Inflammaging as a Systems-Level Integrator of Disease: Biological Foundations of Chronic Low-Grade Inflammation

The concept of inflammaging(definition) — referring to the persistent, low-grade inflammatory state that accompanies biological ageing — has progressively positioned itself as a unifying framework for understanding age-related chronic disease. Unlike acute inflammation, which is adaptive, transient, and fundamentally protective, inflammaging reflects a persistent dysregulation of immune signalling. Its hallmarks include failure to resolve inflammatory signals, alongside mitochondrial decline and the gradual erosion of tissue homeostasis driven by persistent cytokine activity. Increasing evidence suggests that inflammaging is not merely a consequence of ageing, but rather an active systems-level process capable of reshaping metabolic, vascular, neurological, and musculoskeletal physiology. Persistent inflammatory activation contributes to frailty, cardiovascular disease, neurodegeneration, sarcopenia, metabolic dysfunction, and osteoarthritis through interconnected molecular and cellular pathways involving immunosenescence, cellular senescence(definition), oxidative stress, inflammasome activation, and epigenetic remodelling [1]. Recent advances in geroscience have reframed inflammation as a multidirectional biological network integrating immune, endocrine, metabolic, microbiological, and biomechanical signalling. This perspective moves beyond reductionist cytokine models and instead conceptualises inflammation as a distributed regulatory architecture operating across tissues and organ systems. Within this framework, chronic disease may emerge not solely from isolated organ pathology, but from progressive failure of intersystem communication and adaptive resilience [2]. This invited review examines the biological foundations of inflammaging, with particular emphasis on immunosenescence, senescence-associated secretory pathways, mitochondrial dysfunction(definition), inflammasome biology, cytokine network dynamics, and epigenetic regulation. We propose that inflammaging may be best understood as a form of multiscale biological interface failure in which persistent inflammatory signalling progressively destabilises tissue integration across physiological systems. Such a framework may facilitate the development of more precise biomarkers, systems-oriented therapeutic strategies, and translational approaches aimed at extending healthspan(definition) rather than merely prolonging survival.