Rethinking inflammaging: spatiotemporal decoupling and the failure of inflammatory regulation

Chronic low-grade inflammation (inflammaging) is a central feature of aging, yet its magnitude and trajectory vary substantially among individuals and tissues. This variability is not fully explained by chronological age or cumulative inflammatory exposure. We therefore examine inflammaging through a spatiotemporal framework focused on how inflammatory responses are initiated, contained, resolved, and distributed across tissues. The framework integrates established mechanisms-including defective resolution, epigenetic drift, cellular senescence and the senescence-associated secretory phenotype (SASP), cytosolic DNA sensing, inflammasome activation, cytokine dysregulation, and loss of immunometabolic flexibility. We use the term spatiotemporal decoupling to describe the observable divergence between chronological age and inflammatory state across time, tissues, and individuals. The term does not denote a newly discovered molecular pathway; its value lies in organizing existing evidence around failures of regulatory closure and in generating testable predictions about inflammatory persistence and tissue heterogeneity. This perspective suggests that systemic inflammatory markers alone are unlikely to identify the mechanism sustaining inflammation in a given patient or tissue. Therapeutic strategies should therefore be matched to the dominant process and disease context, with attention to tissue delivery, host defense, repair, and other consequences of pathway inhibition. Candidate approaches include restoration of resolution, modulation of senescent-cell burden or SASP, selective control of innate immune sensing and cytokine signaling, and improvement of metabolic flexibility. Overall, the review distinguishes established components of inflammaging from their proposed integration in a spatiotemporal model and identifies the evidence needed to test its translational relevance.