ABSTRACT Survivors of childhood cancer are at increased risk for chronic health conditions (CHCs) and early mortality at rates typically among individuals decades older, suggesting an accelerated aging phenotype. However, there are limited studies applying molecular biomarkers to quantify the acceleration of aging in long-term survivors of childhood cancer. Here, we propose to apply epigenetic age to measure biological aging and investigate the trajectories of epigenetic aging, risk factors and health outcomes in this population. Our proposal is built upon our previous studies reporting that that epigenetic age acceleration (EAA) is significantly higher in survivors of childhood cancer than individuals without a history of cancer, and is associated with treatment exposures, unfavorable health behaviors, and presence of CHCs. To further our research, we will take advantage of the rich resources of the St. Jude Lifetime Cohort Study (SJLIFE), which includes 4,263 5+ year survivors of childhood cancer who have been characterized with genome-wide epigenetic profiling (MethylationEPIC BeadChip) using peripheral blood mononuclear cells (PBMCs) collected at one time point (T1), and are well documented for cancer treatment exposures, health behaviors, social determinants of health (SDOH) as well as comprehensive clinical assessments of CHCs. We will also measure EAA for a set of 1,804 survivors with PBMCs collected at a second time point (T2) and 1,000 survivors for a third time point (T3), with an interval of approximately 5-years between adjacent time points. In addition, we will leverage two ongoing NIH-funded intervention trials: Telehealth-based intervention to improve fitness [CA246570], and eHealth intervention for late effects of childhood cancer [CA239689], where biospecimens will be collected before and after the intervention and will undergo epigenetic profiling. The overarching goals are to: 1) examine the effect of health behaviors and SDOH factors on the rate of change in EAA during follow-up of the SJLIFE cohort; 2) evaluate the association between the rate of change in EAA and subsequent long-term outcomes including prevalence/severity/cumulative burden of CHCs and mortality during follow-up of the SJLIFE cohort; and 3) determine the impact of behavioral interventions for physical fitness and sleep quality on the changes in EAA. Our novel study will encompass observational and interventional components, each with a longitudinal repeated measures of EAA at up to three time-points to enable evaluation of the changes in EAA. Findings from non-Hispanic White survivors will be evaluated in diverse populations including non-Hispanic Black and Hispanic survivors as well as non-cancer controls in an exploratory fashion. Successful completion of the proposed study will substantially advance our understanding and generate new insights into the accelerated aging phenomenon, inform development of novel interventions to slow down accelerated aging and...