Histone modifications as molecular drivers of cardiac aging: Metabolic alterations, epigenetic mechanisms, and emerging therapeutic strategies

Abstract

Cardiac aging represents a complex pathophysiological process characterized by progressive metabolic recombination and functional dedifferentiation of cardiac cellular components. Despite advancements in cardiovascular medicine, a critical research gap persists in understanding the precise epigenetic mechanisms that drive age-related cardiac dysfunction. This comprehensive review elucidates the pivotal role of histone modifications—including methylation, acetylation, and phosphorylation—in orchestrating the molecular landscape of cardiac aging. Significant gaps remain in our understanding of site-specific histone modification impacts on cardiac function, the intricate crosstalk between different histone marks, and their integration with metabolic alterations that characterize the aging myocardium. Current evidence reveals a dynamic epigenetic signature in aged cardiac tissue, typically featuring increased transcriptional activation markers alongside decreased repressive marks, though context-dependent variations exist. This review explores how histone modifications influence critical pathways governing mitochondrial dysfunction, DNA damage repair, inflammation, and fibrosis in aging hearts. Innovative therapeutic approaches targeting specific histone-modifying enzymes promise to mitigate age-related cardiac deterioration, potentially revolutionizing treatment paradigms for cardiovascular diseases in aging populations. Addressing these knowledge gaps requires multidimensional approaches that integrate epigenomics with functional assessment of cardiac performance.