Epigenetic dynamics of cellular senescence: From mechanistic insights to precision senotherapy

Cellular senescence functions as a pivotal stress response with dual roles; it serves as a barrier against early tumorigenesis while paradoxically driving late-stage tumor progression and the pathogenesis of many other age-related diseases, including cardiovascular, neurodegenerative, metabolic, and fibrotic disorders. This review comprehensively elucidates how the senescent phenotype is orchestrated by a dynamic epigenetic landscape. We detail how dysregulation in chromatin remodeling (e.g., heterochromatin loss), histone modifications, DNA methylation, and the epitranscriptome rewrites genome architecture to govern the initiation and maintenance of the senescent phenotype within these specific disease contexts. Crucially, we highlight the profound heterogeneity of senescence across different pathologies, contrasting its detrimental role in driving tissue degeneration in organs like the lung and kidney against its context-dependent beneficial effects, such as limiting fibrosis in the liver. Furthermore, we evaluate the translational potential of epigenetic drugs-categorized by targets such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), and histone deacetylases (HDACs)-as dual-purpose therapeutics. Unlike genetic mutations, epigenetic alterations are reversible. We discuss strategies to either enforce senescence barriers for cancer suppression (pro-senescence) or reverse epigenetic aging signatures for tissue rejuvenation (anti-senescence). This review proposes a roadmap for leveraging epigenetic plasticity, offering a precision medicine approach to target specific senescent cell populations and extend health span.