Senescence: a stochastic molecular control theory.

A theoretical model of transcriptional control, in a preliminary form, is presented. The model has a critical boundary between a region of values in which the system is stable and essentially self-perpetuating and a region in which the essential macromolecules tend to disappear and not to be regenerated. The possibility of the transition results from cell division. Variation in the values of kinetic parameters or fluctuation in the partition of the macromolecules between the daughter cells of a division subject some cells in the population to the instability. Cells on the wrong side of the critical boundary may accumulate in G2, and will eventually die, at rates and frequencies depending on the specific peculiarities of various cell types (e.g., tissues). Such phenomena, in association with the characteristic division patterns predicted by the theory, have been observed in vitro and in vivo. "Programmed death" in morphogenesis may be an instance. Problems in the future development of the theory are outlined. The significance of clonal selection for atherogenesis and perhaps oncogenesis is noted. The theory is briefly contrasted with "damage" and "error" theories; and the eventual possibility of constructive intervention in ageing at the molecular level is suggested.