作为代谢活跃、高度耗能的器官，脑的衰老与线粒体能量代谢失衡密切相关。髓鞘是神经冲动快速传导的结构基础，髓鞘的退行性变是脑衰老的早期事件，是脑内脱髓鞘疾病的特征性病理基础。目前尚无有效促进脑内髓鞘修复的药物，这已成为临床治疗脑内脱髓鞘疾病的瓶颈问题之一。我们未发表的前期研究发现，在老年动物，提高NAD+水平不仅在结构上能够延缓髓鞘的老化并增强髓鞘损伤后的修复效率，而且在功能上能够改善髓鞘损伤区轴突的神经信号传导速度，这表明提高NAD+水平能够延缓髓鞘老化并显著增强老年脑内髓鞘修复效率。本研究拟在前期结果的基础上，以端粒酶敲除小鼠的第三代G3 Terc-/-早衰小鼠和自然衰老小鼠为模型，从线粒体结构、功能和代谢及表观遗传学两个角度，深入解析通过调节NAD+-sirtuins通路延缓髓鞘老化和促进老年脑内髓鞘损伤后修复效率的分子机制，以期为开发延缓髓鞘老化和增强老年髓鞘修复效率的药物提供新思路。

Brain is an organ with active metabolism and high energy consumption, and brain aging is closely related to the imbalance of mitochondrial energy metabolism or mitochondria dysfunction. Myelin is the structural basis for rapid nerve impulse conduction. Myelin degeneration is an early event of brain aging and the characteristic pathological change for demyelinating diseases in the brain. So far there has been yet no drug available that can effectively enhance the myelin repair efficiency in the brain, and this has become one of the bottlenecks for clinical treatment of demyelinating diseases in the brain. Our unpublished previous studies found that increasing nicotinamide adenine dinucleotide (NAD+) levels not only structurally delayed the age-related myelin degeneration and enhanced the repair efficiency after myelin sheath injury, but also functionally improved the nerve signal transmission velocity of the axons with damaged myelin sheath. Our unpublished results demonstrated that increasing NAD+ levels can delay the age-related myelin degeneration and significantly enhance the repair efficiency of myelin sheath in the aged brain. Based on our unpublished previous results, this study intends to explore further the molecular mechanisms on how regulating NAD+-sirtuins pathway can delay myelin degeneration in the aged brain and enhance myelin repair efficiency in the aged. We plan to dissect the underlying molecular mechanism from the perspective of 1) the structure, function and metabolism of mitochondria and 2) epigenetics, using the third generation G3 Terc-/- (Telomerase RNA component knockout mice, third generation, G3 Terc-/-) premature aging mice and normal aging mice as aging models. This study aims to provide new ideas for developing new drugs to delay age-related myelin degeneration and promote myelin repair efficiency in the aged brain.