We have shown that p53 balances the energy generated by oxidative phosphorylation and glycolysis and promotes aerobic metabolism through it positive regulation of mitochondrial respiration. p53 null mice, a model of premature tumorigenesis, display profound deficiencies in aerobic exercise capacity. Remarkably, the promotion of exercise capacity by a tumor suppressor gene in a mouse model parallels the human epidemiologic observation of a strong inverse relationship between exercise capacity and cancer incidence. We believe these two disparate observations may share a common mechanism in tumor suppression, therefore, we are investigating the regulation of mitochondrial function by p53 using in vitro and in vivo models. Importantly, we are studying cardiovascular and metabolic functions in individuals with Li-Fraumeni syndrome, a premature cancer syndrome caused by germline mutations in the p53 gene. A goal of this research is to derive basic insights that may assist in the development of new strategies for preventing cancer and improving cardiovascular fitness.