Abstract

Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans.
We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31
(elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak
and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein
oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved
diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was
independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase
(mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function
of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping
mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed
by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling
as therapeutic targets for cardiac aging.