Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA.
Nature. 2011 May 12;473(7346):226-9. doi: 10.1038/nature10007.
Dietary restriction is a robust means of extending adult lifespan and postponing age-related disease in many species, including yeast, nematode worms, flies and rodents. Studies of the genetic requirements for lifespan extension by dietary restriction in the nematode Caenorhabditis elegans have implicated a number of key molecules in this process, including the nutrient-sensing target of rapamycin (TOR) pathway and the Foxa transcription factor PHA-4 (ref. 7). However, little is known about the metabolic signals that coordinate the organismal response to dietary restriction and maintain homeostasis when nutrients are limited. The endocannabinoid system is an excellent candidate for such a role given its involvement in regulating nutrient intake and energy balance. Despite this, a direct role for endocannabinoid signalling in dietary restriction or lifespan determination has yet to be demonstrated, in part due to the apparent absence of endocannabinoid signalling pathways in model organisms that are amenable to lifespan analysis. N-acylethanolamines (NAEs) are lipid-derived signalling molecules, which include the mammalian endocannabinoid arachidonoyl ethanolamide. Here we identify NAEs in C. elegans, show that NAE abundance is reduced under dietary restriction and that NAE deficiency is sufficient to extend lifespan through a dietary restriction mechanism requiring PHA-4. Conversely, dietary supplementation with the nematode NAE eicosapentaenoyl ethanolamide not only inhibits dietary-restriction-induced lifespan extension in wild-type worms, but also suppresses lifespan extension in a TOR pathway mutant. This demonstrates a role for NAE signalling in ageing and indicates that NAEs represent a signal that coordinates nutrient status with metabolic changes that ultimately determine lifespan.
饮食限制是一种强有力的方法，可以延长许多物种（包括酵母、线虫、苍蝇和啮齿动物）的成年寿命并推迟与年龄相关的疾病。对饮食限制延长线虫秀丽隐杆线虫寿命的遗传要求的研究表明，该过程涉及许多关键分子，包括营养感应雷帕霉素（TOR）途径的靶标和 Foxa 转录因子 PHA-4（参考文献 7）。然而，对于协调机体对饮食限制的反应并在营养有限时维持体内平衡的代谢信号知之甚少。内源性大麻素系统是这种作用的理想候选者，因为它参与调节营养摄入和能量平衡。尽管如此，内源性大麻素信号在饮食限制或寿命决定中的直接作用尚未得到证明，部分原因是在适合寿命分析的模型生物中似乎不存在内源性大麻素信号通路。N-酰基乙醇胺（NAEs）是脂质衍生的信号分子，其中包括哺乳动物内源性大麻素花生四烯酰乙醇胺。在这里，我们在秀丽隐杆线虫中鉴定出 NAE，表明在饮食限制下 NAE 的丰度降低，并且 NAE 缺乏足以通过需要 PHA-4 的饮食限制机制延长寿命。相反，用线虫 NAE 二十碳五烯酰乙醇胺补充饮食不仅抑制了野生型蠕虫中饮食限制诱导的寿命延长，而且还抑制了 TOR 途径突变体中寿命延长。这表明 NAE 信号在衰老中的作用，并表明 NAEs 代表一种信号，它协调营养状况与代谢变化，最终决定寿命。
