtuins and aging and life span. Finally, I will discuss the roles of sirtuins in diseases of aging and the prospects of translating these findings to novel therapeutic strategies to treat major diseases.
在过去的15年里，关于沉默调节蛋白的论文数量呈爆炸式增长。沉默调节蛋白与衰老之间的最初联系来自于对酵母的研究，研究表明酵母母细胞的寿命（复制性衰老）与SIR2基因剂量成正比。随后的研究表明，SIR2同源物也能延缓秀丽隐杆线虫、果蝇和小鼠的衰老。对沉默调节蛋白功能的一个重要认识来自于发现酵母Sir2p和哺乳动物SIRT1是依赖烟酰胺腺嘌呤二核苷酸（NAD(+)）的蛋白质脱乙酰酶。在哺乳动物中，有七种沉默调节蛋白（SIRT1 - 7）。它们的功能似乎并非冗余，部分原因在于其中三种主要位于细胞核（SIRT1、6和7），三种位于线粒体（SIRT3、4和5），还有一种位于细胞质（SIRT2）。在过去十年中，涌现出大量数据表明许多关键转录因子发生了去乙酰化。在本章中，我将阐述沉默调节蛋白介导热量限制对生理影响的证据，然后探讨沉默调节蛋白与衰老和寿命之间关系的证据。最后，我将讨论沉默调节蛋白在衰老相关疾病中的作用，以及将这些发现转化为治疗重大疾病新治疗策略的前景。
