Abstract PROJECT SUMMARY Obesity-related cancers, type 2 diabetes mellitus and cardiovascular disease, are characterized by a chronic breakdown in metabolic functioning that impacts quality of life, physical functioning and longevity. Though obesity plays a pivotal role in the etiology of at least 13 cancer types, the traditional metric for measuring obesity, body mass index (BMI), is imperfect and may fail to identify a third of individuals at risk of these cancers owing to metabolic dysfunction. While accumulated cellular damage and abrogated resilience mechanisms are part of the natural aging process, damage accumulation and dysregulation of homeostasis mechanisms, potentially driven by metabolic dysfunction, may lead to accelerated biological aging that has recently been linked to cancer risk and survival. A better understanding of the relationship between metabolic health, regardless of BMI, with accelerated aging and cancer is needed to inform who to target for prevention efforts. The long-term goal of this application is to understand how metabolic dysfunction influences biological aging and risk of cancer, at all levels of adiposity, to inform interventions that prevent or delay these deadly diseases. The central hypothesis is that metabolic dysfunction, independent of obesity, is associated with accelerated biological aging and obesity-related cancers. Aim 1 (F99 phase) will leverage data from the Utah Obesity Study to measure the association between metabolic dysfunction (metabolic syndrome and diabetes) across BMI categories (i.e., “metabolic health phenotype”) and risk of developing obesity-related cancer (esophageal, gastric, colorectal, liver, gallbladder, pancreas, uterus, ovary, thyroid, meningioma, kidney, and breast cancers, and multiple myeloma). In the Women’s Health Initiative (WHI), diabetes status at cancer diagnosis will be measured in relation to cancer-specific and overall survival. This research will be extended in Aim 2 (K00 phase) where metabolic health phenotype will be studied in relation to accelerated biological aging and obesity-related cancer risk. In Aim 2a, data from the prospective WHI, Jackson Heart Study, Health and Retirement Study, Framingham Heart Study and others will be used to measure the extent to which accelerated biological age explains the association of metabolic health phenotype with obesity-related cancer risk. In Aim 2b, using data from The Cancer Genomic Atlas (TCGA) cohort, accelerated biological aging will be evaluated in relation to survival after obesity-related cancer diagnosis. The pre-doctoral to post-doctoral candidate will expand upon her didactic and experiential training in biostatistics, epidemiology, aging and epigenetics research both at the University of Utah, Huntsman Cancer Institute, and Yale School of Medicine. Practical training will be obtained in human metabolism, biostatistics, epidemiology, aging and epigenetics research. The proposed project will help to better identi...