CaMKII at the Crossroads of Cardiac Ageing: A Central Integrator of Molecular Stress Signaling in Age-Related Cardiac Disease

Cardiac ageing is a major biological substrate underlying the increasing burden of age-associated cardiovascular disease. It is characterized by structural and functional remodeling, mitochondrial dysfunction, chronic low-grade inflammation, genomic instability, defective proteostatic control, and impaired regenerative capacity. Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), particularly the cardiac-predominant CaMKIIδ isoform, has emerged as a central stress-responsive signaling node linking Ca²⁺ mishandling, redox imbalance, inflammatory activation, impaired autophagic flux, mitochondrial injury, and maladaptive transcriptional remodeling in the ageing myocardium. Under physiological conditions, CaMKII activation is transient and Ca²⁺/calmodulin dependent. In the ageing heart, sustained oxidation, O-GlcNAcylation, and autophosphorylation prolong kinase activity and amplify pathological signaling. Evidence from aged rodent models, pressure-overload and ischemia-reperfusion models, diabetic cardiomyopathy models, and human failing cardiomyocytes supports a contributory role for CaMKII in multiple age-related cardiovascular disorders. Experimental inhibition of CaMKII has been shown to attenuate pathological remodeling and improve stress maladaptation in preclinical settings. This review integrates current evidence on the role of CaMKII across major hallmarks of cardiac ageing and proposes a conceptual framework in which CaMKII connects molecular stress signaling to age-related cardiac disease phenotypes. Current evidence remains limited by the predominance of animal and cell-based studies, limited direct evidence from older human myocardium without overt cardiovascular disease, incomplete definition of splice-variant-specific actions, and lack of late-stage clinical validation. Selective targeting of pathological CaMKII signaling may therefore warrant further investigation as a strategy for attenuating cardiac ageing and its related disease burden.