Chronic accumulation of senescent cells — those locked in irreversible cell cycle arrest while secreting pro-inflammatory cytokines (the SASP) — operates as a master accelerator across six organ systems: reproductive, pulmonary, hepatic, neurological, skeletal, and metabolic. The review maps how upstream hallmarks, specifically genomic instability and epigenetic dysregulation, converge to trigger senescence, and how the resulting inflammaging cascade translates into distinct age-related pathologies rather than a single uniform decline.
This synthesis arrives at a pivotal moment in geroscience. The past decade established senolytics — drugs like dasatinib plus quercetin and navitoclax — as proof-of-concept tools capable of clearing senescent cells and improving physical function in small human trials. What this framework adds is a systems-level map connecting mechanism to disease manifestation across organs, which matters enormously for clinical translation. Targeting senescence is complicated by heterogeneity: a senescent hepatocyte and a senescent neuron share the cell-cycle arrest but diverge substantially in SASP composition and surface markers, making universal senolytics blunt instruments. The review honestly flags specificity, heterogeneity, and equitable access as unresolved barriers — a candor that strengthens its roadmap value. Because this is a review rather than primary data, it generates no new effect sizes or mechanistic discoveries. Its contribution is organizational and strategic: providing researchers and clinicians a unified model to prioritize which organ-senescence axes warrant first-in-human senolytic trials targeting healthspan extension rather than disease-by-disease management.
