When it comes to reasons to exercise, one stands out: exercise not only strengthens the body but is also a free anti-aging and longevity booster. However, excuses for skipping exercise are endless – busy work, endless chores, or simply… laziness.
But a long-cherished dream of scientists and "lazy enthusiasts" has finally come true: Could there be an "exercise pill" that makes the body mimic the benefits of exercise on its own?
Recently, a rigorous human study by Professor Liu Guanghui’s team from the Chinese Academy of Sciences identified a natural substance in everyday foods – betaine – that not only perfectly replicates the anti-inflammatory and anti-aging effects of long-term exercise but even showed rejuvenating potential in elderly mice[1]!
01 Identifying the "Exercise Molecule"
An "exercise mimetic" is a compound or intervention that mimics exercise benefits – such as enhanced endurance, improved metabolism, reduced inflammation, and delayed aging – by activating exercise-related pathways or metabolic processes[2].
Though the concept sounds new, scientists have been exploring it for over two decades. Early efforts focused on targeting key exercise-regulating proteins (e.g., AMPK, PPAR-δ) with drugs, leading to first-generation "potent but risky" mimetics like AICAR and GW501516[3].
After setbacks, researchers shifted to gentler, systemic exercise-mimicking solutions. However, drugs like metformin (repurposed old medicine) or resveratrol (nature-derived) act more as pathway modulators with similar effects to exercise, rather than true exercise mimetics.
So, how to find the "most authentic" exercise mimetic? The answer lies in exercise itself: exercise triggers molecular changes in the body – identifying key molecules would uncover the most natural and safe exercise mimetic.
To find this "exercise molecule," the team conducted a human experiment. They recruited healthy young men and monitored changes in over 16,000 blood molecules across three states: rest, single bout of running (acute exercise), and long-term running (chronic exercise).
Results showed that acute exercise acts like a "stress test," while chronic exercise drives gradual bodily adaptation and optimization, delivering true anti-inflammatory and anti-aging benefits.
Figure note: Chronic exercise improves multiple health indicators, such as reduced resting heart rate and lower levels of inflammatory factors hsCRP and TNF-α, while acute exercise mainly causes transient stress-related changes in bodily indicators.
Among the massive molecular changes from chronic exercise, one substance stood out: betaine. Its levels showed the most stable and significant increase after long-term exercise. Critically, betaine is not purely exogenous – even without dietary intake, the kidneys actively synthesize and release it into the bloodstream in response to long-term exercise.
Figure note: After chronic exercise, plasma betaine levels increase significantly, and the expression of betaine synthesis-related genes and key enzyme CHDH in the kidneys is upregulated.
In other words, betaine is not just a nutrient from food but an "endogenous protective substance" actively produced by the body to link exercise and health!
Notably, we previously highlighted betaine’s potential in anti-aging in 2021. Traditionally, betaine was known for converting harmful homocysteine (Hcy), reducing risks of cardiovascular disease, dementia, and osteoporosis in the elderly.
In recent years, it has gained attention as a "golden partner" to anti-aging supplements like NMN. However, as a tool to lower Hcy, betaine is not always the best choice and may not suit everyone… So, could its performance as an "exercise mimetic" be more impressive?
02 Naturally Mimicking Exercise – And Anti-Aging Too?
To verify the "exercise molecule" found in humans, researchers fed betaine to elderly mice. After 12 weeks, remarkable effects emerged:
Behavioral Rejuvenation
First, as an exercise mimetic, betaine excelled in physical performance: 体能测试 showed improved grip strength, balance, and endurance on the rotarod test.
Figure note: Betaine supplementation improves endurance, grip strength, balance, and cognitive performance in elderly mice.
Whole-Body Organ "Renovation"
Overall, after betaine supplementation, the area of senescence marker SA-β-Gal (senescence-associated β-galactosidase) expression significantly decreased in multiple tissues, including skin, liver, muscle, and kidneys. In the liver and kidneys, the number of cells highly expressing senescence-driving proteins p53 and p21 also dropped significantly.
Additionally, betaine reduced age-related infiltration of immune cells (e.g., CD45+, CD68+, IBA1+ cells) in the brain, kidneys, and liver of elderly mice, "cooling down" systemic chronic inflammatory aging.
Figure note: After betaine supplementation in elderly mice, SA-β-Gal, p21, and p53 levels decrease significantly in multiple tissues, while inflammatory immune cell infiltration is markedly reduced.
