Beyond senescence entry: Individual-cell fates, population outcomes and therapeutic implications in ageing and...

Cellular senescence is a stress-response program characterized by durable proliferative arrest, but senescence entry does not determine a single biological outcome. Confusion between the fate of an individual cell and the behavior of a senescent-cell population has obscured interpretation across development, ageing and disease. This Review develops a fate-resolved framework that distinguishes continued arrest, cell death, physical shedding and, under restricted conditions, sustained proliferative recovery from population-level resolution or persistence. We reserve senescence escape for sustained proliferation by the same cell or lineage after validated senescence entry; failed resolution is instead one process that can produce persistence. We examine how checkpoint integrity, chromatin organization, metabolism, secretory signaling and immune surveillance shape these outcomes in development, tissue repair, ageing-associated disorders and cancer. The strength of evidence differs sharply by context. Longitudinal cancer models provide the clearest support for strict escape, alongside a restricted developmental lineage-tracing example, whereas fibrosis, neurodegeneration and metabolic or vascular disease more often support population persistence or impaired resolution without demonstrated cell-cycle re-entry. Accordingly, static markers, single-cell and spatial profiles, and computational trajectories can identify senescence-associated states but cannot establish subsequent fate without lineage tracing, live imaging or equivalent temporal evidence. Therapeutic strategies should therefore be matched to the dominant biological problem: preserving beneficial physiological senescence, resolving or modulating harmful persistent populations, or preventing recovery of residual senescent tumour cells. Because most approaches remain preclinical or early-stage, translation will require appropriate timing, cell-type specificity and protection of beneficial senescent populations.