CaMKII Emerges as Central Molecular Hub Driving the Ageing Heart

A new review published in Artery Research argues that Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), particularly the cardiac-predominant CaMKIIδ isoform, acts as a central stress-responsive signaling node that links many of the hallmark processes of cardiac ageing into a single, self-reinforcing network. Rather than treating calcium mishandling, oxidative stress, chronic inflammation, defective autophagy, mitochondrial decline and genomic instability as separate problems, the authors assemble evidence that CaMKII sits upstream of, and is in turn amplified by, each of these disturbances in the ageing myocardium.

Under normal physiological conditions, CaMKII activation is transient and strictly dependent on Ca²⁺/calmodulin binding. The review emphasizes that ageing changes this fundamentally. Three post-translational mechanisms can prolong kinase activity well beyond the initiating calcium signal: autophosphorylation at Thr286 or Thr287, oxidation of Met281 or Met282, and O-GlcNAcylation at Ser280. Autophosphorylation sustains activity after repetitive calcium oscillations, oxidation ties the kinase to reactive oxygen species accumulation, and O-GlcNAcylation couples its signaling to nutrient excess and metabolic stress. All three alternative activation modes tend to accumulate under ageing-associated conditions such as chronic inflammation, rising oxidative burden, metabolic stress and pathological calcium leak.

The review grounds its framework in the epidemiology of cardiac ageing. Cardiovascular ageing is one of the strongest independent risk factors for heart failure, atrial fibrillation, coronary artery disease and conduction abnormalities. Heart failure with preserved ejection fraction (HFpEF), characterized centrally by diastolic dysfunction, is presented as the most characteristic clinical manifestation of the ageing heart: large community-based studies indicate that roughly half of heart failure patients fall into the HFpEF category, and its incidence rises steeply with advancing age, particularly in populations with multimorbidity. The authors argue that HFpEF reflects hallmark-driven remodeling of the ageing heart rather than chronological age alone, converging on myocardial stiffening, impaired relaxation, microvascular dysfunction and inflammatory activation.

On the calcium-handling front, the review details how hyperactive CaMKII phosphorylates the ryanodine receptor RyR2 at Ser2814, increasing channel open probability and destabilizing sarcoplasmic reticulum calcium retention. The result is pathological diastolic calcium leak, spontaneous calcium waves, triggered activity and arrhythmia susceptibility. In parallel, CaMKII phosphorylates phospholamban at Thr17, and under chronic ageing-related stress the phospholamban/SERCA2a axis shifts from adaptive compensation toward maladaptive remodeling, producing reduced sarcoplasmic reticulum calcium load, delayed diastolic calcium clearance, elevated diastolic intracellular calcium and HFpEF-like diastolic dysfunction. Importantly, the review cites experimental work showing that suppressing age-related CaMKII hyperactivation attenuates aberrant diastolic leak and calcium waves in aged hearts, supporting a causal contribution of kinase overactivity to age-associated calcium mishandling.

Inflammaging, the chronic low-grade sterile inflammation of ageing, is the second hallmark the review connects to CaMKII. Evidence indicates that CaMKIIδ can interact with the IKKβ–NF-κB signaling axis, facilitating NF-κB activation and transcription of inflammatory mediators. Cardiomyocyte-specific deletion of CaMKIIδ dampens NF-κB signaling, inflammatory gene expression, macrophage recruitment and NLRP3 inflammasome priming before detectable cardiomyocyte death. Direct evidence from ageing models shows that CaMKII activity increases with age and sustains chronic inflammatory tone: genetic inhibition alleviates NF-κB activation, senescence-associated secretory phenotype expression and age-related cardiac dysfunction, whereas CaMKII activation exacerbates inflammatory and senescent phenotypes.

Autophagy and mitochondrial quality control form a third axis. Ageing hearts show progressive decline in autophagy and mitophagy, tightly coupled to sustained CaMKII activation. Persistent CaMKII signaling is associated with heightened AKT–mTORC1 signaling that restrains autophagosome biogenesis, reduced expression of autophagy genes such as LC3 and ATG5/7, and diminished lysosomal proton pump subunit expression, collectively impairing autophagosome maturation and lysosomal acidification. In HFpEF-like ageing mouse models, pharmacologic or genetic suppression of CaMKIIδ improved lysosomal integrity, reflected by restoration of the lysosomal marker Lamp1, and reduced accumulation of the autophagy cargo markers LC3-II and p62, benefits blunted under lysosomal inhibition, implicating a flux-level mechanism.

