"Demographic and Evolutionary Consequences of Damage Dynamics in Single-Cell Ageing"Tugrul, MuratAgeing plays an important role in evolutionary dynamics by affecting the fitness components of individuals and changing the fate of newly arriving mutations. At the molecular level, ageing is driven by damage accumulation leading to a decline in function over time. This damage accumulation is not only inherently stochastic but also — in the case of damage partitioning at cell divisions — asymmetric. Despite empirical single-cell studies providing quantitative data at the molecular and demographic level, there is not a comprehensive theory of how cellular damage production and asymmetric partitioning lead to demographic patterns. We develop a generic and flexible damage model using a stochastic differential equation approach which can be scaled further to population and evolutionary scales. Our model incorporates stochastic damage accumulation and asymmetric damage partitioning at cell divisions. We formulate an analytical approximation linking cellular and damage parameters to demographic functions such as mortality rates. This allows us to show explicitly how stochasticity (noise) in damage production, asymmetry in damage partitioning, and division frequency shape lifespans. Interestingly, the lifespan of cells follows an inverse-gaussian distribution whose underlying properties derive from cellular and damage parameters. We apply our model to various empirical E.coli data revealing non-exponential scaling in mortality rates, which cannot be captured by classical Gompertz-Makeham models. Our findings provide a deep understanding of how fundamental processes contribute to cellular damage dynamics and generate demographic patterns, and provide us with the necessary theoretical framework linking cellular damage processes to demographic, population and evolutionary dynamics. |
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