Qu Qi, Chen Yan, Wang Yu, Long Shating, Wang Weiche, Yang Heng-Ye, Li Mengqi, Tian Xiao, Wei Xiaoyan, Liu Yan-Hui, Xu Shengrong, Zhang Cixiong, Zhu Mingxia, Lam Sin Man, Wu Jianfeng, Yun Chuyu, Chen Junjie, Xue Shengye, Zhang Baoding, Zheng Zhong-Zheng, Piao Hai-Long, Jiang Changtao, Guo Hao, Shui Guanghou, Deng Xianming, Zhang Chen-Song, Lin Sheng-Cai
State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
LipidALL Technologies, Changzhou, China.
Nature. 2024 Dec 18. doi: 10.1038/s41586-024-08329-5.
Calorie restriction (CR) is a dietary intervention used to promote health and longevity. CR causes various metabolic changes in both the production and the circulation of metabolites; 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.
热量限制（CR）是一种用于促进健康和延长寿命的饮食干预措施。CR会在代谢物的产生和循环方面引发各种代谢变化；然而，目前尚不清楚哪些代谢物的改变导致了CR的生理益处。在此，我们利用代谢组学分析在CR期间丰度发生变化的代谢物，并进行后续的功能验证。我们发现，石胆酸（LCA）是仅其自身就能在小鼠中重现CR效果的代谢物之一。这些效果包括激活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还能激活秀丽隐杆线虫和黑腹果蝇中的AMPK，并诱导延长寿命和促进健康的效果。由于秀丽隐杆线虫和黑腹果蝇无法合成LCA，这些结果表明，这些动物在给予LCA后能够传递其信号效应。敲除AMPK可消除LCA在所有这三种动物模型中诱导的表型。总之，我们确定单独给予CR介导的上调代谢物LCA能够以依赖AMPK的方式赋予后生动物抗衰老益处。
