Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, PO BOX 616 (VIJV), 6200 MD Maastricht, The Netherlands.
Curr Alzheimer Res. 2013 Oct;10(8):868-76. doi: 10.2174/1567205011310080009.
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.
海马体的衰老过程与异常的表观遗传标记有关，如 DNA 甲基化和组蛋白尾部改变。最近的证据表明，热量限制（CR）可能延迟衰老过程，而抗氧化剂的上调也可能对此有有益的影响。我们最近观察到，CR 可减弱与年龄相关的在小鼠海马体中表观遗传分子 DNA 甲基转移酶 3a、5-甲基胞嘧啶（5-mC）和 5-羟甲基胞嘧啶水平的变化，而抗氧化剂铜/锌超氧化物歧化酶 1（SOD1）的过表达则没有。然而，衰老对海马体中组蛋白修饰酶（如组蛋白去乙酰化酶 2（HDAC2））水平的影响尚未进行详细研究。在这里，我们研究了来自大群衰老的野生型和转 SOD1 正常人类基因的转基因小鼠的三个海马体亚区（齿状回、CA3 和 CA1-2）中 HDAC2 的免疫反应性（IR）。这些小鼠从断奶后开始一直处于正常饮食或 CR 条件下。与基因型无关，衰老（12 至 24 个月）增加了海马体中 HDAC2 IR 的水平。此外，CR 可防止这种与年龄相关的增加，特别是在 CA3 和 CA1-2 亚区，而过表达 SOD1 则没有。定量图像分析表明，HDAC2 IR 与 5-mC IR 呈正相关，而这些标志物被证明在海马体细胞的核内共定位。结合最近的文献报道，这些发现表明，包括 HDAC2 在内的表观遗传调节蛋白水平的改变调节了小鼠海马体与年龄相关的变化，而 CR 可能预防这些与年龄相关的变化。
