Epigenetic aging during adjuvant chemotherapy for colon cancer and modification by a resistance training intervention.

Abstract

Cancer survivors experience excess morbidity and functional decline compared with age-matched individuals without cancer, potentially reflecting acceleration of biological aging during cancer treatment. Epigenetic clocks derived from DNA methylation (DNAm) quantify biological aging, but whether changes in these measures during chemotherapy are modifiable remains unclear. We evaluated longitudinal changes in epigenetic age acceleration among adults with stage II-III colon cancer undergoing adjuvant chemotherapy in the FORCE randomized trial. Participants were assigned to usual care or resistance training during chemotherapy. Blood DNAm was assessed at baseline and follow-up to derive multiple clocks, including DNAmPhenoAge, GrimAge, and DunedinPACE acceleration measures. Body composition and physical function were measured longitudinally. Linear mixed-effects models estimated changes in epigenetic age acceleration and intervention effects. DunedinPACE acceleration showed the largest increase during treatment (0.70 SD per 6 months, 95% CI: 0.41, 0.98), followed by GrimAge acceleration (0.29 SD per 6 months, 95% CI: 0.13, 0.46; approximately 1.2 years). At baseline, higher DunedinPACE acceleration was associated with greater adiposity and poorer physical function. Resistance training attenuated increases in GrimAge acceleration: usual care participants showed significant acceleration (0.45 SD per 6 months, 95% CI: 0.24, 0.60), whereas intervention participants did not. Changes in epigenetic age acceleration were not strongly associated with body composition or physical function changes. Epigenetic age acceleration increased during colon cancer treatment, with resistance training attenuating GrimAge acceleration. These intervention-responsive changes suggest DNAm-based aging measures may capture treatment-period physiologic changes not fully reflected by body composition or physical function.