Threshold control of growth arrest in quiescence and senescence: implications for cell fate plasticity in aging and cancer

For decades, cellular senescence has been treated as a terminal cell fate defined by durable proliferative arrest and a pro-inflammatory secretory program. Quiescence, by contrast, has been viewed as a reversible, metabolically restrained state that enables tissue homeostasis and stem cell maintenance. Rather than treating these as categorically distinct fates, recent work across aging, stem cell, and cancer biology suggests that arrested cells continuously evaluate whether to maintain a reversible state, progress toward stable senescent arrest, or re-enter proliferation. These outcomes are governed not by categorical state identity alone, but also by switch-like regulatory behavior within stress-response networks integrating cellular stress, metabolic capacity, and quality-control machinery. This perspective reframes quiescence and senescence not as categorically distinct endpoints, but as positions along a continuum of arrested states defined by their stability and by the magnitude of the perturbation required to reverse them. Importantly, this reframing does not diminish the biological complexity of senescence. Features that distinguish senescent cells from quiescent cells, including the senescence-associated secretory phenotype (SASP), metabolic reprogramming, and chromatin remodeling, are retained as active, context-dependent components of the senescent program. Within this framework, senescence is viewed not as a unique or exceptional state, but as one outcome within a broader landscape of cell-cycle exit decisions. Consequently, cellular fate is better understood as a dynamic balance between damage accumulation and the capacity of quality-control systems to preserve reactivation competence. We propose a Maintenance Threshold Model (MTM) in which arrest-state stability emerges from the balance between maintenance capacity and accumulated cellular stress. Rather than pooling these inputs, the model proposes that they are gated in series, such that proteostatic and organellar maintenance capacity determines whether an arrested cell can complete division independently of whether the Rb-E2F restriction point is traversed. It further proposes that senescent-cell persistence is set by two independent, aging-sensitive thresholds: cell-autonomous maintenance capacity and non-cell-autonomous immune surveillance. We introduce a therapeutic framework comprising three strategies; state-locking, metabolic inflexibility targeting, and program hijacking, that exploit fate plasticity for cancer treatment and aging interventions. This review develops a decision-centric framework in which quiescence, senescence, and proliferation emerge as dynamically stabilized states shaped by tunable regulatory thresholds rather than fixed endpoints.