Randomly occurring mutations to nuclear DNA accumulate with age. While DNA repair machinery in the cell nucleus has evolved to be highly efficient, nonetheless some fraction of the damage accumulated via radiation and molecular interactions slips through. There is considerable debate over the degree to which the accumulation of mutations contributes to degenerative aging, and which effects are important. Clearly mutation burden increases risk of cancer, that conclusion is solid and well supported: the more mutations, the more likely it is that a cancerous combination of mutations will occur. Going beyond this, matters become less clear, however.
The current consensus on this subject is that mutations occurring in stem cell populations is important, as these mutations can spread throughout a tissue via the daughter cells created by mutated stem cells. One sees patchy waves of mutational combinations arising with age in tissues throughout the body, a phenomenon called somatic mosaicism. There is at least some correlational evidence to link somatic mosaicism with a few age-related conditions, but it is by no means a foregone conclusion that it does provide an important contribution to general metabolic dysfunction.
Many varieties of malfunction in DNA repair produce both an accelerated accumulation of mutations and the appearance of accelerated aging. It is important to note that one can argue over whether this is in fact accelerated aging, versus just an excessive accumulation of a form of damage that plays a lesser role (or even possibly insignificant role, yet to be robustly determined either way) in normal aging. It is possible that researchers will ultimately learn little of importance from DNA repair deficiencies, for all that the research community makes a great deal of use of this phenomenon in animal models in order to obtain support for theories of aging relating to DNA damage.
One final thought on DNA damage is the more recent work suggesting that the damage is important insofar as it produces double strand breaks, as repeated repair of these breaks acts to alter epigenetic marks and the structure of DNA regardless of the location of this damage in the genome. This model dispenses of the idea that random breakage in gene sequences, largely only important where it is spread though somatic mosaicism, is collectively causing metabolic dysfunction. Instead, the repeated act of repair causes the epigenetic changes to gene expression that are characteristic of aging in all cells throughout the body. This also is work in need of confirmation and further exploration.
Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength
Aging is linked to reduced tissue function and regeneration, with genomic instability, marked by accumulating somatic mutation, being a key hallmark. These mutations, arising from replication errors or DNA repair defects, are not inherited but lead to tissue mosaicism. Although genome instability and DNA damage have been characterized in aging, the functional role of somatic mutation accumulation in age-related tissue decline and age-related diseases beyond cancer remains less explored.
Whole-genome sequencing (WGS) studies have shown that somatic mutations accumulate with age in human skeletal muscle progenitor cells and other tissues, with similar observations in most tumor types. Differentiated cells often carry even higher mutation loads, highlighting the underestimated extent of age-related somatic mutagenesis. Although we previously showed that high mutation burden impairs satellite cell (SC) function in vitro, in vivo evidence for the role of somatic mutations in muscle tissue function remains limited.
Aged human cells, including SCs, show structural genetic variations such as chromosomal aberrations, single-nucleotide variants (SNVs), and short insertions/deletions (InDels). To model this, we generated muscle somatic mutator (MSM) mice by deleting the DNA repair genes Msh2 and Blm specifically in SCs. This allowed us to assess how elevated DNA damage and somatic mutations affect muscle regeneration following injury. These mice exhibited impaired muscle regeneration, characterized by smaller muscle fibers, reduced muscle mass gain, and decreased grip strength. Importantly, similar muscle deficits were observed in a second mouse model where somatic mutations were elevated with less substantial DNA damage. These findings provide evidence that the accumulation of somatic mutations can potentially compromise the function of somatic cells, contributing to the aging phenotype in skeletal muscle.
View the full article at FightAging
