Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy.
Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy.
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DOI：
10.1038/cddis.2009.8
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发表时间：
2010
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
热量限制和诱导自噬的药理学试剂可以延长包括小鼠、苍蝇和线虫在内的模型生物的寿命。在这项研究中，我们表明，转基因表达的Sirtuin-1诱导自噬在人体细胞在体外和秀丽隐杆线虫在体内。敲低或敲除Sirtuin-1可以防止白藜芦醇和人类细胞中营养缺乏以及C.优雅的。相反，Sirtuin-1不是雷帕霉素或p53抑制诱导自噬所必需的，无论是在人类细胞还是在C.优雅的。Sirtuin-1的敲低或药理学抑制增强了人类细胞对代谢应激的脆弱性，除非它们被雷帕霉素或p53抑制剂刺激进行自噬。沿着类似的路线，白藜芦醇和饮食限制只延长了自噬熟练线虫的寿命，而这些对寿命的有益影响被基本自噬调节剂Beclin-1的敲除所消除。我们的结论是，自噬是普遍需要的寿命延长的热量限制和药理学Sirtuin-1激活剂的效果。
Caloric restriction and autophagy-inducing pharmacological agents can prolong lifespan in model organisms including mice, flies, and nematodes. In this study, we show that transgenic expression of Sirtuin-1 induces autophagy in human cells in vitro and in Caenorhabditis elegans in vivo. The knockdown or knockout of Sirtuin-1 prevented the induction of autophagy by resveratrol and by nutrient deprivation in human cells as well as by dietary restriction in C. elegans. Conversely, Sirtuin-1 was not required for the induction of autophagy by rapamycin or p53 inhibition, neither in human cells nor in C. elegans. The knockdown or pharmacological inhibition of Sirtuin-1 enhanced the vulnerability of human cells to metabolic stress, unless they were stimulated to undergo autophagy by treatment with rapamycin or p53 inhibition. Along similar lines, resveratrol and dietary restriction only prolonged the lifespan of autophagy-proficient nematodes, whereas these beneficial effects on longevity were abolished by the knockdown of the essential autophagic modulator Beclin-1. We conclude that autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.
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