Exercise and physical fitness has been shown to reduce the predicted biological age generated by various epigenetic clocks. Researchers here provide evidence for some of this effect to be mediated by a reduction in inflammatory signaling, also well known as an outcome of exercise and physical fitness. Chronic inflammation is harmful to tissue structure and function, and is also a feature of aging and age-related disease. To the degree that long-term inflammatory signaling unrelated to injury and infection can be minimized, the results should be improved health and modestly slowed aging.
Physical activity (PA) is recognized as a cornerstone of healthy aging, yet the molecular mechanisms linking PA to biological aging remain poorly understood. DNA methylation (DNAm)-based biological aging indicators, such as PhenoAge, provide a means to assess the relationship between PA and aging at the molecular level.β2-microglobulin (β2M) is elevated in states of chronic inflammation and is implicated in immune senescence. Elevated levels are detected in the plasma and cerebrospinal fluid of aged mice and older adults. This study analyzed data from 936 participants in the U.S. population, assessing associations between PA, β2M levels, and PhenoAge.
Our study showed that increased PA was significantly associated with lower β2M levels, and mediation analysis revealed that reductions in β2M explained 37.67% of the association between PA and PhenoAge. These results align with findings that PA mitigates inflammation by reducing pro-inflammatory cytokines and improving immune function. Importantly, the direct effect of PA on PhenoAge remained significant even after accounting for β2M, suggesting additional pathways through which PA exerts anti-aging effects, such as epigenetic regulation or mitochondrial function.
Link: https://doi.org/10.1016/j.jare.2025.11.047
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