Restored Cardiomyocyte Proteostasis Ameliorates Cardiac Aging

Cardiac aging is characterized by progressive functional decline and increased risk of heart failure, yet the molecular drivers linking proteostasis collapse to cardiac aging remain elusive. Here, we identified Elp5, a core subunit of the Elongator complex, whose expression declines in aged hearts. Cardiomyocyte-specific deletion of Elp5 in mice (Elp5-cKO) destabilized the Elongator complex and triggered late-onset cardiac dysfunction. While young Elp5-cKO hearts maintained normal function, middle-aged Elp5-cKO mice exhibited premature cardiac aging phenotypes driven by proteotoxic stress, which was ameliorated by pharmacological inhibition of proteotoxicity with TUDCA. Mechanistically, young Elp5-cKO hearts displayed mitochondrial import and buffering of mistranslated proteins dependent on elevated mitochondrial membrane potential. Notably, both ELP5 overexpression and TUDCA treatment reduced proteotoxicity, mitigated senescence phenotypes, and restored cardiac function in aged hearts. Collectively, our findings delineate a pathway in which the age-associated decline in cardiac ELP5 expression initiates cardiomyocyte proteostasis collapse, ultimately driving cardiac aging. Restoring cardiomyocyte proteostasis, through either genetic augmentation of ELP5 or pharmacological intervention, represents a promising strategy to counteract age-related cardiac decline.