Arguing for the Role of Nuclear DNA Damage in Aging
There is some debate over whether the accumulation of damage to nuclear DNA contributes meaningfully to degenerative aging. It certainly raises the odds of cancer, but are its effects beyond that significant? Here is an open access paper in search of evidence, in which the authors suggest that epigenetic changes in individual cells result from repair of significant forms of damage such double strand breaks. The theory is that a growing disarray in cellular behavior is caused by scattered mutations and epigenetic changes, and this disarray contributes to aging, for example via degrading the ability of stem cells to maintain tissues - but again there are the questions of degree, and whether this sort of thing is significant in comparison to the other causes of aging:
The DNA damage theory of aging postulates that the main cause of the functional decline associated with aging is the accumulation of DNA damage, ensuing cellular alterations and disruption of tissue homeostasis. Stem cells are at high risk of accumulating deleterious DNA lesions because they are so long-lived. Such damage may limit the survival or functionality of the stem cell population and may even initiate or promote carcinogenesis.The ultra-high resolution of transmission electron microscopy (TEM) offers the intriguing possibility of detecting core components of the DNA repair machinery at the single-molecule level and visualizing their molecular interactions with specific histone modifications. We showed that damage-response proteins [such as] 53BP1 can be found exclusively at heterochromatin-associated DNA double-strand breaks (DSBs).
Using 53BP1-foci as a marker for DSBs, hair follicle stem cells (HFSCs) in mouse epidermis were analyzed for age-related DNA damage response (DDR). We observed increasing amounts of 53BP1-foci during the natural aging process independent of telomere shortening [suggesting] substantial accumulation of DSBs in HFSCs. Electron microscopy [showed] multiple small 53BP1 clusters diffusely distributed throughout the highly compacted heterochromatin of aged HFSCs.
Based on these results we hypothesize that these lesions were not persistently unrepaired DSBs, but may reflect chromatin rearrangements caused by the repair or misrepair of DSBs. Collectively, our findings support the hypothesis that aging might be largely the remit of structural changes to chromatin potentially leading to epigenetically induced transcriptional deregulation.