Lithocholic acid phenocopies anti-ageing effects of calorie restriction
Calorie restriction (CR) is a dietary intervention used to promote health and longevity<sup>1,2</sup>. CR causes various metabolic changes in both the production and the circulation of metabolites<sup>1</sup>; 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.
Authors
- Zhong-Zheng Zheng
- Hao Guo (ORCID: https://orcid.org/0000-0001-8374-0132)
- Changtao Jiang (ORCID: https://orcid.org/0000-0002-5206-2372)
- Sin Man Lam (ORCID: https://orcid.org/0000-0001-9037-904X)
- Mingxia Zhu (ORCID: https://orcid.org/0000-0002-1858-5655)
- Xianming Deng (ORCID: https://orcid.org/0000-0002-9354-5864)
- Shating Long
- Sheng‐Cai Lin (ORCID: https://orcid.org/0000-0003-1993-8376)
- S. Xue (ORCID: https://orcid.org/0000-0001-5842-1164)
- Hai‐long Piao (ORCID: https://orcid.org/0000-0001-7451-0386)
- Chuyu Yun (ORCID: https://orcid.org/0009-0009-8931-6370)
- Weiche Wang
- Baoding Zhang (ORCID: https://orcid.org/0000-0002-6011-9930)
- Chen‐Song Zhang (ORCID: https://orcid.org/0000-0001-5218-0101)
- Cixiong Zhang
- Guanghou Shui (ORCID: https://orcid.org/0000-0002-1621-9643)
- Junjie Chen (ORCID: https://orcid.org/0000-0002-3046-4821)
- Yan Chen (ORCID: https://orcid.org/0000-0001-5325-1151)
- Yu Wang (ORCID: https://orcid.org/0000-0001-5853-3019)
- Mengqi Li (ORCID: https://orcid.org/0000-0002-1171-5648)
- Yan‐Hui Liu (ORCID: https://orcid.org/0000-0002-3722-3334)
- Jianfeng Wu (ORCID: https://orcid.org/0000-0002-8992-2030)
- Xiaoyan Wei (ORCID: https://orcid.org/0000-0001-9168-1048)
- Xiao Tian (ORCID: https://orcid.org/0009-0002-9927-7191)
- Heng-Ye Yang
- Qi Qu (ORCID: https://orcid.org/0000-0002-4870-6606)
- Shengrong Xu
Institutions
- Dalian Institute of Chemical Physics (CN)
- Xiamen University (CN)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- LipidALL Technologies (China) (CN)
- Institute of Genetics and Developmental Biology (CN)
- Peking University Third Hospital (CN)
Publication Details
- Journal
- Nature
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1038/s41586-024-08329-5
- Citations
- 70
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 22.86
Funders
- National Natural Science Foundation of China
- Ministry of Education of the People's Republic of China
- Chinese Academy of Sciences
- Servier
- Fonds Spéciaux de Recherche
- Fundamental Research Funds for the Central Universities