Every day, cells are subjected to several hundred thousand lesions affecting proteins, lipids and DNA. In the nervous system alone, there are around 200 cytosine deaminations, 3,000 guanine methylations, 10,000 spontaneous depurations, up to 100,000 oxidative lesions, 10,000 single-strand breaks (SSBs) and 10 to 50 double-strand breaks (DSBs) per cell per day. DSBs may not seem like much, but they are the most toxic of all breaks, and probably the basis of most brain ageing "diseases". With age, lesions accumulate that are either unrepaired or repaired with unfavorable sequence and epigenetic modifications.
Analysis of the genes expressed in the human brain(post mortem) shows, from the age of 40, a drop in the expression of genes involved in memorization and an increase in the expression of stress-related genes (Lu et al., 2004), with a clear deterioration between the ages of 60 and 70. Genes with decreased expression have oxidized guanines in their promoters.
Physiological changes can be induced acutely by DNA-toxic agents. For example, exposure of cells to H2O2, and the subsequent formation of DSBs, induces recruitment of sirtuin 1 (SIRT1) to injured sites. This relocation - essential for DNA repair - has, if sustained, global effects on transcription. The transcriptional changes observed under these conditions are similar to those observed in the mouse brain during aging.