The study noted here provides numbers for the mutation rates in muscle stem cells, the stochastic damage that occurs over time as small numbers of errors slip past the highly efficient molecular machinery of cellular replication and DNA repair. The researchers used single cell genomic sequencing, a very useful and still comparatively new capability. It produces a much more detailed view of the state of nuclear DNA inside a cell population, showing the enormous variations in stochastic mutational damage that takes place over the years. Every cell has thousands of different areas of damage in their DNA, and it is becoming apparent that the damage in stem cell populations is cloned out into tissues. Stem cells maintain tissues by providing a supply of somatic cells, and those somatic cells divide many times before they reach the Hayflick limit. So the mutations present in a stem cell will over time propagate into a fraction of the supported tissue.
Is this important? Mutation in nuclear DNA is certainly a contributing cause of cancer, though it can be argued that the decline of the immune system - responsible for killing cancers before it gets underway - is actually more significant than mutations when it comes to the age-related nature of cancer risk. One can look at the numbers for mutational damage in old cells and it sounds fairly horrific out of context, but everything irelated cells and cellular biochemistry involves huge numbers. We know that nuclear DNA becomes more mutated over time, and we know that many of the methods of slowing aging, such as calorie restriction, produce reduced levels of mutation at a given age in comparison to normally aging individuals. However: at present there is no compelling causal evidence to show that nuclear DNA damage alone has a significant effect over the present human life span in comparison to other contributions to degenerative aging. If anything, the slight tilt in the present indirect evidence is in the opposite direction, towards skepticism for a significant role over the present human life span.
Nonetheless, it is the present consensus that nuclear DNA damage does cause meaningful metabolic dysfunction; a lot of research proceeds upon this assumption. The authors of the open access paper here are quite ready to theorize a connection between stem cell mutation level and age-related declines in muscle mass and strength, but their data only shows a correlation. A great many things happen over the course of aging, and not all are directly connected to one another: aging is a tree, a spreading set of damage and issues stemming from a few root causes. The far branches will appear correlated even if they have little to do with one another.
I'm in the camp of those who would like to see more work directed towards the production of a compelling demonstration to show that nuclear DNA damage either is or is not a major factor in aging beyond cancer risk. The best way to do that is to repair a significant amount of the damaged DNA, but that is exceptionally challenging, beyond present capabilities. It might be possible in the near future to use one of the new forms of genetic technology to tackle the clonal expansions of specific mutations, provided there are only a few of them and they are present in large numbers of cells. Once we start talking about scores or hundreds of mutations, however, then that is just not a near term prospect. So a less direct approach is called for, something clever yet to be assembled, that will be obvious in hindsight to the rest of us.
It has already been established that natural ageing impairs the function of our skeletal muscles. We also know that the number and the activity of the muscles' stem cells decline with age. However, the reasons for this has not been fully understood. In a new study, researchers have investigated the number of mutations that accumulate in the muscle's stem cells (satellite cells). "What is most surprising is the high number of mutations. We have seen how a healthy 70-year-old has accumulated more than 1,000 mutations in each stem cell in the muscle, and that these mutations are not random but there are certain regions that are better protected."
The researchers have benefited from new methods to complete the study. The study was performed using single stem cells cultivated to provide sufficient DNA for whole genome sequencing. The mutations occur during natural cell division, and the regions that are protected are those that are important for the function or survival of the cells. Nonetheless, the researchers were able to identify that this protection declines with age. "We can demonstrate that this protection diminishes the older you become, indicating an impairment in the cell's capacity to repair their DNA. And this is something we should be able to influence with new drugs."
"We achieved this in the skeletal muscle tissue, which is absolutely unique. We have also found that there is very little overlap of mutations, despite the cells being located close to each other, representing an extremely complex mutational burden." The researchers will now continue their work to investigate whether physical exercise can affect the number of accumulated mutations. Is it true that physical exercise from a young age clears out cells with many mutations, or does it result in the generation of a higher number of such cells?
Satellite cells (SCs) are a heterogeneous population of stem and progenitor cells that have been demonstrated to play a pivotal role in skeletal muscle (SkM) regeneration. The SCs are normally kept in a quiescent state and activated upon exposure to stimuli, such as exercise or SkM injury. When committed to myogenic differentiation, SCs proliferate further, fuse to existing SkM fibers, and contribute new nuclei to the growing and regenerating fibers. Aged human SkMs show a decline in the number and proliferative potential of the SCs. As a consequence, a dysfunctional SC compartment is envisaged as a major contributor to age-related defects, including reduced capacity to respond to hypertrophic stimuli such as exercise and impaired recovery from muscle disuse and injury.
A well-known factor in the decline of stem cell function is the loss of genome integrity, for example, caused by the appearance of somatic mutations. These modifications of the genome range from single-base changes (single-nucleotide variants) to insertions or deletions of a few bases (indels) to chromosomal rearrangements and occur during the whole life, starting from the first division of the embryo. In contrast to germline variants, somatic variants are not propagated to the whole individual but to a subpopulation of cells in the body, with the final consequence that adult human tissues are a mosaic of genetically different cells. Moreover, somatic mutation burden increases during a lifetime as a result of accumulating errors occurring either during cell division or because of environment-induced DNA damage. At present, nothing is known about somatic mutation burden in human SCs or SkM.
Here, we investigate the genetic changes that occur with aging in the genome of human adult SCs and use the results to elucidate mutational processes and SC replication rate occurring in vivo in adult human muscles. We assess the functional effects of somatic mutations on SC proliferation and differentiation and predict the global consequence on muscle aging and sarcopenia. Our analyses reveal an accumulation of 13 mutations per genome per year that results in a 2-3-fold higher mutation load in active genes and promoters in aged SCs. High mutation burden correlates with defective SC function. Overall, our work points to the accumulation of somatic mutations as an intrinsic factor contributing to impaired muscle function with aging.