PROJECT 1: MITOCHONDRIAL ROS AND CARDIAC AGING – PROJECT SUMMARY/ABSTRACT Aging is accompanied by slowly progressive and irreversible structural changes and functional declines in the heart that include increased prevalence of left ventricular hypertrophy, decline in diastolic function, and a decline in exercise capacity that contributes to frailty in the elderly. Extending work begun with mitochondrial targeted catalase, mCAT, we have recently demonstrated that short term (8 week) treatment with the mitochondrial protective drug SS-31 “rejuvenates” cardiac function in old mice, reducing hypertrophy, improving diastolic function and remodeling the cardiac structure and proteome to a more youthful state. We hypothesize that SS-31 enhanced mitochondrial energetics and redox signaling subsequently result in remodeling of the cardiomyocyte and extracellular matrix to a more youthful state. This proposal will define the mechanisms that mediate both acute mitochondrial (Aim 1) and subacute cardiomyocyte and extracellular matrix (Aim 2) rejuvenating effects. As this approach offers the promise of substantial improvement in cardiac health of older humans, Aim 3 will help establish the potential longer-term benefits of these changes to murine healthspan and lifespan. Specifically, in Aim 1 In order to test the hypothesis that treatment with SS-31 restores redox and energy dependent signaling that results in improved mitochondrial structure and function we will measure mitochondrial and cardiac function, comparing and contrasting the mechanisms of mCAT, SS- 20 and SS-31 effects and their ability reverse cardiac aging in old mice and to protect mice challenged with doxorubicin to disrupt electron transport chain function. In Aim 2 we will determine the mechanisms by which SS-31 treatment of old mice rejuvenates cardiomyocytes and extracellular matrix (ECM) to improve aging diastolic function and cardiac performance. Aim 3 is shared across the entire P01, and will establish the translational benefits of SS-31 by determining whether SS31 can attenuate the decline of murine healthspan and extend lifespan after SS-31 is continuously delivered to mice beginning at middle age on regular and high fat diets. In this aim Project 1 will focus on cardiac healthspan.