Late-life exercise may partly reset epigenetic aging in skeletal muscle. Digest
Age-related decline in muscle strength and function is accompanied by changes in how genes are controlled (epigenetic changes), yet it is unclear whether starting exercise late in life can meaningfully shift this trajectory. In a controlled mouse study, researchers tested whether a demanding training program could make old skeletal muscle look epigenetically younger.
The experiment included young and aged mice. Older animals either remained sedentary or completed eight weeks of voluntary progressive weighted-wheel running, a protocol that combines endurance and resistance-like loading. Researchers then examined DNA methylation, a chemical tag that helps regulate gene activity, in skeletal muscle. They examined nuclear DNA, which holds most genetic instructions, ribosomal DNA, which supplies the code used to build ribosomes for protein production, mitochondrial DNA, which supports the cell's energy system, and epigenetic age scores that estimate biological age based on methylation patterns.
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The experiment revealed extensive age-related epigenetic shifts in mouse muscle and showed that late-life exercise reversed specific aspects of this pattern:
- Aging was linked to widespread changes in nuclear DNA methylation. Some gene control regions that changed with age no longer differed between young and old mice after the exercise intervention.
- Ribosomal DNA showed altered methylation in old sedentary mice compared to young mice. In the exercised old group, some of these age-related shifts moved back toward the young pattern.
- Within the limited set of mitochondrial DNA, no clear methylation differences were detected between groups.
- Aging also made the overall pattern of DNA methylation more irregular, and this broad aging effect did not change with exercise.
- A nuclear-DNA-based epigenetic clock known as DNAge, a model that translates methylation patterns into an estimate of biological age, indicated that exercised old muscle was about 10 percent younger than sedentary old muscle. However, this result needs to be interpreted with caution, because there was only a clear difference after excluding one sedentary mouse with an unusually young methylation profile from the analysis, and a second aging test based on ribosomal DNA showed the same trend but the result was even less certain.
These findings show that epigenetic aging in muscle is not a single process that can be reversed or slowed in a uniform way. Some DNA control marks still responded to exercise in old age, while others remained unchanged. This suggests that exercise can rejuvenate certain aspects of epigenetic muscle age. However, many age-related changes did not shift with this eight-week training program and may be harder to influence at this stage of life or might require a longer or different type of intervention.
This study offers early molecular evidence that skeletal muscle retains some epigenetic plasticity even at advanced ages. Future work will need to test whether earlier or longer-term exercise, possibly in combination with other lifestyle strategies, can influence more stable layers of the aging epigenome and translate into meaningful gains in muscle function or resilience. In episode #62, Dr. Steve Horvath discusses epigenetic aging clocks and their use in predicting biological aging and healthspan.