WHO-Recommended Exercise Dose Is Associated With Slower Epigenetic Aging in Older Adults

The dose-response of six months of controlled exercise was studied in 72 subjects aged 50 to 70 years, with 1-4 training sessions per week, focusing on DNA methylation-based aging. Epigenetic age reduction increased with exercise dose, with about 255 MET-hours aligning with a one-year decrease in Robust PhenoAge acceleration - a volume consistent with WHO physical activity guidelines. The finding that relative ventricular posterior wall thickness and muscular quotient change in tandem with Robust PhenoAge acceleration suggests that epigenetic clocks reflect genuine organ-level rejuvenation. The DNA methylation-based protein prediction identified TGF-α, TIMP1, and adrenomedullin as showing a dose-response relationship with exercise volume. The exercise intervention yielded systemic health benefits, improved some cardiac parameters measured by echocardiogram, increased HDL levels, lowered blood pressure, reduced android fat mass, and notably, enhanced physiological functions, including cognitive performance. The program increased the relative abundance of microbes supporting intestinal barrier integrity and decreased pro-inflammatory bacterial populations. Serum N-lactoyl-phenylalanine levels showed a downward trend after six months of exercise, while trimethylamine N-oxide levels rose in male participants. This single-arm exercise study identified a dose–response relationship between cumulative exercise dose and Robust PhenoAge or GrimAge acceleration, strengthening the evidence that the observed associations are attributable to exercise exposure rather than background factors or confounders. The results further support the idea that regular physical activity can influence biological age by improving cardiac structure and function, and indicate that PhenoAge and GrimAge effectively reflect age-related cardiac changes.