School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
Neurobiol Aging. 2012 Aug;33(8):1672-81. doi: 10.1016/j.neurobiolaging.2011.06.003. Epub 2011 Jul 18.
Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1-2 regions, which was prevented by CR but not by SOD1 overexpression. Moreover, positive correlations between 5-mC and Dnmt3a immunoreactivity were observed in the CA3 and CA1-2. These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging.
异常的 DNA 甲基化模式与衰老大脑中的分子和细胞变化有关。热量限制 (CR) 和抗氧化剂的上调被认为是预防或延缓与年龄相关的脑病理的干预措施。此前，我们在大量衰老小鼠队列中表明，CR 可减弱小鼠海马体中 DNA 甲基转移酶 3a (Dnmt3a) 免疫反应性随年龄的增加，但不能通过过表达超氧化物歧化酶 1 (SOD1) 来减弱。在这里，我们以海马亚区特异性的方式研究了与年龄相关的 5-甲基胞嘧啶 (5-mC) 改变，5-mC 是 DNA 甲基化水平的标志物。在对照饮食的 12 个月和 24 个月大的野生型 (WT) 小鼠、对照饮食中超表达 SOD1 的小鼠、CR 饮食的野生型小鼠和 CR 饮食中的 SOD1 小鼠中检查 5-mC 免疫反应性，表明海马齿状回、CA3 和 CA1-2 区的 5-mC 免疫反应性随年龄的增加而增加，这可以通过 CR 来预防，但不能通过 SOD1 过表达来预防。此外，CA3 和 CA1-2 中观察到 5-mC 和 Dnmt3a 免疫反应性之间存在正相关。这些发现表明 DNA 甲基化在海马体衰老和 CR 对衰老的有益影响的介导中起着至关重要的作用。
