Abstract Aging is a risk factor for cardiovascular diseases. Coronary artery disease is the leading cause of death and morbidity world-wide. Metabolic shifts and oxidative stress that occur in the myocardium during the phases of ischemia as well as reperfusion cause myocardial injury and play a pivotal role in the development and progression of myocardial damage and heart failure (HF). Humanin (HN), a novel small peptide generated by mitochondria, has been shown to exhibit strong cytoprotection in many age-related diseases with increased oxidative stress including Alzheimer’s disease, atherosclerosis, myocardial and cerebral ischemia, and type 2 diabetes. Our group has demonstrated that administration of HN results in a decrease in infarct size and preservation of cardiac function in a mouse model of myocardial ischemia-reperfusion (MI-R) injury. Additionally, our preliminary data presented in this grant submission shows that HN administration results in: 1) infarct size reduction following MI-R injury in aging rodent and clinically-relevant porcine models of MI-R; 2) improved cardiac function as evidenced by decreased end diastolic volume in old mice with myocardial ischemia-induced heart failure; 3) increased peroxisomal fatty acid oxidation, and inhibition of mitochondrial fatty acid oxidation in primary cardiomyocytes and heart lysates; 4) decreases ROS and 5) improved survival of cardiomyocytes following hypoxia and oxidative stress. Based on these data, we hypothesize that HN treatment will improve cardiac function in MI-R injury or MI induced heart failure (HF) through its unique ability to induce metabolic adaptations in cardiac myocytes, improve peroxisomal function and decrease ROS, thereby limiting acute myocardial cell death, and preventing the progression to HF. In this grant application, we will delineate the cardioprotective efficacy of HN in murine models of MI-R injury and MI induced HF in aging and elucidate the mechanisms that underlie HN’s cardioprotective effects on the myocardium. In an exploratory sub aim, we will assess HN levels in heart and circulation in human subjects with post-ischemia cardiac failure. Results from these experiments may potentially have a tremendous impact in treating cardiovascular diseases. HN may provide a much-needed therapeutic option for patients to protect the myocardium from ischemic and reperfusion injuries, and prevent the progression to HF.