New research uncovers how the kidney-derived metabolite betaine mirrors exercise’s rejuvenating effects
A study published in Cell by researchers from the Chinese Academy of Sciences and Xuanwu Hospital at Capital Medical University has revealed how exercise helps the body fight aging on a systemic level. The team also identified betaine, a metabolite produced by the kidney, as an orally available compound capable of reproducing many of exercise’s rejuvenating effects.
Over six years, scientists examined how people’s bodies respond to exercise across different time periods. Using a carefully structured experiment with 13 healthy male volunteers, they monitored multiple biological layers—single-cell transcriptomics, proteomics, metabolomics, and the microbiome—at rest, after acute exercise (a single 5 km run), and following long-term training (a 25-day running program).
Their findings pinpointed the kidney as the body’s central regulator during exercise, where increased levels of betaine coordinated protective, anti-aging signals throughout the body.
Decoding the Exercise Paradox
The researchers also uncovered what they call the “exercise paradox.” A single workout caused short-term inflammatory “metabolic chaos,” but consistent training restored balance and stability. Over time, regular exercise reshaped the gut microbiome, strengthened antioxidant defenses by activating key enzymes, and reversed T-cell aging by maintaining DNA integrity and altering epigenetic patterns through suppression of the transcription factor ETS1. Together, these effects rejuvenated the immune system.
Long-term training increased the kidney’s production of betaine, in part through the mitochondrial enzyme CHDH. Remarkably, when betaine was given as a supplement, it reproduced many of the same benefits seen with physical exercise. These included slowing cellular aging in human kidney, vascular, and immune cells, improving metabolism, kidney performance, coordination, and cognitive function, reducing depressive-like behaviors in older mice, and lowering inflammation throughout the body.
A Molecular Key to Youthfulness
Betaine directly binds and inhibits kinase TBK1, a master inflammation regulator, blocking downstream IRF3/NF-κB pathways. This silences chronic “inflammaging,” mirroring exercise’s protective shield. The discovery resolves the exercise paradox: acute stress activates survival pathways (IL-6/corticosterone), while sustained effort engages the kidney-betaine-TBK1 axis to rebuild youthfulness. Betaine’s safety and efficacy position it as a viable exercise alternative for mobility-limited individuals.
“This redefines ‘exercise as medicine’,” says co-corresponding author Dr. Liu Guang-Hui. “This study gives us a fresh way to turn how our body works into something we can target with chemicals. It opens the door to geroprotective treatments that can tweak how multiple organs work together.”
Reference: “Systematic profiling reveals betaine as an exercise mimetic for geroprotection” by 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 and Guang-Hui Liu, 25 June 2025, Cell.
DOI: 10.1016/j.cell.2025.06.001
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6 Comments
Which Betaine?? Betaine Anhydrous (TMG) or Betaine Hydrochloride (HCl) ??
Yes.
Not a Doctor or a Chemist, but some longevity/performance folks have been advocating supplementing with TMG for a while. I’m not familiar with the latter.
Not a Doctor or a Chemist, but some longevity/performance folks have been advocating supplementing with TMG for a while. I’m not familiar with the latter.
The study did not include women. How would it affect women’s bodies?
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