Predictions of the somatic mutation and mortalization theories of cellular ageing are contrary to experimental observations

Abstract

An accumulation of recessive lethal somatic mutations has often been proposed as a basis of cellular ageing. We have developed a mathematical model for the somatic mutation theory as applied to the finite in vitro lifespan of diploid fibroblast populations. Provided the mutation rate is sufficiently high, the model readily explains the cessation of proliferation of fibroblast cultures, but it predicts a much lower proportion of viable cells than is observed experimentally and also requires an unrealistically short cell division time. It is noted that the somatic mutation model is formally quite similar to the “mortalization” theory of Shall & Stein (1979), and that the mortalization theory is also incompatible with the same experimental data. We conclude that neither the somatic mutation theory nor the mortalization theory can explain the observed features of the growth of fibroblast populations in vitro. We discuss the possibility that deleterious mutations become important in the terminal stages of the lifespan, when they may accumulate as an indirect result of a general breakdown in information transfer between macromolecules.