Systems-level modelling of DNA damage, senescence, and stem cell dynamics in ageing

Ageing entails a variety of cellular and physiological changes that increase susceptibility to disease and death. A significant contributor to ageing is cellular senescence, a state of irreversible cell cycle arrest triggered by stressors such as DNA damage, telomere shortening, and the senescence-associated secretory phenotype. It is challenging to understand the nonlinear interactions between these complex mechanisms using conventional laboratory approaches. Mathematical modelling is capable of representing this complexity. In this study we introduce a mathematical model that captures the dynamics of cellular ageing within a population of cells. The model integrates key processes including DNA damage repair, senescence, quiescence, apoptosis, and cell division. The model was used to simulate the effects of ageing and to evaluate the efficacy of several interventions, including senolytics, telomere length preservation, and stem cell therapy. Deterministic and stochastic simulations reproduce core ageing features: progressive accumulation of senescent cells, a generation distribution centred near experimentally observed Hayflick limits, and an exponential-like age distribution of non-senescent cells. This model captures the long-lasting effects of interventions such as telomere lengthening and stem-cell therapy. It offers a quantitative, extendable platform that supports hypothesis testing and helps identify which ageing interventions warrant experimental validation. Overall, it provides a predictive framework for interpreting cellular ageing and for guiding future experimental work.