The initiation of senescence and its relationship to embryonic cell differentiation

Mouse embryonic stem cells have an unlimited lifespan in cultures if they are prevented from differentiating. After differentiating, they produce cells which divide only a limited number of times. These changes seen in cultures parallel events that occur in the developing embryo, where immortal embryonic cells differentiate and produce mortal somatic ones. The data strongly suggest that differentiation initiates senescence, but this view entails additional assumptions in order to explain how the highly differentiated sexual gametes manage to remain potentially immortal. Cells differentiate by blocking expression from large parts of their genome and it is suggested that losses or gains of genetic totipotency determine cellular lifespans. Cells destined to be somatic do not regain totipotency and senesce, while germ-line cells regain complete genome expression and immortality after meiosis and gamete fusions. Losses of genetic totipotency could induce senescence by lowering the levels of repair and maintenance enzymes.