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For instance, in nondividing cells like neurons, it seems that HR is not an option, and doublestrand breaks have to be repaired by NHEJ. The NHEJ pathway simply links the ends of a doublestrand break together, without using any strand as a template.This pathway is more error prone than the HR pathway, and it tends to insert deletions or insertions in DNA strands.Nonetheless, in mammalian cells NHEJ seems to be the main pathway for the repair of doublestrand breaks resulting from ionizing radiation. KU is one of the most abundant proteins in human cells, it associates with telomeres and telomerase, and it also forms a complex with WRN, and with PARP, suggesting that these proteins act together as caretakers of genome integrity. Evidence for the KU complexs role in ageing has been shown in several studies with mice knockouts, as follows.There is also evidence that NHEJ activity is considerably reduced with age in rat cortical neurons. This decreased NHEJ activity cannot be trivially explained as a consequence of a reduced number of doublestrand breaks, because the number of doublestrand breaks in the neurons of rat cerebral cortex has been shown to considerably increase with age. Also, genetic defects in the NHEJ pathway have been shown to reduce hematopoietic stem function in an agedependent manner under conditions of stress in mice. Turning to human ageing, the level of mRNA expression of KU was observed to decrease considerably with age in human hematopoietic stem and progenitor cells. Furthermore, the levels of the KU protein and of MRE were observed to signicantly decline with age. Hence, the authors suggested that KU expression in lymphocytes may be considered a biomarker of ageing. This shows that DNA repair is crucial for survival, but this is not incompatible with the fact that DNA repair is also important for ageing.Nonetheless, as discussed above, some DNA repair pathways clearly have been more strongly linked to ageing than others, suggesting that specic types of damage or those that trigger particular downstream events are crucial for ageing.However, one prediction of the DNA damage theory of ageing is that improved DNA repair should lead to slower or postponed ageing, ultimately leading to longer lifespan and this has not been demonstrated to date compared the efciency with which cells from young, old and centenarian subjects repair DNA strand breaks caused by sublethal concentrations of hydrogen peroxide.They observed that cells from centenarians are about as efcient in that kind of repair as the cells from young subjects, and both types of cell were considerably more efcient in that task than the cells of old subjects.They also observed that the expression level of PARP was signicantly decreased in the cells of old subjects, but not in the cells of young and centenarian subjects.In addition, centenarians have signicantly higher levels of the KU protein.Although these results support the hypothesis that improved DNA repair systems may lead to longer lifespan, they are correlative in nature and far from conclusive.Similarly, ERCC polymorphisms associated with low ERCC expression are associated with longevity.

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