Aging is a major risk factor for ischemic heart disease, often caused by heart attack (myocardial infarction, MI). MI occurs at an alarmingly high rate in the United States (approximately one case every 40 seconds) and is the leading cause of morbidity and mortality in the geriatric population. At present, heart failure (HF) represents an unmet need with no approved clinical therapies to repair the damaged myocardium. As the population ages, the number of HF patients is projected to increase, doubling the annual cost by 2030. Identifying novel and translational mechanisms for robust cardiac repair presents a critical approach to counter aging-associated cardiac diseases and guide the design of future successful therapies. Acomys (African Spiny mouse) is a mammal closely related to Mus (laboratory mouse). Recently, independent groups have reported that Acomys are capable of regenerating injured tissue in multiple organs. Most importantly, after MI, Acomys demonstrated significant cardiac protection, with a higher survival rate than mice. Our preliminary studies revealed that Acomys hearts retained a high frequency of young, proliferative phenotype cardiomyocytes (CM). This proposal will further dissect the mechanisms driving the youthful cardiac phenotype and cardiac protection in Acomys. The candidate will study Acomys and Mus side by side to test the central hypothesis that cytoprotective resilience to reactive oxygen species (ROS) preserves young phenotype CM into adulthood and drives enhanced myocardial preservation in Acomys after a heart attack. In the F99 phase of training, the candidate will continue investigating the contribution of Acomys cardiomyocytes in endogenous cardiac repair following MI in both young and aged animals. Specifically, the candidate will examine cardiomyocyte proliferation in both species and different age groups after MI. Scar size, cardiac function, and angiogenesis will also be characterized to determine the extent of recovery. In the K00 phase, the candidate will switch focus to identify molecular targets and pathways that allow Acomys to maintain a “young heart” into adulthood. The proposed work is designed to provide a robust transition training into aging research that will prepare the candidate for an academic career in translational anti-aging cardiac therapy. The proposed work will yield valuable information on endogenous cardiac repair in adult mammals. This knowledge will aid in the discovery of novel therapies and approaches for maintaining cardiac health throughout adulthood.