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 α-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.
Keywords: 5-hydroxymethylcytosine; 5-methylcytosine; DNA methylation; DNMTs; TETs; aging; dopaminergic; striatum; substantia nigra; α-ketoglutarate.