Age-dependent decline of DNA base excision repair activity in rat cortical neurons.

Synthetic oligonucleotide duplexes containing a single uracil (U) or 8-oxoguanine (8-oxoG) were used as a model substrates to assess the base excision repair (BER) ability of neuronal extracts prepared from the cerebral cortex of young (7 days), adult (180 days) and old (720 days) rats. Our results demonstrate that BER activity in neurons markedly declines with age. The decline in BER could be attributed to decrease in the expression levels and activities of BER enzymes. Supplementing neuronal extracts with uracil DNA-glycosylase (UDG), 8-oxoguanine DNA glycosylase (OGG1), apurinic endonuclease 1, pol β and T(4) DNA ligase independently could not restore the loss of BER activity in adult and old neuronal extracts. However, supplementation of pol β in combination of T(4) DNA ligase to neuronal extract, improved the BER in adult and old neuronal extracts. Additional supplementation of the extracts with UDG or OGG1 apart from pol β and T(4) DNA ligase, or with all pure enzymes restored very markedly the loss of BER in aging neurons. These results suggest the age-dependent decline in BER is due to an overall deficiency of the various factors needed for BER but pol β and DNA ligase seem to be the most limiting factors.