Unlocking exercise’s anti-aging key: Betaine as first oral mimetic

June 25, 2025 —A Cell-published study led by Chinese Academy of Sciences and Xuanwu Hospital Capital Medical University reveals how exercise systemically counters aging and identifies betaine—a kidney-derived metabolite—as an oral compound mimicking exercise’s rejuvenating effects.

In a six-year study, scientists delved into human responses to exercise across different timescales. With a unique trial design involving 13 healthy male volunteers, they tracked multi-omics dynamics, including single-cell transcriptomics, proteomics, metabolomics, and the microbiome, during rest, acute exercise (a single 5 km run), and long-term training (a 25-day running regimen). Crucially, they identified the kidney as the command center for exercise, where surges in betaine orchestrate body-wide geroprotective signals.

The exercise paradox was decoded as follows: Acute exercise triggered inflammatory "metabolic chaos," while sustained training rebuilt homeostasis. Chronic exercise modulated gut microbiomes, enhanced antioxidant defenses by upregulating antioxidant enzymes, and reversed T-cell aging by stabilizing DNA integrity and modulating epigenetic marks through the repression of transcription factor ETS1 expression, rejuvenating the immune system. Long-term exercise boosted kidney betaine production partially via mitochondrial enzyme CHDH. Strikingly, betaine supplementation alone replicated many of exercise’s benefits, such as alleviating cellular aging in human kidney, vascular, and immune cells, enhancing metabolism, kidney function, coordination, cognition, and reducing depressive-like behaviors in aged mice, and slashing inflammation systemically.

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.”

The study “Systematic profiling reveals betaine as an exercise mimetic for geroprotection” appears in Cell (June 25, 2025). Corresponding authors: Liu Guang-Hui, Qu Jing, Song Moshi (IOZ, CAS); Zhang Weiqi (CNCB); Wang Si (Xuanwu Hospital).