Basic & Clinical Genomics Laboratory, School of Medical Sciences and Bosch Institute, Building F13, University of Sydney, NSW 2006, Australia.
Free Radic Biol Med. 2013 Mar;56:133-71. doi: 10.1016/j.freeradbiomed.2012.10.525. Epub 2012 Oct 24.
Sirtuins are a class of NAD(+)-dependent deacetylases having beneficial health effects. This extensive review describes the numerous intracellular actions of the seven mammalian sirtuins, their protein targets, intracellular localization, the pathways they modulate, and their role in common diseases of aging. Selective pharmacological targeting of sirtuins is of current interest in helping to alleviate global disease burden. Since all sirtuins are activated by NAD(+), strategies that boost NAD(+) in cells are of interest. While most is known about SIRT1, the functions of the six other sirtuins are now emerging. Best known is the involvement of sirtuins in helping cells adapt energy output to match energy requirements. SIRT1 and some of the other sirtuins enhance fat metabolism and modulate mitochondrial respiration to optimize energy harvesting. The AMP kinase/SIRT1-PGC-1α-PPAR axis and mitochondrial sirtuins appear pivotal to maintaining mitochondrial function. Downregulation with aging explains much of the pathophysiology that accumulates with aging. Posttranslational modifications of sirtuins and their substrates affect specificity. Although SIRT1 activation seems not to affect life span, activation of some of the other sirtuins might. Since sirtuins are crucial to pathways that counter the decline in health that accompanies aging, pharmacological agents that boost sirtuin activity have clinical potential in treatment of diabetes, cardiovascular disease, dementia, osteoporosis, arthritis, and other conditions. In cancer, however, SIRT1 inhibitors could have therapeutic value. Nutraceuticals such as resveratrol have a multiplicity of actions besides sirtuin activation. Their net health benefit and relative safety may have originated from the ability of animals to survive environmental changes by utilizing these stress resistance chemicals in the diet during evolution. Each sirtuin forms a key hub to the intracellular pathways affected.
Sirtuins 是一类依赖 NAD(+)的去乙酰化酶，具有有益的健康效应。这篇广泛的综述描述了哺乳动物中 7 种 sirtuins 的众多细胞内作用、它们的蛋白质靶标、细胞内定位、它们调节的途径以及它们在衰老相关常见疾病中的作用。选择性地靶向 sirtuins 以帮助减轻全球疾病负担是目前的研究热点。由于所有 sirtuins 都被 NAD(+)激活，因此提高细胞内 NAD(+)的策略是有意义的。虽然人们对 SIRT1 了解最多，但其他 6 种 sirtuins 的功能现在也逐渐显现出来。最著名的是 sirtuins 参与帮助细胞适应能量输出以匹配能量需求。SIRT1 和一些其他 sirtuins 增强脂肪代谢并调节线粒体呼吸以优化能量捕获。AMP 激酶/SIRT1-PGC-1α-PPAR 轴和线粒体 sirtuins 似乎对维持线粒体功能至关重要。随着衰老的下调，解释了衰老过程中积累的大部分病理生理学。sirtuins 和它们的底物的翻译后修饰影响特异性。尽管 SIRT1 的激活似乎不会影响寿命，但一些其他 sirtuins 的激活可能会。由于 sirtuins 对那些对抗衰老伴随的健康下降的途径至关重要，因此，提高 sirtuin 活性的药物在治疗糖尿病、心血管疾病、痴呆、骨质疏松症、关节炎和其他疾病方面具有临床潜力。然而，在癌症中，SIRT1 抑制剂可能具有治疗价值。除了激活 sirtuins 之外，营养保健品如白藜芦醇还有多种作用。它们的净健康益处和相对安全性可能源于动物在进化过程中通过在饮食中利用这些应激抵抗化学物质来适应环境变化的能力。每个 sirtuin 都形成了受影响的细胞内途径的关键枢纽。
