Somatic mutations in aging, cancer and neurodegeneration

Abstract

The somatic mutation theory of aging posits that the accumulation of mutations in the genetic material of somatic cells as a function of time results in a decrease in cellular function. In particular, the accumulation of random mutations may inactivate genes that are important for the functioning of the somatic cells of various organ systems of the adult, result in a decrease in organ function. When the organ function decreases below a critical level, death occurs. A significant amount of research has shown that somatic mutations play an important role in aging and a number of age related pathologies. In this review, we explore evidence for increases in somatic nuclear mutation burden with age and the consequences for aging, cancer, and neurodegeneration. We then review evidence for increases in mitochondrial mutation burden and the consequences for dysfunction in the disease processes.

Figure 1. Accumulation of somatic mutations during cancer formation

During normal organismal aging, cells (blue) are continually exposed to DNA damaging events, that eventually results in cells harboring multiple mutations (red). Some mutations occur in regions of the genome that lead to uncontrolled cell proliferation. The acquisition of a mutator phenotype allows for more rapid somatic evolution that continually acts to select for cells able to bypass many of the defense mechanisms that limit unrestricted cell proliferation.

Figure 2. Heavy mutation load limits the lifespan and health-span of mutator mice

Due to the dramatically reduced lifespan of these mutator mice, it has not been established whether they age more rapidly than do wild type mice. WT=wild-type; Pole^e/e=homozygous exonuclease deficient pol ε; Pold1^e/e=homozygous exonuclease deficient pol δ. Data are reported in Albertson et. al.