A two-step hypothesis on the mechanisms of in vitro cell aging: cell differentiation followed by intrinsic mitochondrial mutagenesis.

Despite vigorous research, there is yet no agreement on the biochemical mechanisms responsible for the loss of replicative potential of diploid cultured cells. In contrast to the program theories of in vitro cell aging, we propose that, as already suggested by Minot in 1907, senescence is the result of cell differentiation. We further maintain that the fundamental cause of cell aging is an instability of the mitochondrial genome because of a lack of balance between mitochondrial repair and the disorganizing effects of oxygen radicals which arise in the respiring mitochondria of terminally differentiated cells. This probably results in intrinsic mitochondrial mutagenesis which may be followed by endonuclease degradation of the altered mitochondrial DNA. Since the mitochondrial genome controls the synthesis of several hydrophobic proteins of the inner mitochondrial membrane, the postulated denaturation or loss of mtDNA will prevent the replication of the organelles. Thus, deprived of the ability to regenerate their mitochondrial populations, the cells will sustain an irreversible decline in their ability to synthesize ATP, with concomitant senescent degradation of physiological performance and eventual death.