Rat Anaïs, Martinez Fernandez Veronica, Doumic Marie, Teixeira Maria Teresa, Xu Zhou
Aix Marseille Univ, CNRS, I2M, Centrale Marseille, Marseille, France.
Sorbonne Université, CNRS, Université de Paris, Inria, Laboratoire Jacques-Louis Lions UMR7598, Paris, France.
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 composition 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.
端粒缩短最终会导致复制性衰老。然而，由于端粒长度的异质性和衰老起始的不同步性，确定细胞群体中驱动复制性衰老的机制具有挑战性。在此，我们提出了一个酿酒酵母中端粒缩短和复制性衰老的数学模型，该模型使用端粒酶缺陷型单细胞的数据进行了定量校准和验证。对酵母群体的模拟表明，具有不同增殖能力的细胞相互竞争，初始群体的端粒长度分布塑造了群体生长，特别是通过细胞最短端粒长度的分布。我们还量化了独立于端粒影响细胞活力的因素如何影响衰老速率。总体而言，我们证明了衰老细胞群体组成的时间演变——从与临界短端粒直接相关的状态到衰老起始变得随机的状态。这种群体结构可能会促进基因组不稳定并促进衰老逃逸。
