Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Pharmacol Rev. 2012 Jan;64(1):166-87. doi: 10.1124/pr.110.003905. Epub 2011 Nov 21.
Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent deacetylase that is at the pinnacle of metabolic control, all the way from yeast to humans. SIRT1 senses changes in intracellular NAD(+) levels, which reflect energy level, and uses this information to adapt the cellular energy output such that it matches cellular energy requirements. The changes induced by SIRT1 activation are generally (but not exclusively) transcriptional in nature and are related to an increase in mitochondrial metabolism and antioxidant protection. These attractive features have validated SIRT1 as a therapeutic target in the management of metabolic disease and prompted an intensive search to identify pharmacological SIRT1 activators. In this review, we first give an overview of the SIRT1 biology with a particular focus on its role in metabolic control. We then analyze the pros and cons of the current strategies used to activate SIRT1 and explore the emerging evidence indicating that modulation of NAD(+) levels could provide an effective way to achieve such goals.
Sirtuin 1（SIRT1）是一种进化上保守的 NAD（+）依赖性去乙酰化酶，处于从酵母到人等代谢控制的顶峰。SIRT1 感知细胞内 NAD（+）水平的变化，这些变化反映了能量水平，并利用这些信息来调整细胞的能量输出，使其与细胞的能量需求相匹配。SIRT1 激活所诱导的变化通常（但并非专门）是转录性质的，与线粒体代谢和抗氧化保护的增加有关。这些吸引人的特征使 SIRT1 成为代谢疾病管理的治疗靶点，并促使人们积极寻找药理学 SIRT1 激活剂。在这篇综述中，我们首先概述了 SIRT1 的生物学特性，特别关注其在代谢控制中的作用。然后，我们分析了目前用于激活 SIRT1 的策略的优缺点，并探讨了新兴的证据表明，调节 NAD（+）水平可能是实现这些目标的有效途径。
