When it comes to reasons to exercise, there’s one universal truth: exercise not only strengthens the body but also acts as a cost-free anti-aging and lifespan-extending remedy. Yet excuses for skipping exercise are endless – busy work, countless chores, or simply one word: laziness.
However, a long-cherished dream of scientists and "laziness sufferers" has finally come true: Is there a way to take an "exercise pill" (Exercise Mimetics) that lets the body mimic all the benefits of physical activity on its own?
Recently, a rigorous human study led by Liu Guanghui’s team from the Chinese Academy of Sciences identified a natural substance hidden in everyday foods – Betaine – that not only perfectly replicates the anti-inflammatory and anti-aging effects of long-term exercise but also showed "rejuvenation" potential in aged mice[1]!
Part 1: Identifying the "Exercise Molecule"
An "exercise mimetic" is a compound or intervention that simulates the benefits of exercise (e.g., enhanced endurance, improved metabolism, reduced inflammation, delayed aging) by activating exercise-related pathways or metabolic processes[2].
While the concept may sound new, scientists have been researching exercise mimetics for over 20 years. Early efforts focused on a straightforward approach: identifying key proteins that regulate exercise effects (e.g., AMPK, PPAR-δ) and developing drugs to activate them. This led to first-generation "potent but risky drugs" like AICAR and GW501516[3], which showed impressive effects but raised serious safety concerns.
After these setbacks, scientists shifted to finding gentler, systemic ways to mimic exercise. However, substances like metformin (a repurposed old drug) and resveratrol (a nature-derived compound) act more as pathway modulators with effects similar to exercise, rather than true exercise mimetics.
So, how can we find the "most authentic" exercise mimetic? The answer lies in exercise itself: physical activity triggers molecular changes in the body. Identifying these key molecules would unlock the most natural and safe exercise mimetics.
To find this "exercise molecule," the research team conducted a human experiment. They recruited healthy young men and monitored changes in over 16,000 molecules in their blood under three conditions: rest, a single bout of running (acute exercise), and long-term running (chronic exercise).
Results showed that acute exercise acts like a "stress test" for the body, while chronic exercise drives gradual adaptation and "optimization," delivering true anti-inflammatory and anti-aging benefits.
Figure Notes: Chronic exercise improves multiple health indicators (e.g., reduced resting heart rate, lower levels of inflammatory factors hsCRP and TNF-α), while acute exercise mainly causes temporary stress-related changes in bodily indicators.
Among the numerous molecular changes induced by chronic exercise, one substance stood out: Betaine. Its levels showed the most stable and significant increase after long-term exercise. Crucially, betaine is not an exogenous substance – even without dietary intake, the kidneys actively synthesize and release betaine into the bloodstream in response to long-term exercise.
Figure Notes: After chronic exercise, plasma betaine levels increase significantly, and the expression of betaine synthesis-related genes and the key enzyme CHDH in the kidneys is upregulated.
In other words, betaine is not just a nutrient from food – it is an endogenous protective substance that the body actively produces to connect exercise and health!
Part 2: Naturally Mimics Exercise – Can It Also Fight Aging?
To verify the efficacy of this "exercise molecule" identified in humans, researchers fed betaine to aged mice. After 12 weeks, striking results emerged:
1. Behavioral Rejuvenation
As an exercise mimetic, betaine first showed effects in physical performance:
- Grip strength, balance, and time spent maintaining movement on a rotarod (endurance test) all improved.
Figure Notes: After betaine supplementation, aged mice showed enhanced endurance, grip strength, balance, and cognitive function (Y-maze test).
2. "Renewal" of Multiple Organs
Overall, betaine supplementation significantly reduced the area of cells with high expression of SA-β-Gal (a senescence marker) in multiple tissues of aged mice, including the skin, liver, muscle, and kidneys. In the liver and kidneys, the number of cells with high expression of p53 and p21 (proteins that drive cellular senescence) also decreased significantly.
Additionally, betaine reduced the infiltration of senescence-induced immune cells (e.g., CD45+, CD68+, IBA1+ cells) in the brain, kidneys, and liver of aged mice, effectively "cooling down" systemic chronic inflammatory aging.
Figure Notes: After betaine supplementation in aged mice, levels of SA-β-Gal, p21, and p53 (senescence markers) decreased significantly in multiple tissues, and immune cell infiltration (a marker of inflammation) was also reduced.
Closer examination of individual organs revealed more specific improvements:
- Kidney fibrosis caused by aging was reduced.
- Muscle fiber cross-sectional area increased by 11.3%, making muscles stronger.
- The thinning skin basal layer (a sign of aging) thickened.
- Fat accumulation in the liver, lungs, and pancreas decreased.
- Age-related kidney atrophy was alleviated.
- Activation of microglia (a marker of neuroinflammation) in the brain was reduced, and cognitive function improved.
Figure Notes: Betaine supplementation increased muscle fiber size, "rejuvenated" the skin, reduced visceral fat, alleviated kidney atrophy, and inhibited neuroinflammation in the brain of aged mice.
