Epigenetic regulation of the complement system in age-related chronic inflammation: mechanisms and therapeutic prospects

Aging is accompanied by progressive changes in epigenetic regulation, immune function, and tissue homeostasis, which may contribute to chronic low-grade inflammation and age-related disease. The complement system is an important component of innate immunity and participates in immune surveillance, tissue homeostasis, and inflammatory regulation. Increasing evidence suggests that DNA methylation, histone modifications, and non-coding RNAs can influence the expression of complement components and regulatory proteins, while complement-associated inflammatory signaling may reciprocally affect cellular epigenetic states. In this review, we summarize current evidence linking epigenetic regulation with complement biology during aging and discuss how this relationship varies across tissues and disease contexts. Particular attention is given to the central nervous system, where complement-dependent synaptic remodeling can support physiological circuit refinement but may become excessive or dysregulated under pathological conditions. We further examine the epigenetic–complement relationship in Alzheimer’s disease, age-related macular degeneration, and atherosclerosis, and consider age-associated clonal hematopoiesis as a potential modifier of myeloid and inflammatory states. Rather than proposing a uniform linear pathway from epigenetic aging to complement activation and disease, we propose a context-dependent framework in which age-associated epigenetic remodeling may coexist with physiological adaptation or, under specific genetic, metabolic, environmental, cellular, and tissue contexts, contribute to reduced regulatory reserve and persistent complement-associated inflammation. This framework highlights the potential of cell-, tissue-, and disease-stage-specific strategies targeting the epigenetic–complement axis while preserving physiological complement functions. The Epigenetic-Complement Axis in Age-Related Neuroinflammation. The flowchart was created using Biorender.com