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<p>Cellular aging is characterized by the progressive accumulation of intracellular damage, declining repair capacity, and altered mechanochemical signaling, ultimately leading to cellular senescence and loss of tissue homeostasis. Despite extensive experimental and theoretical efforts, the fundamental origin of senescence and its irreversible nature remain incompletely understood. In particular, it is unclear whether senescence must be imposed as a predefined cellular state or can instead emerge dynamically from more basic damage–repair mechanisms. In this work, we propose a unified age–damage structured mathematical framework for cellular aging that integrates intracellular damage accumulation, biochemical signaling, mechanical stress, and population renewal within a thermodynamically consistent variational structure. The model combines continuum thermodynamics with age–structured population dynamics, ensuring compliance with the second law of thermodynamics and providing a rigorous basis for irreversible aging processes. A central result of the model is the emergence of a damage-driven loss of homeostasis at a critical threshold of effective load, beyond which no steady intracellular damage state exists. This transition generates irreversibility at the single-cell level and propagates to the population scale through transport in age–damage space, leading naturally to the emergence of cellular senescence without introducing ad hoc senescence rules. Mechanical stress enters the model through a quadratic contribution to the effective damage load, producing a pronounced nonlinear sensitivity and predicting abrupt acceleration of aging beyond a critical stress level. To facilitate analysis and computation, we derive a reduced ODE–PDE system that retains the essential couplings between damage accumulation, biochemical signaling, mechanical stress, and population renewal. Analytical arguments and numerical illustrations demonstrate how transient mechanical or biochemical perturbations can induce persistent senescence at the population level. Overall, the proposed framework provides a mechanistic and thermodynamically grounded explanation of irreversible senescence as an emergent phenomenon in age-structured cell populations.</p>

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Damage-Driven Irreversibility and Emergent Senescence in Age–Structured Cell Populations

  • 期刊论文

  • 发表日期：

    2026年5月19日

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  • Koffi Enakoutsa

摘要

Cellular aging is characterized by the progressive accumulation of intracellular damage, declining repair capacity, and altered mechanochemical signaling, ultimately leading to cellular senescence and loss of tissue homeostasis. Despite extensive experimental and theoretical efforts, the fundamental origin of senescence and its irreversible nature remain incompletely understood. In particular, it is unclear whether senescence must be imposed as a predefined cellular state or can instead emerge dynamically from more basic damage–repair mechanisms. In this work, we propose a unified age–damage structured mathematical framework for cellular aging that integrates intracellular damage accumulation, biochemical signaling, mechanical stress, and population renewal within a thermodynamically consistent variational structure. The model combines continuum thermodynamics with age–structured population dynamics, ensuring compliance with the second law of thermodynamics and providing a rigorous basis for irreversible aging processes. A central result of the model is the emergence of a damage-driven loss of homeostasis at a critical threshold of effective load, beyond which no steady intracellular damage state exists. This transition generates irreversibility at the single-cell level and propagates to the population scale through transport in age–damage space, leading naturally to the emergence of cellular senescence without introducing ad hoc senescence rules. Mechanical stress enters the model through a quadratic contribution to the effective damage load, producing a pronounced nonlinear sensitivity and predicting abrupt acceleration of aging beyond a critical stress level. To facilitate analysis and computation, we derive a reduced ODE–PDE system that retains the essential couplings between damage accumulation, biochemical signaling, mechanical stress, and population renewal. Analytical arguments and numerical illustrations demonstrate how transient mechanical or biochemical perturbations can induce persistent senescence at the population level. Overall, the proposed framework provides a mechanistic and thermodynamically grounded explanation of irreversible senescence as an emergent phenomenon in age-structured cell populations.