Folate, DNA damage and the aging brain

Folate plays an essential role as a methyl donor for the synthesis of DNA nucleotides such as thymine and, via S-adenosylmethionine, for maintenance of methylation of cytosine which is required for control of gene expression and for chromatin structure in critical regions of the genome such as centromeres and the subtelomere. If folate is deficient, damage to nuclear and mitochondrial DNA increases and regenerative potential of normal tissues declines. Folate deficiency may contribute to the high burden of DNA damage consistently observed in neurodegenerative disease by causing excessive incorporation of uracil into the genome and increasing susceptibility to DNA damage by causative agents such as Aβ42 and reactive oxygen species. In this brief review the current evidence that folate deficiency and associated metabolites, such as homocysteine, may accelerate DNA damage and aging of the brain is explored and important knowledge gaps are identified.