Jessop Peter, Toledo-Rodriguez Maria
School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
Front Cell Dev Biol. 2018 Apr 19;6:45. doi: 10.3389/fcell.2018.00045. eCollection 2018.
The function of 5-hydroxymethylcytosine (5hmC) is poorly understood. 5hmC is an epigenetic modification of DNA, resulting from the oxidation of 5-methylcytosine (5mC) by the Fe2, and 2-oxoglutarate-dependent, 10-11 translocation methylcytosine dioxygenases (TET1, TET2, and TET3). Recent evidence suggests that, in addition to being an intermediate in active demethylation, 5hmC may also have an epigenetic role. 5hmC is enriched in the adult brain, where it has been implicated in regulating neurogenesis. The rate of adult neurogenesis decreases with age, however physical exercise has been shown to counteract this deficit. Here, we investigated the impact of voluntary exercise on the age-related changes of , expression and 5hmC content in the hippocampus and hypothalamus. For this purpose, we used voluntary exercise in young adult (3 months) and aged (18 months) mice as a rodent model of healthy brain aging. We measured the levels of hippocampal and hypothalamic mRNA, and 5hmC and memory [Object Location (OL) test] in mice that either exercised for 1 month or remained sedentary. While aging was associated with decreased and expression, voluntary exercise counteracted the decline in expression. Moreover, aged mice that exercised had higher hippocampal 5hmC content in the promoter region of , an miRNA involved in adult neurogenesis. Exercise improved memory in aged mice, and there was a positive correlation between 5hmC miR-137 levels and performance in the OL test. In the hypothalamus neither exercise nor aging affected or expression. These results suggest that exercise partially restores the age-related decrease in hippocampal and expression, which may be linked to the improvement in memory. Future studies should further determine the specific genes where changes in 5hmC levels may mediate the exercise-induced improvements in memory and neurogenesis in aged animals.
5-羟甲基胞嘧啶（5hmC）的功能尚不清楚。5hmC是DNA的一种表观遗传修饰，由5-甲基胞嘧啶（5mC）在Fe2+和2-酮戊二酸依赖性的10-11易位甲基胞嘧啶双加氧酶（TET1、TET2和TET3）作用下氧化产生。最近的证据表明，5hmC除了是活性去甲基化的中间体之外，可能还具有表观遗传作用。5hmC在成人大脑中含量丰富，与神经发生的调节有关。成体神经发生的速率随年龄增长而降低，然而体育锻炼已被证明可抵消这种缺陷。在此，我们研究了自愿运动对海马体和下丘脑与年龄相关的 、表达及5hmC含量变化的影响。为此，我们将年轻成年（3个月）和老年（18个月）小鼠的自愿运动作为健康大脑衰老的啮齿动物模型。我们测量了运动1个月或保持久坐的小鼠海马体和下丘脑的 mRNA水平、5hmC水平以及记忆[物体位置（OL）测试]。衰老与 和 表达降低有关，而自愿运动抵消了表达的下降。此外，运动的老年小鼠在参与成体神经发生的一种miRNA即 的启动子区域具有更高的海马体5hmC含量。运动改善了老年小鼠的记忆，并且5hmC miR-137水平与OL测试中的表现呈正相关。在下丘脑中，运动和衰老均未影响 或 的表达。这些结果表明，运动部分恢复了与年龄相关的海马体 和 表达下降，这可能与记忆改善有关。未来的研究应进一步确定5hmC水平变化可能介导衰老动物运动诱导的记忆和神经发生改善的具体基因。
