Beyond binary senescence: Intermediate cellular states, tissue distribution, and therapeutic implications in ageing.

Abstract

Ageing is closely linked to cellular senescence, but this relationship remains incompletely defined. Although many studies have reported age-associated increases in senescence markers, no review has systematically integrated the available quantitative data across tissues and species to clarify how senescence-associated cell populations change with age. In addition, the field has often used inconsistent definitions for intermediate and senescent states, making cross-study interpretation difficult. In this review, we synthesize evidence from replicative senescence models, human tissues, and mouse ageing studies to reframe senescence as a continuum rather than a simple binary state. We compare how intermediate-stage and senescent cells have been defined across studies, summarize their tissue distribution and relative abundance during ageing, and discuss how even numerically rare intermediate and senescent populations may exert disproportionate effects on tissue function. We further highlight the therapeutic implications of this framework, including the possibility that intermediate-stage cells represent a distinct and potentially reversible intervention window. This review provides a quantitative and conceptual framework for interpreting cellular senescence in physiological ageing.