Examining individual organs revealed clear improvements:
Betaine reduced age-related kidney fibrosis in mice. Muscle fiber cross-sectional area increased by 11.3%, making muscles thicker. Age-thinned skin basal layers thickened. Fat accumulation in the liver, lungs, and pancreas decreased, and age-related kidney atrophy was alleviated. Even microglial activation (a marker of neuroinflammation) in the brain weakened, with improved cognition.
Betaine reduced age-related kidney fibrosis in mice. Muscle fiber cross-sectional area increased by 11.3%, making muscles thicker. Age-thinned skin basal layers thickened. Fat accumulation in the liver, lungs, and pancreas decreased, and age-related kidney atrophy was alleviated. Even microglial activation (a marker of neuroinflammation) in the brain weakened, with improved cognition.
Figure note: Betaine supplementation leads to thicker muscle fibers, "rejuvenated" skin, reduced visceral fat, alleviated kidney atrophy, and suppressed neuroinflammation in the brain of elderly mice.
Targeting the Root of Aging
Mechanistically, betaine inhibited the activity of TBK1, a key pro-aging and pro-inflammatory protein. In the kidneys of elderly mice, TBK1 activity and downstream "inflammatory molecules" (p-IRF3, p-p65) were suppressed after betaine supplementation.
Figure note: Betaine significantly inhibits TBK1 and its downstream p-IRF3 and p-p65 activity in the kidneys of elderly mice.
Furthermore, betaine enhanced genomic stability (another aging hallmark) by reducing DNA damage marker γ-H2AX levels and increasing "genome-stabilizing" molecules 5-mC and H3K9me3. It also exerted antioxidant effects and reduced pro-aging factors secreted by senescent cells.
Figure note: Betaine decreases γ-H2A.X levels and increases H3K9me3 and 5-mC levels in elderly mice.
Having proven betaine’s "exercise-mimicking" effects, how does it compare to other exercise mimetics? What makes it stand out?
03 The "Little Beet" That Mimics Exercise!
Current exercise mimetics mainly target pathways like AMPK (improving energy metabolism efficiency, e.g., AICAR, metformin), PPAR-δ (metabolism, anti-inflammation, cardiovascular health, e.g., GW501516), PGC-1α/SIRT1 (mitochondrial function, e.g., resveratrol), or BDNF (cognitive improvement).
However, these mimetics share a flaw – excessive "specificity." Renowned exercise physiologist John A. Hawley noted that all previous exercise mimetic studies suffer from "muscle-centrism," targeting only a few pathways in skeletal muscle and failing to replicate exercise’s complex, systemic regulation of multiple organs and systems[4].
Figure note: Real exercise broadly impacts multiple organs (brain, heart, liver, bones, fat, etc.); existing mimetics mostly target only a few pathways in skeletal muscle.
Additionally, safety risks exist: AICAR may cause hypoglycemia and nephrotoxicity, while GW501516 even has carcinogenic potential.
In contrast, betaine is no "one-trick pony." It more closely mimics the systemic benefits of real exercise than single-target drugs[5]. Starting at the molecular level (inhibiting TBK1, stabilizing the genome), it reduces senescence and inflammation at the cellular level, then repairs structures and optimizes functions at the tissue/organ level.
Moreover, as a naturally occurring substance in the body, betaine is far safer than chemical drugs. It exists in natural foods[6], is safe at low doses, and has no genotoxicity – offering superior safety.
However, betaine is not perfect. As a key molecule in exercise, it targets certain anti-aging pathways but may still lag behind the comprehensive effects of real, long-term exercise in some indicators. Its efficacy and onset speed may be weaker than specially designed drugs, and optimal dosing, long-term effects, and population-specific responses require further research.
Overall, betaine remains an excellent "candidate." So, how to supplement it?
In daily diets, betaine can be increased through whole grains (highest in germ and bran), goji berries, amaranth, quinoa, seafood, spinach, and beetroot.
Supplements are also an efficient option, but note two forms: anhydrous betaine and betaine hydrochloride. Studies show anhydrous betaine better mimics exercise effects, while betaine hydrochloride lacks sufficient evidence and may irritate the stomach[5].
Clinically, effective doses of anhydrous betaine supplements range from 2–5 g/day. However, high-dose supplements are not for everyone – individuals with dyslipidemia, obesity, prediabetes, or diabetes should avoid upplementation, as high doses may affect cholesterol levels. Consult a doctor first [5]!
With such an excellent substance, can we "lie flat" to lose weight, extend lifespan, and bid farewell to exercise?
