How does stochastic nuclear DNA damage contribute to degenerative aging? Most mutation occurs in regions of the genome that are not used, in somatic cells with few divisions remaining before the Hayflick limit and self-destruction. Thus the impact is minimal. One point of view on this topic is that only mutations in stem cells are important. These mutations spread slowly in waves throughout a tissue, replicated in the somatic cell lineages descended from mutated stem cells, a process known as somatic mosaicism. There is some evidence for somatic mosaicism to contribute to a few age-related dysfunctions, but not very much of it.
Another point of view with limited evidence, but very interesting evidence, is that the process of repairing repeated double strand breaks, wherever they occur in the genome, changes the molecular mechanisms responsible for controlling the structure of nuclear DNA in deterministic ways, such as by depleting specific factors. This leads to the characteristic epigenetic changes of aging in every cell, as every cell undergoes this form of stochastic DNA damage.
In today's open access paper, researchers propose another, quite different way in which DNA damage can be linked to epigenetic changes. The authors argue for mutational damage to the genome to directly alter epigenetic regulation of the structure of DNA. The researchers looked at mutations occurring at CpG sites where the genome is methylated to adjust its structure, and found that mutation at a CpG site doesn't just affect the methylation status of that CpG site, but also nearby sites as well, altering the expression of numerous genes in predictable way.
Why Our Biological Clock Ticks: Research Reconciles Major Theories of Aging
There are two prevailing theories about the relationship between aging and DNA. The somatic mutation theory suggests that aging is caused by the accumulation of mutations, permanent changes in our DNA sequence that occur randomly. The epigenetic clock theory suggests that aging occurs due to the accumulation of epigenetic modifications, minor changes to the chemical structure of DNA that do not alter the underlying sequence, but instead change which genes are on or off. Unlike mutations, epigenetic modifications can also be reversed in some cases.
Researchers analyzed data from 9,331 patients catalogued in the Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes. By comparing genetic mutations to epigenetic modifications, they found that mutations were predictably correlated with changes in DNA methylation, one type of epigenetic modification. They found that a single mutation could cause a cascade of epigenetic changes across the genome, not just where the mutation occurred. Using this relationship, the researchers were able to make similar predictions of age using either mutations or epigenetic changes.
Somatic mutation as an explanation for epigenetic aging
DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
View the full article at FightAging
