THE 2-PROCESS MODEL OF CELLULAR AGING

To understand the mechanism of aging at the cellular level, cellular s enescence has been extensively studied as an experimental model of agi ng in vitro. Although several hypotheses have been proposed for the me chanism of cellular senescence, none of them could give a comprehensiv e framework to the mechanism. In this study, we showed our results of extensive computer simulation designed to identify possible molecular models of cellular senescence. By examining representative cases of va rious molecular models, we elucidated the requirements for the plausib le mechanism of cellular senescence. Based on these simulation results , we proposed a new molecular model of cellular senescence-the two-pro cess model. In this model, we assumed that two independent, but time-a ligned regulatory processes functioned in individual cells. We defined these two processes as S- and C-processes. The S-process mainly deter mines the rate of decline in the proliferative potential of the cell p opulation. The simulation results suggested that the growth-inhibitory cell-to-cell interaction was required to drive the S-process. The C-p rocess determines the latent proliferative potential of individual cel ls. The effector genes for the C-process are suggested to be regulated by a certain threshold-type mechanism. Both growth kinetics and senes cence-associated gene expression were generated with high accuracy by the combined effect of these two processes. We also succeeded in simul ating the effects of simian virus 40 large T antigen and its inducible variant on cellular senescence. From these theoretical considerations , we discuss the validity of the two-process model and the possible in volvement of the heterochromatin structure as a determinant of the rep licative lifespan of cells. (C) 1998 Elsevier Science Inc.