Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C-elegans
Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C-elegans
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DOI：
10.1038/nature07583
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发表时间：
2009-02-05
期刊：
影响因子：
64.8
通讯作者：
Nishida, Eisuke
中科院分区：
文献类型：
--
作者：
Honjoh, Sakiko;Yamamoto, Takuya;Nishida, Eisuke
饮食限制是延长不同物种寿命的最有效和最可重复的干预措施(1)。在哺乳动物中，两种饮食限制方案，间歇性禁食(IF)和慢性热量限制，已被证明可以延长寿命并减少与年龄相关的疾病的发生率(2)。IF的一个重要特征是，即使在卡路里摄入量几乎没有或没有总体减少的情况下，它也可以延长寿命。然而，IF诱导长寿的分子机制在很大程度上仍不清楚。在这里，我们建立了一种有效延长秀丽线虫寿命的IF方案，并表明低分子GTP酶Rheb-1在寿命调节中具有双重作用；Rheb-1是IF诱导长寿所必需的，而抑制Rheb-1模拟热量限制效应。Rheb-1的作用部分是通过IF中的胰岛素/胰岛素生长因子(IGF)样信号效应器DAF-16来实现的。我们的分析表明，大多数禁食诱导的上调基因需要Rheb-1的功能来诱导，而Rheb-1和TOR信号是禁食诱导的胰岛素样肽INS-7下调所必需的。这些发现确认了Rheb-1的信号在IF诱导的长寿和基因表达变化中的重要作用，并表明IF诱导的长寿与胰岛素/IGF样信号通路之间存在分子联系。
Dietary restriction is the most effective and reproducible intervention to extend lifespan in divergent species(1). In mammals, two regimens of dietary restriction, intermittent fasting ( IF) and chronic caloric restriction, have proven to extend lifespan and reduce the incidence of age- related disorders(2). An important characteristic of IF is that it can increase lifespan even when there is little or no overall decrease in calorie intake(2). The molecular mechanisms underlying IF- induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that the low molecular weight GTPase RHEB- 1 has a dual role in lifespan regulation; RHEB- 1 is required for the IF- induced longevity, whereas inhibition of RHEB- 1 mimics the caloric- restriction effects. RHEB- 1 exerts its effects in part by the insulin/ insulin growth factor ( IGF)- like signalling effector DAF- 16 in IF. Our analyses demonstrate that most fasting- induced upregulated genes require RHEB- 1 function for their induction, and that RHEB- 1 and TOR signalling are required for the fasting- induced downregulation of an insulin- like peptide, INS- 7. These findings identify the essential role of signalling by RHEB- 1 in IF- induced longevity and gene expression changes, and suggest a molecular link between the IF- induced longevity and the insulin/ IGF- like signalling pathway.