Cellular senescence as a systems-level driver of cardiovascular ageing.

Abstract

Cellular senescence is increasingly recognized as a fundamental driver of cardiovascular ageing; however, its molecular heterogeneity, cell-type specificity, and translational relevance remain incompletely understood. Accumulating evidence indicates that cardiovascular senescence is not a uniform or cell-autonomous process, but rather an emergent property of interacting endothelial, vascular smooth muscle, immune, and stromal cell networks shaped by metabolic stress, immune dysregulation, and chromatin reorganization. In this review, we synthesize recent advances in the molecular hallmarks of cardiovascular senescence, including DNA damage responses, telomere attrition, mitochondrial dysfunction, SASP, and epigenetic remodeling, with an emphasis on how these features diverge across cardiovascular cell types. We highlight key transcriptional and post-transcriptional regulators as nodal integrators of oxidative stress, inflammation, and metabolic reprogramming. At the systems level, we propose an inflammation-coagulation-senescence axis to conceptualize how chronic inflammatory burden, immunothrombosis, arterial stiffening, and heart failure. We further discuss emerging metabolic checkpoints in vascular smooth muscle cell ageing, as modulators of senescence initiation and progression. Finally, we critically assess current senescence-targeted strategies emphasizing that their efficacy is constrained by senescence heterogeneity, disease stage, and context-dependent cellular interactions. Rather than supporting uniform anti-senescence approaches, accumulating evidence underscores the need for precision-guided interventions that account for temporal hierarchy, cell-type specificity, and metabolic state. We argue that integrating single-cell and spatial multi-omics with biological age metrics and machine-learning will be essential to define biologically vulnerable states, identify actionable therapeutic windows, and translate senescence biology into stage-specific and cell-targeted strategies for healthier cardiovascular ageing.