Histone deacetylase 2 in the mouse hippocampus: attenuation of age-related increase by caloric restriction.

The aging process in the hippocampus is associated with aberrant epigenetic marks, such as DNA methylation and histone tail alterations. Recent evidence suggests that caloric restriction (CR) can potentially delay the aging process, while upregulation of antioxidants may also have a beneficial effect in this respect. We have recently observed that CR attenuates age-related changes in the levels of the epigenetic molecules DNA methyltransferase 3a, 5-methylcytidine (5- mC) and 5-hydroxymethylcytosine in the mouse hippocampus while overexpression of the antioxidant Cu/Zn superoxide dismutase 1 (SOD1) does not. However, the impact of aging on the levels of histone-modifying enzymes such as histone deacetylase 2 (HDAC2) in the hippocampus has not been studied in much detail. Here, we investigated immunoreactivity (IR) of HDAC2 in three subregions of the hippocampus (dentate gyrus, CA3 and CA1-2) of mice taken from large cohorts of aging wild-type and transgenic mice overexpressing normal human SOD1, which were kept under normal diet or CR from weaning onwards. Independent from the genotype, aging (between 12 and 24 months) increased levels of HDAC2 IR in the hippocampus. Moreover, CR prevented this age-related increase, particularly in the CA3 and CA1-2 subregions, while SOD1 overexpression did not. Quantitative image analyses showed that HDAC2 IR correlated positively with 5-mC IR while these markers were shown to colocalize in the nucleus of hippocampal cells. Together with recent literature reports, these findings suggest that altered levels of epigenetic regulatory proteins including HDAC2 regulate age-related changes in the mouse hippocampus and that CR may prevent these age-related changes.