Abstract
Aging is a major risk factor for cardiovascular diseases, yet the underlying molecular mechanisms remain poorly understood. In this study, we integrated physiological characterization of cardiomyocyte (CM) aging with concurrent single-nucleus RNA-seq and ATAC-seq, and reduced representation bisulfite sequencing to delineate the cellular and molecular landscape of CM aging in mice. Our analysis revealed significant age-associated changes in CM physiology, including hypertrophy, fibrosis, and diastolic dysfunction. We uncovered dramatic epigenetic remodeling in aged CMs, characterized by increased chromatin accessibility and altered DNA methylation patterns. Overexpression of the DNA methylase DNMT3A in young adult mouse hearts recapitulated key features of the aged heart phenotype, establishing DNA hypermethylation as a significant regulator of age-related CM function. Furthermore, ESRRG, an orphan nuclear receptor, functions as a mediator of diastolic function in the heart. Its overexpression significantly improved diastolic function and reduced expression of a non-coding RNA that is upregulated in aged CMs. These novel insights into the molecular mechanisms underlying cardiac aging identify molecular regulators involved in age-associated cardiac remodeling.