Mitochondrial dysfunction is presented as a CaMKII-mediated feed-forward circuit. ROS-mediated oxidation confers calcium-independent autonomous activity on CaMKII, and ox-CaMKII is increased and persistent in the aged myocardium. Activated CaMKII promotes mitochondrial calcium overload through MCU-mediated uptake, sensitizes the mitochondrial permeability transition pore, and phosphorylates the fission regulator Drp1 at Ser616, driving excessive fragmentation. In mtCaMKII transgenic mice, mitochondrial CaMKII activation compromised electron transport chain complex function and TCA cycle enzyme activity, and mice with myocardial mitochondrial CaMKII overexpression developed severe dilated cardiomyopathy with reduced ATP and contractile dysfunction, while genetic inhibition of mitochondrial CaMKII conferred protection against post-infarction left ventricular dilation. Knock-in mice expressing oxidation-resistant CaMKII showed reduced myocardial injury and improved early left ventricular function after ischemia/reperfusion.

The review also positions CaMKII as a systems-level integrator of DNA damage. Persistent activation, particularly of the CaMKIIδ9 splice variant, is associated with elevated DNA damage response markers such as γH2AX and increased DNA strand breaks. Mechanistically, CaMKIIδ9 disrupts UBE2T-dependent DNA repair through phosphorylation-coupled degradation of UBE2T, causing persistent DNA damage accumulation; downstream PARP1 hyperactivation promotes NAD⁺ depletion and metabolic dysfunction. In parallel, CaMKII–HDAC4 signaling, via HDAC4 phosphorylation and nuclear export, may relieve transcriptional repression of stress-responsive remodeling programs, creating durable maladaptive chromatin states. Unresolved DNA damage engages p53–p21 and p16–Rb senescence pathways and promotes a pro-inflammatory, pro-fibrotic senescence-associated secretory phenotype linked to myocardial stiffening and diastolic dysfunction.

Across disease phenotypes, the review reports convergent preclinical findings. In ageing-associated arrhythmia models, elevated ox-CaMKII in aged atrial and ventricular tissue promotes RyR2 Ser2814 phosphorylation, diastolic leak and delayed afterdepolarizations; genetic or pharmacologic strategies blunting pathological activation, including AC3-I, oxidation-resistant M281/282V knock-in and ROS suppression, consistently reduced atrial fibrillation inducibility and ventricular arrhythmia burden. In ischemic and pressure-overload remodeling, attenuation of CaMKII signaling reduced myocardial injury, limited ventricular dilation and suppressed maladaptive hypertrophic and fibrotic remodeling in preclinical models. In diabetic cardiomyopathy, hyperglycaemia, advanced glycation end products and mitochondrial ROS activate CaMKII through oxidation and O-GlcNAcylation, and reducing O-GlcNAc flux, suppressing oxidative stress or inhibiting CaMKII improved electrical stability and cardiac function.

The authors are explicit about translational limits. Current evidence remains dominated by animal and cell-based studies, with limited direct evidence from older human myocardium without overt cardiovascular disease, incomplete definition of splice-variant-specific actions, and no late-stage clinical validation. They note that several guideline-directed heart failure therapies functionally intersect with CaMKII signaling: SGLT2 inhibitors reduced CaMKII-dependent phosphorylation of RyR2 and phospholamban and suppressed proarrhythmogenic diastolic calcium leak in murine models and human failing cardiomyocytes, sacubitrilat directly reduced sarcoplasmic reticulum calcium leak, β-adrenergic blockade limits conditions facilitating CaMKII engagement, and mineralocorticoid receptor antagonism reduces oxidative stress and ox-CaMKII levels. However, direct clinical attribution of these benefits to CaMKII modulation remains inferential. The review concludes that indiscriminate CaMKII inhibition risks disrupting essential physiological functions, including frequency-dependent relaxation and β-adrenergic adaptation, and argues that future efforts should pursue isoform-specific, activation-mode-specific and compartment-specific targeting, with efficacy and safety requiring validation in human ageing-related disease.

Subject of Research: The role of CaMKII signaling as an integrator of molecular stress pathways in cardiac ageing and age-related cardiac disease

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

Article References: Li, T., Chen, Y., Xu, B., Li, J., & Meng, Y. (2026). CaMKII at the Crossroads of Cardiac Ageing: A Central Integrator of Molecular Stress Signaling in Age-Related Cardiac Disease. Artery Research, 32(1), Article 29. https://doi.org/10.1007/s44200-026-00127-w

Image Credits: AI Generated

DOI: 10.1007/s44200-026-00127-w

Keywords: CaMKII, cardiac ageing, CaMKIIδ, HFpEF, inflammaging, mitochondrial dysfunction, autophagy, calcium handling, oxidative stress, DNA damage, arrhythmia, heart failure