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.
Lingling Geng  1 ,  Jiale Ping  2 ,  Ruochen Wu  3 ,  Haoteng Yan  1 ,  Hui Zhang  4 ,  Yuan Zhuang  5 ,  Taixin Ning  1 ,  Jun Wang  6 ,  Chuqian Liang  3 ,  Jiachen Zhang  1 ,  Qingqing Chu  4 ,  Jing Zhang  1 ,  Yifan Wen  3 ,  Yaobin Jing  7 ,  Shuhui Sun  4 ,  Qin Qiao  8 ,  Qian Zhao  1 ,  Qianzhao Ji  9 ,  Shuai Ma  10 ,  Yusheng Cai  9 ,  Yandong Zheng  11 ,  Zhiran Zou  3 ,  Zhiqing Diao  3 ,  Mingheng Li  3 ,  Hao Zhang  3 ,  Jianli Hu  2 ,  Liangzheng Fu  3 ,  Wang Kang  2 ,  Ruijun Bai  12 ,  Hongkai Zhao  3 ,  Sheng Zhang  3 ,  Yingjie Ding  2 ,  Jinghui Lei  1 ,  Wei Wang  3 ,  Yun Ji  3 ,  Bo Gou  3 ,  Guoqiang Sun  3 ,  Jian Yin  3 ,  Pengze Yan  3 ,  Hao Li  2 ,  Zehua Wang  3 ,  Shikun Ma  12 ,  Zunpeng Liu  3 ,  Hezhen Shan  12 ,  Qiaoran Wang  2 ,  Tianling Cao  3 ,  Shanshan Yang  1 ,  Cui Wang  2 ,  Ping Yang  3 ,  Yanling Fan  8 ,  Yanxia Ye  9 ,  Jinghao Hu  1 ,  Mengmeng Jiang  9 ,  Ye Wang  13 ,  Kan Liu  13 ,  Yujing Li  3 ,  Yuanxiang Li  3 ,  Jingyi Li  14 ,  Weimin Ci  13 ,  Zi-Bing Jin  15 ,  Xiaobing Fu  16 ,  Xu Zhang  13 ,  Guoguang Zhao  17 ,  Juan Carlos Izpisua Belmonte  18 ,  Si Wang  19 ,  Moshi Song  20 ,  Weiqi Zhang  21 ,  Jing Qu  22 ,  Guang-Hui Liu  23
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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.
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