DNA Damage Theory of Aging - Mutation Theories of Aging

Mutation Theories of Aging

A popular idea, that has failed to gain significant experimental support, is the idea that mutation, as distinct from DNA damage, is the primary cause of aging. As discussed above, mutations tend to arise in frequently replicating cells as a result of errors of DNA synthesis when template DNA is damaged, and can give rise to cancer. However, in the mouse there is no increase in mutation in the brain with aging (Dolle et al., 1997; Stuart et al., 2000; Hille et al., 2005). Mice defective in a gene (Pms2) that ordinarily corrects base mispairs in DNA have about a 100-fold elevated mutation frequency in all tissues, but do not appear to age more rapidly (Narayanan et al., 1997). On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation (Dolle et al., 2006).

One variation of the idea that mutation is the basis of aging, that has received much attention, is that mutations specifically in mitochondrial DNA are the cause of aging. Several studies have shown that mutations accumulate in mitochondrial DNA in infrequently replicating cells with age. DNA polymerase gamma is the enzyme that replicates mitochondrial DNA. A mouse mutant with a defect in this DNA polymerase is only able to replicate its mitochondrial DNA inaccurately, so that the mutation rate is 500-fold higher than in normal mice. Yet these mice showed no obvious features of rapidly accelerated aging (Vermulst et al., 2007). The probable explanation for the apparent lack of effect of the additional mutations in mitochondrial DNA is that, within a typical cell, there are large numbers of mitochondria and each mitochondrion can have multiple copies of mitochondrial DNA. Since most mutations are recessive, any particular deleterious mutation would not be expected to have a pronounced effect when many copies of the correct DNA sequence are present in the same and in other mitochondria in the cell. Overall, the observations discussed in this section indicate that mutations are not the primary cause of aging.