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.

中文翻译：

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晚年线粒体功能恢复可逆转老年小鼠的心脏功能障碍


舒张功能障碍是小鼠和人类心脏衰老的一个突出特征。我们在此表明​​，用线粒体靶向肽 SS-31（elamipretide）对老年小鼠进行 8 周治疗可以基本上扭转这种缺陷。 SS-31使老年小鼠心肌细胞中质子泄漏的增加正常化并减少线粒体ROS，同时伴随着老年心脏中蛋白质氧化的减少和蛋白质硫醇氧化还原状态的转变。舒张功能的改善与 cMyBP-C Ser282 磷酸化的增加一致，但与肌联蛋白亚型转变无关。线粒体靶向过氧化氢酶 (mCAT) 的晚年病毒表达在老年小鼠中产生了类似的功能益处，而 SS-31 并未改善老年 mCAT 小鼠的心脏功能，这表明线粒体氧化应激正常化是一种重叠机制。这些结果表明，可以通过针对线粒体功能障碍来逆转预先存在的心脏衰老表型，并暗示线粒体能量学和氧化还原信号传导可以作为心脏衰老的治疗靶点。