Inflammaging as a Dynamic Process in Ageing: Context, Regulation and Functional Consequences.

Abstract

Inflammaging (InfA) is a chronic, sterile, low-grade inflammatory condition associated with ageing and the development of age-related diseases (ARDs), including cancer. Conventional models often portray InfA as a relatively homogeneous and progressively worsening process, which may not adequately capture its temporal dynamics, tissue specificity, reversibility and context-dependent biological consequences. Here, we propose that InfA is better understood as a dynamic state-transition process comprising resolved/adaptive (S0), compensatory (S1), maladaptive but potentially reversible (S2) and self-sustaining (S3) inflammatory states. Transitions among these states are shaped by the balance between inflammatory induction and resolution, senescent cell (SC) generation and immune-mediated clearance, metabolic and mitochondrial resilience and microenvironmental feedback. We further integrate SC heterogeneity and immune surveillance into this framework, proposing that declining clearance and emerging immune escape permit persistent senescent phenotypes to establish self-reinforcing inflammatory microenvironments. This model also provides a mechanistic perspective on the cancer-ageing paradox by explaining how initially protective processes, including senescence, autophagy and immune surveillance, may be progressively re-tuned toward maladaptive functions during ageing. S2 emerges as a particularly important therapeutic window during which inflammatory dysregulation and immune escape are established but may remain conditionally reversible. Tissue-specific biomarkers may enable state- and timing-informed InfA interventions and provide a foundation for precision geroscience. This article is part of the theme issue 'Developmental circuits in ageing'.