THE TWO-PROCESS MODEL OF CELLULAR AGING HIROAKI KITANO 1 and SHIN-ICHIRO IMAI 2,3 1 Sony Computer Science Laboratory, 3-14-13 Higashi-Gotanda, Shinagawa-ku, Tokyo, Japan and 2 Department of Microbiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan Abstract— To understand the mechanism of aging at the cellular level, cellular senescence has been extensively studied as an experimental model of aging in vitro. Although several hypotheses have been proposed for the mechanism of cellular senescence, none of them could give a comprehensive 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 various molecular models, we elucidated the requirements for the plausible mechanism of cellular senescence. Based on these simu- lation results, we proposed a new molecular model of cellular senescence—the two-process model. In this model, we assumed that two independent, but time-aligned regulatory pro- cesses functioned in individual cells. We defined these two processes as S- and C-processes. The S-process mainly determines the rate of decline in the proliferative potential of the cell population. The simulation results suggested that the growth-inhibitory cell-to-cell interaction was required to drive the S-process. The C-process determines the latent proliferative potential of individual cells. The effector genes for the C-process are suggested to be regulated by a certain threshold-type mechanism. Both growth kinetics and senescence- associated gene expression were generated with high accuracy by the combined effect of these two processes. We also succeeded in simulating the effects of simian virus 40 large T antigen and its inducible variant on cellular senescence. From these theoretical consider- ations, we discuss the validity of the two-process model and the possible involvement of the heterochromatin structure as a determinant of the replicative lifespan of cells. © 1998 Elsevier Science Inc. Key Words: cellular senescence, computer simulation, growth kinetics, transcription, two-process model, S-process, C-process, heterochromatin 3 Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Correspondence to: Hiroaki Kitano, Sony Computer Science Laboratory, 3-14-13 Higashi-Gotanda, Shinagawa-ku, Tokyo-141, Japan e-mail: kitano@csl.sony.co.jp, and Shin-ichiro Imai, c/o Prof. Leonard Guarente’s laboratory, Department of Biology, Building 68-283, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139-4307. E-mail: shinimai@mit.edu (Received 7 November 1997; accepted 26 January 1998.) Experimental Gerontology, Vol. 33, No. 5, pp. 393– 419, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0531-5565/98 $19.00 + .00 PII S0531-5565(98)00008-4 393