Müller Jakob¹, Chen Liying², Al-Farsi Hamdan³, García Elena⁴, Novak Lukas⁵, Dubois Amélie⁶
ABSTRACT:
Background: Cardiac aging is a major contributor to cardiovascular morbidity and mortality, yet therapeutic options to reverse or slow this process remain limited. The progressive decline in myocardial performance is linked to cumulative molecular damage, chronic inflammation, metabolic inflexibility, and loss of regenerative capacity. Emerging evidence highlights epigenomic remodeling—specifically histone modifications and DNA methylation—as a critical determinant of cardiomyocyte senescence and myocardial dysfunction. These alterations affect chromatin structure and transcriptional programs essential for maintaining cardiac homeostasis, leading to silencing of protective genes and activation of pathogenic pathways. Methods and Results: This study investigated genome-wide epigenomic changes in aged murine and human myocardium, correlating chromatin accessibility and methylation profiles with transcriptomic and functional outcomes. Aged cardiac tissues were subjected to ATAC-seq to assess open chromatin regions, ChIP-seq to evaluate histone modifications, and whole-genome bisulfite sequencing (WGBS) to map DNA methylation patterns. Integrated multi-omics analysis revealed age-associated silencing of mitochondrial biogenesis genes, oxidative phosphorylation regulators, and antifibrotic factors. This silencing was driven by increased promoter methylation and loss of activating histone marks such as H3K27ac and H3K4me3. Conclusion: Our findings provide compelling evidence that cardiac aging is governed, at least in part, by modifiable epigenomic alterations that repress genes essential for metabolic flexibility, contractile integrity, and anti-fibrotic balance. By mapping the chromatin landscape of the aged myocardium and demonstrating the efficacy of targeted epigenetic reprogramming in restoring youthful gene expression and cardiac performance, this study establishes a novel paradigm for rejuvenation-based therapy in age-associated cardiovascular disease. These results set the stage for a new class of epigenetic therapeutics that could delay or even reverse functional decline in the aging heart.