Systematic profiling reveals betaine as an exercise mimetic for geroprotection

Lingling Geng; Jiale Ping; Ruochen Wu; Haoteng Yan; Hui Zhang; Yuan Zhuang; Taixin Ning; Jun Wang; Chuqian Liang; Jiachen Zhang; Qingqing Chu; Jing Zhang; Yifan Wen; Yaobin Jing; Shuhui Sun; Qin Qiao; Qian Zhao; Qianzhao Ji; Shuai Ma; Yusheng Cai; Yandong Zheng; Zhiran Zou; Zhiqing Diao; Mingheng Li; Hao Zhang; Jianli Hu; Liangzheng Fu; Wang Kang; Ruijun Bai; Hongkai Zhao; Sheng Zhang; Yingjie Ding; Jinghui Lei; Wei Wang; Yun Ji; Bo Gou; Guoqiang Sun; Jian Yin; Pengze Yan; Hao Li; Zehua Wang; Shikun Ma; Zunpeng Liu; Hezhen Shan; Qiaoran Wang; Tianling Cao; Shanshan Yang; Cui Wang; Ping Yang; Yanling Fan; Yanxia Ye; Jinghao Hu; Mengmeng Jiang; Ye Wang; Kan Liu; Yujing Li; Yuanxiang Li; Jingyi Li; Weimin Ci; Zi-Bing Jin; Xiaobing Fu; Xu Zhang; Guoguang Zhao; Juan Carlos Izpisua Belmonte; Si Wang; Moshi Song; Weiqi Zhang; Jing Qu; Guang-Hui Liu

doi:10.1016/j.cell.2025.06.001

Systematic profiling reveals betaine as an exercise mimetic for geroprotection

Cell. 2025 Jun 25:S0092-8674(25)00635-X. doi: 10.1016/j.cell.2025.06.001. Online ahead of print.

Authors

Lingling Geng¹, Jiale Ping², Ruochen Wu³, Haoteng Yan¹, Hui Zhang⁴, Yuan Zhuang⁵, Taixin Ning¹, Jun Wang⁶, Chuqian Liang³, Jiachen Zhang¹, Qingqing Chu⁴, Jing Zhang¹, Yifan Wen³, Yaobin Jing⁷, Shuhui Sun⁴, Qin Qiao⁸, Qian Zhao¹, Qianzhao Ji⁹, Shuai Ma¹⁰, Yusheng Cai⁹, Yandong Zheng¹¹, Zhiran Zou³, Zhiqing Diao³, Mingheng Li³, Hao Zhang³, Jianli Hu², Liangzheng Fu³, Wang Kang², Ruijun Bai¹², Hongkai Zhao³, Sheng Zhang³, Yingjie Ding², Jinghui Lei¹, Wei Wang³, Yun Ji³, Bo Gou³, Guoqiang Sun³, Jian Yin³, Pengze Yan³, Hao Li², Zehua Wang³, Shikun Ma¹², Zunpeng Liu³, Hezhen Shan¹², Qiaoran Wang², Tianling Cao³, Shanshan Yang¹, Cui Wang², Ping Yang³, Yanling Fan⁸, Yanxia Ye⁹, Jinghao Hu¹, Mengmeng Jiang⁹, Ye Wang¹³, Kan Liu¹³, Yujing Li³, Yuanxiang Li³, Jingyi Li¹⁴, Weimin Ci¹³, Zi-Bing Jin¹⁵, Xiaobing Fu¹⁶, Xu Zhang¹³, Guoguang Zhao¹⁷, Juan Carlos Izpisua Belmonte¹⁸, Si Wang¹⁹, Moshi Song²⁰, Weiqi Zhang²¹, Jing Qu²², Guang-Hui Liu²³

Affiliations

¹ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
² China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
⁵ Department of Blood Transfusion, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
⁶ University of Chinese Academy of Sciences, Beijing 100049, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁷ International Center for Aging and Cancer, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, Hainan, China.
⁸ China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
⁹ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
¹⁰ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
¹¹ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
¹² State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
¹³ Department of Urology, Chinese PLA General Hospital, PLA Medical School, Beijing 100853, China.
¹⁴ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
¹⁵ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Laboratory, Beijing 100730, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
¹⁶ Tissue Repair and Regeneration Research Center, Medical Innovation Department, PLA General Hospital and Medical College, Beijing 100842, China.
¹⁷ Department of Neurosurgery, National Medical Center for Neurological Diseases, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
¹⁸ Altos Labs San Diego Institute of Science, San Diego, CA, USA; Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
¹⁹ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: wangsi@xwh.ccmu.edu.cn.
²⁰ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: songmoshi@ioz.ac.cn.
²¹ China National Center for Bioinformation, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: zhangwq@big.ac.cn.
²² State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China; Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
²³ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 40570836
DOI: 10.1016/j.cell.2025.06.001

Abstract

Exercise has well-established health benefits, yet its molecular underpinnings remain incompletely understood. We conducted an integrated multi-omics analysis to compare the effects of acute vs. long-term exercise in healthy males. Acute exercise induced transient responses, whereas repeated exercise triggered adaptive changes, notably reducing cellular senescence and inflammation and enhancing betaine metabolism. Exercise-driven betaine enrichment, partly mediated by renal biosynthesis, exerts geroprotective effects and rescues age-related health decline in mice. Betaine binds to and inhibits TANK-binding kinase 1 (TBK1), retarding the kinetics of aging. These findings systematically elucidate the molecular benefits of exercise and position betaine as an exercise mimetic for healthy aging.

Keywords: ETS1; TBK1; aging; betaine; exercise; exercise immunology; exercise metabolism; inflammation; kidney; senescence.