Fight Aging!

Mutational damage occurs constantly to nuclear DNA throughout life. Little of that damage goes unrepaired, and little of the lasting breakage occurs in active parts of the genome. Where mutations go unrepaired in active parts of the genome, little of that occurs in important genes. Where it does occur in important genes, that only matters to the extent that (a) the mutation can spread, and (b) the mutation is potentially cancerous. Comparatively few cells in the body have the capacity to create many descendant cells through replication, as the Hayflick limit ensures that near all cells are limited in the number of times they can divide. The cell population of most tissues turns over with time, removing mutations.

Nonetheless, mutations in precursor cell and stem cell populations, responsible for generating new somatic cells to support a given tissue, can lead to patchwork patterns of those mutations spread throughout the tissue. This is known as somatic mosaicism, and it most likely makes some contribution to both cancer risk and altered tissue function with age.

Beyond this, a more recent suggestion is that double strand breaks, regardless of where in the genome they occur, can deplete cellular resources in ways that provoke epigenetic changes characteristic of aging. This work needs replication and greater support, but it would provide a convenient way to directly link mutation rate with contributions to degenerative aging, explaining many of the observations linking mutational burden with degree of aging. Otherwise, it is challenging to explain why a large fraction of age-related dysfunction should result from mutation, given that the vast majority of mutations don't seem to have much of an effect on cell and tissue function.

Age-related somatic mutation burden in human tissues

There is now absolute consensus that somatic mutations accumulate with age in many if not all human tissues, independent of the method used for mutation evaluation. The mutation frequencies in human tissues and the increase with age are dependent on multiple factors, including environmental mutagens, such as exposure to sun and tobacco smoke.

Importantly, the accumulation rate of somatic mutations in humans differs significantly among different tissues. In this respect, the two extremes are germ tissue and colorectal crypts. The possible reasons are multiple, but the main one seems to be driven by the length of time needed for a cell or tissue type to function. This is likely why germ tissue has a very low somatic mutation burden and the expendable colonic crypts are tolerant for mutation accumulation. The intestinal epithelium is one of the most rapidly dividing regions of cells in the human body and mutations easily accumulate as replication errors. Also tissues exposed directly to high levels of exogenous genotoxicity harbor heavier mutation burdens, such as liver, skin, and lung.

Accumulation of somatic mutations will result in intra-tissue genetic heterogeneity, known as genome mosaicism. Thus far, the impact of genome mosaicism on the aging phenotype, other than cancer, remains unclear. Cancer risk increases exponentially as a function of age in both humans and animals through a mechanism of repeated cycles of somatic mutation (often in interaction with germline variants) and selection for a range of characteristics, including growth, tissue invasion, immune suppression, and metastasis. Accumulating somatic mutations are likely to play a role in the age-related increase in tumor incidence.

Elsewhere we proposed three possible general mechanisms for a functional impact of age-accumulated somatic mutations: (1) clonal expansion, (2) somatic evolution, and (3) mutational networking. The first two are based on clonal expansion of a mutation, either because of a selective advantage or genetic drift. They include hyperplastic or neoplastic disease, although mutations that occur early enough can have late-life effects on postmitotic tissues as well. The third possibility involves the actual adverse effects of high mutation burden on cell functioning, possibly through destabilization of gene regulatory networks. Genomes are robust and redundancy buffers them against mutations. However, when the mutation burden rises to very high levels, the functional organization of genomes in multiple regulatory sequences serving networks of extensively interacting genes will amplify the effects of mutations.