Exercise as a “rejuvenator”: how physical activity affects the epigenetic clock

A promising review article was published in the journal Aging (Albany NY): regular exercise and high levels of physical fitness (aerobic and strength) are associated with a slowdown or even a reversal of the so-called epigenetic age, a biomarker calculated using DNA methylation marks. Moreover, the effect is most noticeable in the blood and skeletal muscle, and in intervention studies, training actually shifted the epigenetic clock back in some participants. But the response is highly individual and depends on the organ - so the next step should be personalized protocols and uniform measurement standards.

Background

• What is an "epigenetic clock"? These are mathematical models that estimate the biological age of tissues and the body based on DNA methylation patterns (CpG sites). The most famous are: the "universal" Horvath/Hannum clock, the "health-dependent" PhenoAge and GrimAge (more strongly associated with the risk of disease and mortality), and tissue-specific clocks (for example, "muscle"). The difference between "epigenetic" and calendar age is called epigenetic acceleration: plus - "older than normal", minus - "younger".
• Why exercise can affect them at all. Exercise alters inflammation (↓CRP/IL-6), mitochondrial biogenesis (via PGC-1α), oxidative stress (↑Nrf2), metabolism (AMPK, insulin/IGF-1), and myokines (e.g., irisin). All of these pathways are linked to epigenetic regulatory enzymes (DNA methyltransferases, SIRT1-type deacetylases), so exercise can “rewire” methylation in genes involved in stress resistance, metabolism, and inflammation.
• Observational data (before interventions): Active people and those with higher physical fitness (VO₂max, strength) often show lower epigenetic acceleration, especially in blood and skeletal muscle. However, “passive sedentary behavior” is associated with clock acceleration even in the presence of “training” minutes — the overall structure of the day is important, not just the training.
• Intervention signals: Aerobic and resistance training programs (usually ≥8–12 weeks) showed a “younger” shift in the epigenetic clock in some participants, more pronounced in blood and muscle. People with initially “faster” clocks often responded more strongly; the effect varied by clock type (e.g. PhenoAge/GrimAge responded differently than Horvath).
• Organ specificity - why the results do not always match. The clock is trained on different tissues and outcomes; muscle, fat and liver can be "rejuvenated" differently. That is why in some studies the epigenetic age of the blood changes, and in others - the muscle profile, and this is not a contradiction, but a reflection of local biology.
• Dose and type of activity. The most evidence supports regular moderate-to-vigorous aerobic activity (brisk walking/running/cycling, intervals) combined with strength training 2-3 times per week. Too much volume without recovery may not provide additional epigenetic benefit (possible U-shaped effect).
• Individual differences. Age, gender, genetics, medications, diet, and even the time of day of training influence response. There are “responders” and “non-responders”; personalization by baseline form and comorbidities is important.
• Methodological pitfalls. The literature contains a zoo of clocks, protocols, and activity recording methods (questionnaires vs. accelerometers), as well as batch effects between laboratories and differences in the processing of methylomic data. This makes comparisons between studies difficult and supports calls for standardization.
• We approach causality gradually. Associations appear stable, but direct causality needs to be confirmed: randomized programs, Mendelian randomization, and new “causal clocks” (sets of CpGs more closely associated with disease risk) help. It is important to look at whether the CpGs that affect clinical outcomes change.
• A practical minimum that is no longer controversial.
  • Reduce sedentary time by adding short bursts of movement into your daily routine.
  • 150–300 min/week of aerobic activity (can be done in intervals) + strength training 2–3×/week for large muscle groups.
  • Sleep, a diet rich in protein and polyphenols, and stress management are all “moderator” factors of the epigenetic response to exercise.
• Where to go next for researchers. Large RCTs with uniform protocols, multi-tissue measurements, comparison of different clocks, analysis of “responders” and targeting of pathways (SIRT1/AMPK/PGC-1α). Plus - combined interventions (training + nutrition/sleep) and testing of long-term clinical outcomes, not just “age by the clock”.

What exactly is the work about?

The authors (Tohoku, Waseda, Budapest/Pecs) carefully differentiated the terms:

• Physical activity is any movement that expends energy (walking, cleaning).
• Exercise is a planned, structured activity for the sake of results (running, strength training, swimming).
• Fitness is the outcome for the body (VO₂max, strength, etc.).

This distinction is important: many reviews lump everything together, and in aging studies the effects of these three "entities" are different.

What the data already shows

• Observational studies often find: more activity in free time and less "sedentary" → slower epigenetic aging. At the same time, "heavy physical labor" at work can provide feedback, so it is important to distinguish between contexts.
• Exercise interventions (8 weeks or longer) in human and animal studies have shown epigenetic “rejuvenation,” primarily in blood and skeletal muscle. Some participants with initially “speeded up” clocks had the most pronounced reversals.
• Fitness as a marker. Higher VO₂max, higher ventilation threshold, strength, and other metrics are associated with lower epigenetic acceleration; elite athletes and people with high endurance often have lower epigenetic age than their passport age.
• Not just muscle. In rat models, the “high-fitness” strains also had younger epigenetic profiles in adipose tissue, myocardium, and liver, suggesting that the benefits of exercise are systemic.

Why is this important?

The epigenetic clock is one of the most sensitive biomarkers of biological age: it predicts disease risk and mortality better than the calendar. If training can slow down/reverse this clock, then it is no longer just about “endurance and waistline,” but about the potential extension of the period of healthy life.

Nuances and limitations

• The heterogeneity is enormous. The effect depends on the organ, the type of training, the dosage and the individual predisposition; the average figures hide the "responders" and "non-responders".
• Methodological zoo. Different studies use different watches (Horvath, GrimAge, PhenoAge, “muscle” watches, etc.), different training protocols, and different methods of recording activity (questionnaires vs. accelerometers), which prevents direct comparison. Uniform standards are needed.
• Causality still needs to be tweaked. The review introduces the idea of “causal clocks” (DamAge/AdaptAge) — sets of CpG sites, changes in which are likely to be causal for health. Checking whether exercises “touch” them will help move from associations to mechanism.

Practical conclusion already today

• Movement is a priority. Regular moderate and interval aerobic exercise + strength training 2-3 times a week is the basic recipe, which simultaneously “lectures” your epigenetic clock.
• Sedentary behavior is the enemy. Reducing long periods of sedentary time is itself associated with less accelerated epigenetic aging.
• Accuracy is important. If you want to measure the effect, choose labs/projects that use the same hours and consistent training protocols - otherwise there will be nothing to compare. (The authors explicitly call for standardization of design in future studies.)

What do the authors suggest next?

1. Standardize methods: activity/form assessment, training regimens, and epigenetic clock selection.
2. Conduct research on different groups (age, gender, ethnicity), and also take into account personal responses - whose clocks "roll back" more and why.
3. To understand the mechanisms: which cellular pathways and CpG sites change during training and in which organs.

Source: Kawamura T., Higuchi M., Radak Z., Taki Y. Exercise as a geroprotector: on focusing epigenetic aging. Aging (Albany NY), July 8, 2025. https://doi.org/10.18632/aging.206278