Canonical complement C3a-C3AR1 signalling in ageing and age-related disease: Cellular mechanisms, tissue-specific effects and translational challenges.

As the body ages, chronic low-grade inflammation, metabolic dysregulation, and loss of tissue resilience occur; however, the pathways linking these processes have not been fully characterized. Beyond traditional host defence, the canonical complement C3a-C3AR1 signalling axis has been identified as an ageing-sensitive pathway. Studies involving naturally aged animals, older human cohorts, and models of age-related diseases indicate that chronic C3a-C3AR1 signalling can drive the reprogramming of macrophages and microglia, influence immunometabolic processes, cause endothelial dysfunction, and amplify inflammatory responses. Chronological ageing provides the strongest mechanistic support for complement involvement across the visceral adipose tissue and neurovascular unit, including altered complement signalling and inflammageing, blood-brain barrier disruption, microglial state transitions, and cognitive impairment. There are additional studies on the tissue-specific involvement of this pathway in retinal, skeletal, cardiovascular, and renal diseases, although many of these studies have been conducted in models of injury or disease rather than chronological ageing. The context dependency of C3a-C3AR1 signalling also means that systemic inhibition may be complicated by the roles of C3a and C3AR1 in antimicrobial defense, phagocytosis, debris clearance, and tissue repair. C3a is a candidate biomarker of inflammatory and biological ageing; however, it is currently limited by insufficient specificity and preanalytical stability and needs to be validated longitudinally before being applied in clinical practice. Herein, we critically review the age-dependent regulation of canonical complement C3a-C3AR1 signalling, its cell- and tissue-specific effects, and the evidence linking this axis to ageing and age-related diseases.