Exercise slows biological aging in breast cancer survivors: secondary analysis of a randomized trial.

BACKGROUND: Cancer and its treatments are associated with accelerated biological aging and cognitive impairment among breast cancer survivors. DNA methylation-based epigenetic clocks provide measures of biological aging that predict morbidity and mortality, yet little is known about whether these aging trajectories can be modified by lifestyle intervention. This secondary analysis of a subset of participants in a randomized controlled trial examined the impact of a 12-month exercise intervention on markers of epigenetic aging among breast cancer survivors. METHODS: Sedentary breast cancer survivors within 5 years of diagnosis were randomized to a remotely delivered exercise intervention or a contact-matched health & wellness condition. Whole blood samples and cognitive assessments were obtained at baseline, 6, and 12 months. Epigenetic ages and differential methylation were calculated from normalized data obtained from the Methylation Screening Array. RESULTS: A subsample of 124 participants with complete data was analyzed. The Exercise arm showed slower epigenetic aging than the Health & Wellness arm over the 12-month study, according to GrimAge2 (P = .02) and DNAmFitAge (P = .002) clocks. Changes in epigenetic aging were significantly correlated with alterations in attention and self-reported cognition, with faster epigenetic aging associated with greater cognitive decline. Furthermore, genome-wide analysis of the blood epigenome identified differentially methylated sites, some mapping to genes enriched for BDNF (brain-derived neurotrophic factor) signaling pathways. CONCLUSION: A 12-month exercise intervention was associated with slower epigenetic aging among breast cancer survivors. These findings suggest that biological aging may represent a modifiable mechanism through which exercise supports cognitive health in cancer survivorship. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04049695.