Abstract 428: Interventions Targeting Mitochondrial Function as Therapies to Reverse Cardiac Aging

Abstract

Aging is associated with a higher incidence of cardiovascular disease and a significant decline in cardiac function. In individuals without overt cardiovascular disease, aging results in impaired diastolic function, reduced myocardial performance and increased prevalence of cardiac hypertrophy. Our laboratory has previously shown that transgenic mice expressing mitochondrial catalase (mCAT) have reduced mitochondrial oxidative damage and display delayed cardiac aging. This study aims to determine whether short-term treatments targeting mitochondrial function can reverse cardiac aging in old mice. The mitochondrial protective SS-31 peptide (elamipretide) has previously been shown to provide similar protection as mCAT in models of pressure overload-induced cardiac hypertrophy and failure. SS-31 binds to cardiolipin and improves the electron carrying function of cyt c , while reducing its peroxidase activity. We administered SS-31 to 24-month-old mice via osmotic minipump for 8 weeks, and found it to reduce cardiac hypertrophy and improve diastolic function and myocardial performance. SS-31 treatment attenuated the age-related increase in cyt c oxidation at Met-80, which has been associated with the disruption of Fe-S bond and activation of peroxidase activity of cyt c . SS-31 treatment also improved mitochondrial ultrastructure and induced AMPK activation in old hearts. To investigate whether SS-31 and mCAT protect cardiac aging by overlapping mechanisms, we administered SS-31 to old mCAT mice to study the effects of combined treatments. We found that SS-31 treatment cannot further improve the cardiac function of old mCAT mice. Concordantly, proteomic analysis revealed that changes in the cardiac proteome induced by SS-31 were partially overlapping with changes mediated by mCAT expression, particularly in the mitochondrial proteome, suggesting a convergence of molecular mechanisms of these two treatments. In addition, we showed that mCAT expression transduced by AAV9 in late-life also improved diastolic function, supporting the similar therapeutic effects of short-term mCAT and SS-31. In summary, these results support the therapeutic potential of mitochondrial-targeted interventions to reverse the effects of cardiac aging.