Immune cell-associated DNA methylation responses to exercise in women: A bioinformatics analysis comparing pre- and...

Menopause is associated with immunosenescence and altered immune profiles, potentially reducing immune competence. Physical exercise may counteract these changes by modulating DNA methylation in fitness-related genes.

This observational bioinformatics study analyzed genome-wide DNA methylation profiles derived from whole blood using two publicly available datasets from Brazilian cohorts (Illumina MethylationEPIC 850K). The analysis included pre- (PreM, n = 13; 34 ± 4.7 years) and postmenopausal (PostM, n = 49; 59.8 ± 4.7 years) women who completed supervised combined exercise training. Four linear models were applied to examine associations between DNA methylation, cardiorespiratory fitness (VO₂ peak), and exercise intervention (pre- vs. post-training), while adjusting for age, fat percentage, and estimated immune-cell proportions (EpiDISH). Interaction terms were tested to assess whether immune cell composition or menopausal status modulated the relationship between VO₂ peak, exercise response, and DNA methylation.

After adjusting for baseline values using analysis of covariance (ANCOVA), no statistically significant between-group differences were observed in the estimated immune cell proportions (FDR > 0.05). In PostM, exercise-induced DNA methylation changes were significantly associated with baseline VO₂ peak and were modulated by B cells, CD4⁺ T cells, NK cells, and monocytes. Functional enrichment highlighted pathways involved in lipid kinase regulation, nucleobase metabolism, and membrane organization.

Postmenopausal women showed distinct epigenetic patterns in response to exercise, although these differences must be interpreted cautiously given the small premenopausal sample size. These results suggest potential immune cell-associated DNA methylation markers to inform personalized exercise strategies supporting healthy aging in women.