Epigenetic Age Acceleration Mediates Treatment Effects on Cardiometabolic and Cardiovascular Risk in Childhood Cancer Survivors

Childhood cancer survivors are at increased risk for epigenetic age acceleration (EAA) and subsequent morbidities-including cardiometabolic risk factors (CMRFs) and cardiovascular diseases-due to prior genotoxic treatments. To evaluate the mediating role of EAA in the relationship between cancer treatment exposures and risk of CMRFs and cardiovascular diseases. This study included 2939 five-year survivors from the St. Jude Lifetime Cohort who underwent DNA methylation profiling using peripheral blood mononuclear cells. EAA was calculated using three established epigenetic clocks: DunedinPACE, PCPhenoAge, and GrimAge2. Treatment data-including body region-specific radiotherapy (RT) and chemotherapeutic agents such as anthracyclines and corticosteroids-were abstracted from medical records. Outcomes included three CMRFs (abnormal glucose metabolism, hypertension, and obesity) and two cardiovascular diseases (cardiomyopathy and myocardial infarction). Mediation analysis was conducted to quantify the extent to which EAA mediated the association between each treatment exposure and each clinical outcome. EAA partially mediated the association between abdomen RT and abnormal glucose metabolism (DunedinPACE: 35.4%; GrimAge2: 16.2%), between abdomen RT (DunedinPACE: 25.9%) or anthracyclines (DunedinPACE: 12.5%) and hypertension, and between corticosteroids and obesity (DunedinPACE: 8.6%). EAA also mediated the association between heart RT and cardiomyopathy (PCPhenoAge: 30.3%; DunedinPACE: 19.9%; GrimAge2: 14.4%) and myocardial infarction (PCPhenoAge: 24.1%; DunedinPACE: 15.5%; GrimAge2: 13.2%), as well as anthracyclines and cardiomyopathy (GrimAge2: 6.0%; PCPhenoAge: 5.2%; DunedinPACE: 3.9%). EAA accounted for a substantial proportion of the association between cancer treatment exposures and risk of CMRFs and cardiovascular diseases. These findings provide insight into biological aging as a potential mechanistic pathway and support the development of interventions targeting accelerated aging to mitigate long-term treatment-related toxicities, and reduce premature mortality in this high-risk population.