Mathematical model linking telomeres to senescence in Saccharomyces cerevisiae reveals cell lineage versus population dynamics
Anaïs Rat, Veronica Martinez Fernandez, Marie Doumic,
Maria Teresa Teixeira & Zhou Xu
Nat Commun. 2025 Jan 25;16(1):1024. doi: 10.1038/s41467-025-56196-z
Telomere shortening ultimately causes replicative senescence. However,identifying the mechanisms driving replicative senescence in cell populations is challenging due to the heterogeneity of telomere lengths and the asynchrony of senescence onset. Here, we present a mathematical model of telomere shortening and replicative senescence in Saccharomyces cerevisiae which is quantitatively calibrated and validated using data of telomerase deficient single cells. Simulations of yeast populations, where cells with varying proliferation capacities compete against each other, show that the distribution of telomere lengths of the initial population shapes population growth, especially through the distribution of cells’ shortest telomere lengths. We also quantified how factors influencing cell viability independently of telomeres can impact senescence rates. Overall, we demonstrate a temporal evolution in the com-position of senescent cell populations from a state directly linked to critically short telomeres to a state where senescence onset becomes stochastic. This population structure may promote genome instability and facilitate senescence escape.