Answer: Of course not! No single compound can replicate exercise’s multi-system, multi-dimensional effects – the term "exercise mimetic" may even be an overstatement.
In fact, the goal of finding "exercise mimetics" is not to let healthy people "slack off" but to help those unable to exercise, such as the elderly, disabled, joint disease patients, or bedridden individuals with muscle atrophy. For them, a safe exercise mimetic is a "lifeline" to improve health and quality of life. For most of us, the best "anti-aging drug" remains – moving our legs and exercising!
[This article, titled Systematic profiling reveals betaine as an exercise mimetic for geroprotection, is published in Cell. Corresponding authors include Guang-Hui Liu (Institute of Zoology, Chinese Academy of Sciences), Weiqi Zhang (Beijing Institute of Genomics, Chinese Academy of Sciences), Jing Qu (Institute of Zoology, Chinese Academy of Sciences), Moshi Song (Institute of Zoology, Chinese Academy of Sciences), and Si Wang (Xuanwu Hospital, Capital Medical University). First authors are Lingling Geng, Jiale Ping, and Ruochen Wu. Funding sources: National Natural Science Foundation of China, National Key R&D Program on Non-Communicable Chronic Diseases, National Key R&D Program, and STI2030 Major Program.]
References
[1] Geng, L., Ping, J., Wu, R., Yan, H., Zhang, H., Zhuang, Y., . . . Liu, G.-H. Systematic profiling reveals betaine as an exercise mimetic for geroprotection. Cell. doi:10.1016/j.cell.2025.06.001
[2] Gubert, C., & Hannan, A. J. (2021). Exercise mimetics: harnessing the therapeutic effects of physical activity. Nature Reviews Drug Discovery, 20(11), 862-879. doi:10.1038/s41573-021-00217-1
[3] Fan, W., & Evans, R. M. (2017). Exercise Mimetics: Impact on Health and Performance. Cell Metabolism, 25(2), 242-247. doi:10.1016/j.cmet.2016.10.022
[4] Hawley, J. A., Joyner, M. J., & Green, D. J. (2021). Mimicking exercise: what matters most and where to next? The Journal of Physiology, 599(3), 791-802. doi:https://doi.org/10.1113/JP278761
[5] Zawieja, E., & Chmurzynska, A. (2025). Betaine and aging: A narrative review of findings, possible mechanisms, research perspectives, and practical recommendations. Ageing Research Reviews, 104, 102634. doi:https://doi.org/10.1016/j.arr.2024.102634
[6] Yang, Z.-J., Huang, S.-Y., Cheng, J., Zeng, J.-W., Wusiman, M., Li, H.-B., & Zhu, H.-L. (2025). Betaine: A comprehensive review on dietary sources, health benefits, mechanisms of action, and application. Trends in Food Science & Technology, 159, 104993. doi:https://doi.org/10.1016/j.tifs.2025.104993
[1] Geng, L., Ping, J., Wu, R., Yan, H., Zhang, H., Zhuang, Y., . . . Liu, G.-H. Systematic profiling reveals betaine as an exercise mimetic for geroprotection. Cell. doi:10.1016/j.cell.2025.06.001
[2] Gubert, C., & Hannan, A. J. (2021). Exercise mimetics: harnessing the therapeutic effects of physical activity. Nature Reviews Drug Discovery, 20(11), 862-879. doi:10.1038/s41573-021-00217-1
[3] Fan, W., & Evans, R. M. (2017). Exercise Mimetics: Impact on Health and Performance. Cell Metabolism, 25(2), 242-247. doi:10.1016/j.cmet.2016.10.022
[4] Hawley, J. A., Joyner, M. J., & Green, D. J. (2021). Mimicking exercise: what matters most and where to next? The Journal of Physiology, 599(3), 791-802. doi:https://doi.org/10.1113/JP278761
[5] Zawieja, E., & Chmurzynska, A. (2025). Betaine and aging: A narrative review of findings, possible mechanisms, research perspectives, and practical recommendations. Ageing Research Reviews, 104, 102634. doi:https://doi.org/10.1016/j.arr.2024.102634
[6] Yang, Z.-J., Huang, S.-Y., Cheng, J., Zeng, J.-W., Wusiman, M., Li, H.-B., & Zhu, H.-L. (2025). Betaine: A comprehensive review on dietary sources, health benefits, mechanisms of action, and application. Trends in Food Science & Technology, 159, 104993. doi:https://doi.org/10.1016/j.tifs.2025.104993