3. Targeting the Root of Aging
Mechanistically, researchers found that betaine inhibits the activity of TBK1 – a key pro-senescence and pro-inflammatory protein. In the kidneys of aged mice, the activity of TBK1 and its downstream "inflammatory molecules" (p-IRF3, p-p65) was suppressed after betaine supplementation.
Figure Notes: In the kidneys of aged mice, betaine significantly inhibited the activity of TBK1 and its downstream proteins p-IRF3 and p-p65.
Furthermore, betaine enhanced genomic stability (another hallmark of aging) by:
- Reducing levels of γ-H2AX (a marker of DNA damage).
- Increasing levels of 5-mC and H3K9me3 (molecules that "stabilize" the genome).
- Fighting oxidative stress and reducing pro-senescence factors secreted by senescent cells.
Figure Notes: Betaine reduced γ-H2AX levels (indicating less DNA damage) and increased H3K9me3 and 5-mC levels (indicating enhanced genomic stability) in aged mice.
Part 3: Betaine – The "Little Exercise Mimetic" with Big Advantages
Current exercise mimetics mainly target pathways like:
- AMPK (to improve energy metabolism efficiency, e.g., AICAR, metformin),
- PPAR-δ (for metabolism, anti-inflammation, and cardiovascular health, e.g., GW501516),
- PGC-1α/SIRT1 (to improve mitochondrial function, e.g., resveratrol),
- BDNF (to mimic exercise-induced cognitive improvements).
However, these mimetics share critical flaws:
- Overly "specialized": As noted by renowned exercise physiologist John A. Hawley, most previous exercise mimetic studies suffer from "muscle-centrism"[4] – they only target a few pathways in skeletal muscle and fail to fully simulate exercise’s complex regulatory effects on multiple organs and systems.
Figure Notes: Real exercise exerts broad effects on multiple organs (brain, heart, liver, bones, fat, etc.); in contrast, existing exercise mimetics mostly target only a few pathways in skeletal muscle.
- High side effect risks: For example, AICAR may cause hypoglycemia and nephrotoxicity, while GW501516 even carries a cancer risk.
Betaine, by contrast, avoids these pitfalls:
-
Systemic benefits: Unlike single-target drugs, betaine mimics the systemic benefits of real exercise. It acts at the molecular level (inhibiting TBK1, stabilizing the genome), reduces senescence and inflammation at the cellular level, and repairs tissue structure and optimizes function at the organ level[5].
-
Superior safety: As an endogenously produced substance, betaine is far safer than chemical drugs. It is naturally present in foods[6], and moderate supplementation (e.g., 6mg/kg body weight per day) is considered safe with no genotoxicity.
Limitations of Betaine
Betaine is not perfect:
- While it targets key anti-aging pathways, its improvement in some indicators may still be less pronounced than the comprehensive effects of long-term, real exercise.
- Its efficacy and onset speed may be weaker than specially designed drugs.
- More research is needed to determine its optimal dosage, long-term effects, and impact on different populations.
Part 4: How to Supplement Betaine?
1. Dietary Sources
Increase intake of betaine-rich foods, such as:
- Whole-grain products (highest in germ and bran),
- Goji berries, amaranth, quinoa,
- Seafood, spinach, and beetroot.
2. Supplements
Supplements offer a more efficient way to boost betaine intake, but note the two main forms:
- Anhydrous betaine: Research shows it better exerts exercise-mimicking effects.
- Betaine hydrochloride: Lacks sufficient evidence for exercise-mimicking benefits and may irritate the stomach[5].
In clinical settings, the effective dose of anhydrous betaine supplements is 2–5g per day. However, high-dose supplements are not suitable for everyone: people with dyslipidemia, obesity, prediabetes, or diabetes are advised not to take them without medical consultation, as high doses may affect cholesterol levels[5].
Key Reminder: Betaine Is Not a Substitute for Exercise
Can we rely on betaine to "stay idle, lose weight, and extend lifespan" while ditching exercise entirely? The answer is no. No single compound can replicate the complex, multi-system, multi-dimensional effects of exercise – the term "exercise mimetic" itself may be somewhat exaggerated.
The true purpose of developing "exercise mimetics" is not to let healthy people "cut corners," but to help those unable to exercise – such as the elderly, individuals with disabilities or joint diseases, and patients with muscle atrophy from long-term bed rest. For these groups, a safe exercise mimetic is a "lifeline" to improve quality of life and health. For most healthy people, the best "anti-aging remedy" remains simple: "get up and move."
Study Information
- Title: Systematic profiling reveals betaine as an exercise mimetic for geroprotection
- Journal: Cell
- Corresponding Authors: Guanghui 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), Si Wang (Xuanwu Hospital, Capital Medical University)
- First Authors: Lingling Geng, Jiale Ping, Ruochen Wu
-
Funding Sources:
- National Natural Science Foundation of China (82125011, 82488301, 82361148131, 82422031, 82322025, 82371570)
- National Key R&D Program for Non-Communicable Chronic Diseases (2024ZD0530400)
- National Key R&D Program (2020YFA0804000, 2022YFA1103700)
- STI2030 Major Program (2021ZD0202400, 2021YFA1101401, 2022YFA1103800, 2023YFC3605400, 2022YFC3602503, 2022YFA1104701, 2023YFC3504301)
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