Inflammaging as a systems-level integrator of disease: Biological foundations of chronic low-grade inflammation

Abstract

The concept of inflammaging—defined as the persistent, low-grade inflammatory state accompanying biological aging—has emerged as a unifying framework for understanding chronic disease in later life. Unlike acute inflammation, which is adaptive, transient, and protective, inflammaging reflects persistent dysregulation of immune signaling, impaired resolution of inflammatory responses, mitochondrial decline, and progressive loss of tissue homeostasis. Evidence increasingly indicates that inflammaging is not merely a consequence of aging but an active systems-level process that reshapes metabolic, vascular, neurological, and musculoskeletal physiology. Sustained inflammatory activation contributes to frailty, cardiovascular disease, neurodegeneration, sarcopenia, metabolic dysfunction, and osteoarthritis through interconnected molecular and cellular mechanisms involving immunosenescence, cellular senescence, oxidative stress, inflammasome activation, and epigenetic remodeling. Recent advances in geroscience have reframed inflammation as a multidirectional biological network integrating immune, endocrine, metabolic, microbiological, and biomechanical signals. This perspective moves beyond reductionist cytokine models by conceptualizing inflammation as a distributed regulatory architecture operating across tissues and organ systems. Accordingly, chronic disease may arise not only from local organ pathology but also from progressive failure of intersystem communication and adaptive resilience. This review examines the biological foundations of inflammaging, emphasizing immunosenescence, senescence-associated secretory pathways, mitochondrial dysfunction, inflammasome biology, cytokine network dynamics, and epigenetic regulation. We propose that inflammaging is best understood as multiscale biological interface failure, in which persistent inflammatory signaling progressively destabilizes tissue integration across physiological systems. This framework may support the development of more precise biomarkers, systems-oriented therapeutic strategies, and translational interventions designed to extend health span rather than merely prolong survival.