Calorie restriction (CR) is a dietary intervention used to promote health and longevity^1,2. CR causes various metabolic changes in both the production and the circulation of metabolites¹; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation. We show that lithocholic acid (LCA) is one of the metabolites that alone can recapitulate the effects of CR in mice. These effects include activation of AMP-activated protein kinase (AMPK), enhancement of muscle regeneration and rejuvenation of grip strength and running capacity. LCA also activates AMPK and induces life-extending and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster. As C. elegans and D. melanogaster are not able to synthesize LCA, these results indicate that these animals are able to transmit the signalling effects of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes in all the three animal models. Together, we identify that administration of the CR-mediated upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans in an AMPK-dependent manner.

卡路里限制 （CR） 是一种用于促进健康和长寿的饮食干预 ^1,2 。CR 引起代谢物产生和循环的各种代谢变化 ¹ ;然而，目前尚不清楚哪些改变的代谢物解释了 CR 的生理益处。在这里，我们使用代谢组学来分析在 CR 期间表现出丰度变化的代谢物，并进行后续的功能验证。我们表明，石胆酸 （LCA） 是单独可以概括 CR 在小鼠中的作用的代谢物之一。这些作用包括激活 AMP 活化蛋白激酶 （AMPK）、增强肌肉再生以及恢复握力和跑步能力。LCA 还激活 AMPK，并在秀丽隐杆线虫和黑腹果蝇中诱导延长寿命和延长健康的作用。由于秀丽隐杆线虫和黑腹果蝇无法合成 LCA，这些结果表明，这些动物一旦给药就能够传递 LCA 的信号效应。AMPK 的敲除消除了所有三种动物模型中 LCA 诱导的表型。总之，我们确定单独施用 CR 介导的上调代谢物 LCA 可以以 AMPK 依赖性方式为后生动物带来抗衰老益处。