PROJECT SUMMARY/ABSTRACT More than 3.8 million women living in the United States have a history of invasive breast cancer, a majority of whom are over age 65. With 15-year survival rates exceeding 80%, older breast cancer survivors are a growing population with distinct health considerations relative to patterns of usual aging. Cancer survivors are at an increased risk of age-related conditions, but little is known about the trajectories of aging that underlie this elevated risk, or factors affecting the severity of decline. Evidence from preclinical models suggest cancer treatment contributes to molecular and cellular changes consistent with aging that may underlie the later emergence of functional decline. Frailty is highly prevalent in breast cancer patients and is associated with a greater hazard of long-term morbidity and mortality. Epigenetic age acceleration is an indicator of biologic aging that is influenced by cancer and its treatment, and also a strong predictor of healthspan and lifespan. We hypothesize that cancer and its treatment will contribute to accelerated trajectories of functional and epigenetic aging relative to women without a history of cancer, that these changes will be sustained long-term, and vary by treatment type and intensity. To test these hypotheses, we will combine three decades of pre- and post- diagnosis clinical, self-reported, and physiological data from post-menopausal women in the Women’s Health Initiative (WHI), including annual assessments of functional status in over 9,000 breast cancer survivors matched by age to cancer-free controls. We will estimate epigenetic age from blood samples collected at multiple pre- and post-treatment time points in a subset of breast cancer survivors and ‘usual aging’ controls. With this unique data and multidisciplinary team of relevant experts, we will conduct the first large study with long-term, longitudinal measures of epigenetic and functional aging before and after breast cancer diagnosis and treatment, addressing the following specific aims: 1) Characterize long-term trajectories of physical function in breast cancer survivors (v. usual aging in controls) and test whether they are modified by the type and intensity of cancer treatments; 2) Examine whether breast cancer and its treatment increase the rate of epigenetic aging and whether this aging continues to accelerate after treatment; and 3) Test the relationship between the rate of epigenetic aging and functional decline and how it may differ between breast cancer survivors and usual aging controls. This work is a critical first step to characterize predictors of aging trajectories among cancer survivors and identify those who could benefit from supportive interventions to maximize healthspan in this rapidly growing population.