Multicellular senescence programs in the aged heart

Cardiac aging reflects a convergence of intrinsic molecular damage and maladaptive stress responses that progressively erode myocardial resilience. Accumulating genomic instability, telomere dysfunction, chromatin remodeling, and metabolic dysregulation activate innate immune signaling and cellular senescence across cardiomyocytes, endothelial cells, fibroblasts, and immune cells. At the tissue level, these processes manifest as microvascular rarefaction, fibrosis, hypertrophy, neurovascular uncoupling, and impaired adaptive capacity, creating a substrate that overlaps extensively with cardiomyopathy, heart failure, and atrial fibrillation (AF). Importantly, senescence in the heart is not monolithic. Emerging multi-omics and spatial analyses reveal context-dependent senescence programs, including transient, injury-associated states that support angiogenesis and repair, alongside chronic senescent phenotypes that propagate inflammation and remodeling through the senescence-associated secretory phenotype (SASP). These observations indicate that senescence is not uniformly deleterious but rather comprises functionally heterogeneous responses within the aging myocardium. Non-cell autonomous interactions-spanning cardiomyocyte-fibroblast crosstalk, immune niche signaling, endothelial cell-neuronal axis, and systemic organ-to-heart communication-further amplify or constrain these trajectories. Advances in biomarker discovery, imaging, and circulating epigenetic signatures now enable biological aging of the heart to be quantified beyond chronological aging, although many circulating biomarkers are not cardiac-specific and may also reflect systemic inflammation, fibrosis, frailty, or generalized biological aging. In parallel, preclinical studies demonstrate that senolytic, senomorphic, metabolic, and nutrient-sensing-targeted interventions can partially restore cardiac homeostasis. Together, these insights suggest that cellular senescence may represent a key mechanism and a potentially targetable process in cardiac aging, with important implications for the prevention and treatment of age-related cardiovascular disease.