Modeling the Role of Mitochondrial Mutations in Cellular Aging

Abstract

The mitochondrial theory of aging suggests that an accumulation of defective mitochondria leads to loss of cell viability. The challenge is to explain how mitochondrial defects accumulate within cells, and why this process is more evident in postmitotic than in dividing cells. We describe a new mathematical model incorporating two critical features: (a) defective mitochondria are turned over more slowly than intact ones, and (b) defective mitochondria suffer a growth disadvantage. We also model the effect of cell division on the accumulation of defective mitochondria. The results support the mitochondrial theory and explain many of the observed data. The relationship of the mitochondrial theory to the suggested role of telomere loss in cell replicative senescence is discussed. We suggest that because of differences in the kinetics of their impact on cells, these two mechanisms have different relative importance for in vivo and in vitro cell aging.