Distinct cellular and molecular environments support aging-related DNA methylation changes in the substantia nigra

Aim: We aimed to couple brain region-specific changes in global DNA methylation over aging to underlying cellular and molecular environments. Materials & methods: We measured two major forms of DNA methylation and analyzed Dnmt, Tet and metabolite levels in the striatum and substantia nigra (SN) over aging in healthy male mice. Results: The ratio of 5-hydroxymethylcytosine to 5-methylcytosine increases over aging in the SN, and 5-hydroxymethylcytosine increases preferentially in dopaminergic neurons. Additionally, this age-dependent alteration in methylation correlates with a reduction in the ratio of alpha-ketoglutarate to succinate in the SN. Conclusion: Distinct cellular and molecular environments correlate with aging-associated methylation changes in the SN, implicating this epigenetic mechanism in the susceptibility of this brain region to age-related cell loss.