A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA.
Human diploid fibroblast cells can divide for only a limited number of times in vitro, a phenomenon known as replicative senescence or the Hayflick limit. Variability in doubling potential is observed within a clone of cells, and between two sister cells arising from a single mitotic division. This strongly suggests that the process by which cells become senescent is intrinsically stochastic. Among the various biochemical mechanisms that have been proposed to explain replicative senescence, particular interest has been focussed on the role of telomere reduction. In the absence of telomerase--an enzyme switched off in normal diploid fibro-blasts-cells lose telomeric DNA at each cell division. According to the telomere hypothesis of cell senescence, cells eventually reach a critically short telomere length and cell cycle arrest follows. In support of this concept, forced expression of telomerase in normal fibroblasts appears to prevent cell senescence. Nevertheless, the telomere hypothesis in its basic form has some difficulty in explaining the marked stochastic variations seen in the replicative lifespans of individual cells within a culture, and there is strong empirical and theoretical support for the concept that other kinds of damage may contribute to cellular ageing. We describe a stochastic network model of cell senescence in which a primary role is played by telomere reduction but in which other mechanisms (oxidative stress linked particularly to mitochondrial damage, and nuclear somatic mutations) also contribute. The model gives simulation results that are in good agreement with published data on intra-clonal variability in cell doubling potential and permits an analysis of how the various elements of the stochastic network interact. Such integrative models may aid in developing new experimental approaches aimed at unravelling the intrinsic complexity of the mechanisms contributing to human cell ageing.
Sozou
P D
PD
Department of Operational Research, London School of Economics and Political Science, Houghton Street, London WC2A 2AE, UK. p.sozou@ncl.ac.uk
Kirkwood
T B
TB
D018929:Cell Culture Techniques; D002455:Cell Division / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D003198:Computer Simulation; D004247:DNA / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D018384:Oxidative Stress / Q000502:physiology*; D013269:Stochastic Processes; D016615:Telomere / Q000502:physiology*
D004272:DNA, Mitochondrial; D004247:DNA