Post-mitotic tissue

Failure to repair oxidative damage

The third factor, which is thought to result in an increase in damage from ROS, is the functional decline in the ability to repair DNA damage. The common repair mechanisms include; base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) homologous recombination (HR) and non-homologous end joining (NHEJ). However, repair to DNA normally take place during DNA replication when cells are dividing, but post-mitotic cells do not divide. The main concern in this instance is not whether there is a decrease in the ability of cells to repair DNA with age, but instead whether post-mitotic cells can themselves repair DNA, if at all they need to.
DNA repair in post-mitotic cells

To determine whether DNA repair occurs in post-mitotic cells, a number of studies have specifically concentrated on neural tissue and have found that these tissues do have the capability to repair DNA damage. Most oxidative damage is repaired by BER pathway, which is initiated by specialised DNA glycosylases. Glycosylases are involved in the removal of damaged DNA in the first step of the BER pathway. Newly discovered glycosylases (NEIL1/2) have been found to remove DNA damage from bubble structured DNA, suggesting that NEILs favour repair of transcribed or replicated DNA (Englander et al, 2006). This suggests that DNA replication may not be necessary for the repair of DNA. Measurements of expression and activity of BER during the neuronal transition from proliferative to postmitotic state demonstrated a decline in BER expression and activity, but expression of NEIL1 and NEIL2 glycosylases increased (Englander et al, 2006). The removal of damaged DNA from bubble structured DNA was found to be retained in post-mitotic neurons. This suggests a role for NEIL glycosylases in maintaining the integrity of transcribed DNA in post-mitotic cells.

Other repair mechanisms have also been shown to be present in post-mitotic neurons. Nuclear extracts from human brain neurons have demonstrated that the adult mammalian brain has the ability to carry out MMR (Brooks et al, 1996). Another study also showed the presence of DNA repair activity in neurons and found that this activity correlates with an increase expression of both HR and NHEJ DNA repair factors (Merlo et al, 2005). In regard to NER activity, it was found that neurons do exhibit NER activity and this activity is lower than that found in fibroblasts (Yamamoto et al, 2006). These studies therefore suggest that DNA repair mechanisms do occur in post-mitotic cells.

Since post-mitotic cells have the ability to repair DNA without replication it has been suggested that post-mitotic cells may only repair their expressed genes with little concern for removing damage from most of the genome (Nouspikel and Hanawalt, 2002, 2003). This accumulated damage in silent genes of post-mitotic cells may eventually result in triggering cell death, especially if such cells express these genes in an attempt to resume DNA replication.

Repair mechanisms

Very few studies have sought to determine whether DNA repair mechanisms change with age (Engels et al, 2007). One study however measured NHEJ activity to repair DNA from double strand breaks in extracts prepared from isolated neurons from neonatal, young adult and old rat cerebral cortex (Vyjayanti et al, 2006, Rao, 2007). It was shown that cohesive end-joining activity decreases significantly with age, but blunt and non-matching ends were poorly repaired at all ages. Interestingly, another study has shown that repair of DNA double strand breaks by the NHEJ pathway is deficient in Alzheimer’s disease (AD) (Shackelford, 2006). Another study looked at base excision repair using brain and liver nuclear extracts prepared from mice of various ages (Intano et al, 2003). An 85% decline in repair activity was observed in brain nuclear extracts and a 50% decrease in liver nuclear extracts prepared from old mice compared with 6-day old mice. DNA MMR system has also been investigated in T cells at various stages of the T cell lifespan (Annett et al, 2005). No clear pattern in DNA mismatch frequency with increasing culture age was observed, but the ability to repair induced DNA mismatches revealed an age-related decline in the efficiency of the MMR system.

If DNA damage or mutation frequencies increase with age, the impact, if any, that these changes have on the ageing phenotype is currently unknown. However, genetic disorders in which DNA repair mechanisms are defective may provide some answers. One such disorder known as xeroderma pigmentosum (XP), show the consequences of inherited defects in NER, which include UV hypersensitivity, cancer predisposition and accelerated ageing of skin, lips, tongue and mouth (Lehman, 2003). This accelerated ageing appears to be due to increase damaged as a result of excess environmental factors such as sun damage. Since accelerated ageing is not observed in less exposed tissues, it can be assumed that the lack of NER activity has little or no impact on ageing, and this may partly be due to protection from antioxidant enzymes.

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The main focus of ageing research is to prevent/combat age-related disease and disability, allowing everyone to live healthier lives for longer.