Cells are liquid bags of molecules, constantly interacting and reacting with one another. Many of those reactions are unwanted and damaging to the molecular machinery of the cell, but repair of structures and replacement of damaged molecules is also a constant and ongoing process. The most efficient repair processes are those that attend the DNA that is folded away in the cell nucleus. Despite these processes, mutational damage to nuclear DNA slips though the layered schemes of protection and repair. It has to: without that damage, evolution would not occur.
There is some debate over the degree to which nuclear DNA damage contributes to the aging process. Evidently, and well proven, it is an important reason as to why cancer is an age-related disease – due to the occurrence of mutations in cancer suppression genes, for example. Nonetheless, looking beyond the matter of cancer risk, most mutational damage occurs in places where it will do little to no harm, in unused genes in the nuclear DNA of somatic cells with few divisions remaining before they self-destruct. Still, the consensus in the research community is that sufficient disarray can be caused by random mutational damage to negatively affect the operation of metabolism and tissue function.
The primary mechanism by which random mutational damage is thought to lead to metabolic disarray is known as somatic mosaicism. When a mutation occurs in a stem cell or progenitor cell, it can spread throughout a tissue over time via the daughter somatic cells generated to support that tissue. It remains to be determined as to just how much harm is caused by somatic mosaicism, in comparison to other mechanisms of aging that are known to be important. A meaningful assessment would likely require some way to remove or reduce mosaicism, meaning identification and repair of large numbers of mutations in large numbers of cells in disparate parts of the body, which is a little beyond the capabilities of medical science at the present time.
The main argument against a causal role of random somatic mutations in aging and aging-associated disease has been that the spontaneous mutation frequency, even at an old age, is too low to impair cellular function. The exception is cancer, where particular driver mutations are selected for a growth advantage. Mutation frequencies in somatic cells have been considered to be low because estimates were based on the mutation frequencies observed in the germline of various species, including humans, as deduced from heritable changes in proteins.
However, new single-cell sequencing methods found many more mutations per cell; i.e., up to several thousands of single nucleotide variants (SNVs), depending on the age of the subject and the cell type. This suggests that the somatic mutation rate is higher than the germline mutation rate. Indeed, in a direct comparison of germline and somatic mutation rates in humans and mice, the somatic mutation rate was found to be almost 2 orders of magnitude more frequent than the germline mutation rate. To some extent, this can be explained by selection against deleterious mutations in the germline. However, most random mutations have no effect. So far there is very little insight into the mechanism through which random somatic mutations could be pathogenic in aging mammals. Here we propose that there are essentially three such mechanisms.
Clonal Expansion of Mutations in Human Disease Genes
It has been known for some time that many Mendelian genetic diseases have a somatic mutational counterpart. Somewhat surprisingly, the fraction of cells in a tissue harboring the disease-causing mutation can be as low as 1% and still show disease. In many cases, the somatic mutation confers a growth advantage to mutant cells, but often the mutation is simply clonally amplified by chance. The most dramatic example of clonal amplification of a human disease gene is an individual with sporadic early-onset Alzheimer’s disease who showed somatic mosaicism for a presenilin 1 gene mutation. The degree of mosaicism in this individual at the age of presentation was 8% in peripheral lymphocytes and 14% in the cerebral cortex.
Of course, human development and aging cannot be explained by a simple series of cell divisions, like a cell line in culture, but is subject to complex and hierarchically dictated schemes, with some cells dividing much more frequently than others and others becoming subject to apoptosis. Nevertheless, accidental somatic mutation early in development could be a significant mechanism in the etiology of human disease, alone or in combination with a germline variant. In such cases, the phenotypic effects are straightforward and associated with the known role of the target gene(s) as a germline defect. However, combinations of low-frequency disease gene mosaics could occur, in which case the phenotypic effects in terms of aging phenotypes in organs and tissues are difficult to predict.
Evolution does not only occur in populations of organisms but also in populations of cells which are genetically heterogeneous because of de novo mutations. Most attention has been focused on evolution of somatic cells in relation to the well-documented, age-related increase in cancer incidence and mortality. However, there is evidence that somatic evolution also causally contributes to age-related diseases other than cancer. Somatic evolution has also been considered a potential mechanism for cardiovascular disease, which, like cancer, is a major age-related disorder. Evidence of genomic instability in atherosclerotic cells has been reported, leading to the hypothesis that expansion of mutant cells could be a major causal factor in cardiovascular disease.
In summary, in tissues of mammals, the adaptive landscape of somatic evolution during aging is similar to the adaptive landscape of evolution but from a different perspective. Indeed, in the aging tissue, selection for fitness among individual cells tends to move them away from their optimal peak of functioning, in concert with other cells in their host, to a more selfish pattern of genetic variation. This pushes the aging process toward loss of functionality and increased risk of disease, most notably loss of proliferative homeostasis; e.g., neoplasia, fibrosis, and inflammation, long recognized as a major aging-related phenomenon.
Certain acquired gene mutations that are not by themselves disease causing can confer a selective advantage to the cell, which expands and gradually erodes organ and tissue functioning because of increasingly selfish behavior. Although the magnitude of the adverse effects of these events in aging still await more extensive studies, there is a third possible mechanism by which randomly accumulating mutations eventually affect cell fitness. This does not require clonal outgrowth and depends on the penetration of such mutations in the DNA sequence components of the gene-regulatory networks (GRNs) that provide function to a mammalian organism throughout its life. Virtually all mutations would accumulate not in the about 1% protein-coding part of the genome but in the gene-regulatory regions that make up approximately 11% of all genome sequences.
Accumulated mutations in GRNs could explain the defects in cell signaling that have been observed with age. Cells respond to environmental challenges such as temperature changes, infections, and a variety of other stressors through GRNs and their networks of regulatory interactions. Although the dynamics of these complex networks in humans are far from understood, their actions are ultimately based on genes and the regulatory sequences that control their expression.