Effects of Aging on Blood Vessels in the Cerebellar Vermis

摘要 衰老是一个基本的生物过程，伴随着组织功能的普遍下降和 增加了许多疾病的风险。事实上，精细运动控制、步态和平衡性的下降是 老年人最重要的健康问题。尽管小脑的潜在机制 功能障碍尚不清楚，令人信服的证据表明，当小脑老化时，它开始收缩。 在人类55岁左右的时候，体积是一个整体。特别是将小叶作为一个整体来观察， 控制身体姿势和运动的前小叶(蚯蚓)受 衰老，但不是小脑的外侧部分。众所周知，与衰老相关的结构和功能 大脑宏循环或微循环的功能障碍会导致大脑退化和 功能障碍。然而，衰老是否会损害小脑的血管结构和功能在很大程度上是 未知。我们的初步研究表明，血管的数量和体积是选择性的 衰老小鼠小脑蠕虫减少，谷胱甘肽氧化还原状态增加，但 海马区未受影响。因此，我们的中心假设是：衰老选择性地损害 血管结构和功能的小脑，这反过来，增加氧化损伤 这些区域，导致神经元功能障碍或丧失和运动障碍。我们的具体目标是(1) 确定衰老是否选择性地损害了小脑蠕虫的血管结构和功能， 与其他小脑和大脑区域相比。(2)确定衰老是否会增加氧化作用 与其他小脑和大脑相比，小脑蠕虫中的应激和神经变性 地区。(3)探讨是否通过增加血管内皮细胞NAD+-SIRT1来改善脑血流量 活动减少氧化应激和减轻小脑和大脑皮质的神经变性 改善与年龄相关的小脑运动功能障碍。建议进行这项研究的理由是 成功完成拟议的实验将提供缺失的基础知识 关于衰老对血管结构和功能的影响，以及潜在的机制 老年人的运动功能障碍。

Abstract Aging is a fundamental biological process accompanied by a general decline in tissue function and increased risk for many diseases. Indeed, decline in fine motor control, gait and balance is among the most important health problems in the elderly. Although the mechanism underlying cerebellar dysfunction is unclear, compelling evidence indicate that when the cerebellum ages, it starts to shrink in volume as a whole in the mid-fifties of humans. Looking particularly at the lobules as a whole, the anterior lobules (vermis) that control bodily posture and locomotion are most significantly affected by aging, but not the lateral portions of the cerebellum. It is well-known that aging-related structural and functional disturbances in the macro- or microcirculation of the brain lead to brain degeneration and dysfunction. However, whether aging impairs vascular structure and function of cerebellum is largely unknown. Our preliminary study showed that the number and volume of blood vessels were selectively reduced in vermis of cerebellum in aged mice, along with increased glutathione redox state, but the hippocampus was not affected. Thus, our central hypothesis is that: aging selectively impairs the vascular structure and function in vermis of cerebellum, which, in turn, increase oxidative damage in these regions, leading to neuronal dysfunction or loss and motor deficits. Our SPECIFIC AIM is to (1) determine whether aging selectively impairs vascular structure and function in the vermis of cerebellum, compared to other cerebellar and cerebral regions. (2) Determine whether aging increases oxidative stress and neurodegeneration in the vermis of cerebellum, compared to other cerebellar and cerebral regions. (3) Explore whether improved cerebral blood flow via increase of endothelial NAD+-SIRT1 activity reduces oxidative stress and attenuates neurodegeneration in the vermis of cerebellum and improve age-related cerebellar motor dysfunction. The rationale for the proposed research is that successful completion of the proposed experiments will provide missing, fundamental knowledge regarding the impact of the aging on vessel structure and function, and potential mechanisms underlying motor dysfunction in elderly.