Age-Related Disruption of the Proteome and Acetylome in Mouse Hearts Correlates with Differential Loss of Function that is Attenuated by SS-31 and NMN

We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs SS-31 and NMN to reverse age-related changes, in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are lost with age but only NMN reduced acetylation in a subset of proteins which increased acetylation with age. Primarily, these age-related increases in protein acetylation were in mitochondrial pathways such as mitochondrial dysfunction, oxidative phosphorylation, and TCA cycle signaling. We further assessed how these age-related changes correlated with diastolic function (Ea/Aa) and systolic function (fractional shortening under higher workload) measurements from echocardiography. These results show that diastolic and systolic function in old age correlate inversely with the abundance of a specific subset of proteins. This could indicate that the heart proteome may adapt to preserve diastolic or systolic function with age but cannot preserve both. This adds further evidence to our previous report that SS-31 provides benefit to diastolic function and NMN to systolic function and that the greatest benefit may be when both are administered together, as the combination provides a mechanism to improve both aspects of heart function simultaneously.