Senolytics to Improve Cognition and Mobility in Older Adults at Risk of Alzheimer’s Disease

摘要/项目摘要 认知能力和活动能力的下降是衰老的常见表现， 阿尔茨海默病的发展。在其众多病因中，这些异常与 大脑额叶区的脑血流量调节的改变， 功能和步态速度。我们以前已经证明，可可黄烷醇治疗可以改善血液 对认知任务的反应（神经血管耦合[NVC]）以及老年人的执行功能 NVC受损的人这些化合物还可以减少衰老细胞的数量及其毒性。 分泌产物（SASP）在各种组织中。在小鼠中，“衰老清除”化合物如黄烷醇和 酪氨酸激酶抑制剂，已显示减少神经元缠结密度，神经元损失， 心室扩大，并在人类特发性肺纤维化，改善步态速度和其他 功能能力。基于这些发现，我们假设黄烷醇、槲皮素和酪氨酸激酶 抑制剂达沙替尼（Q+D）将改善NVC对执行任务的反应，降低循环SASP 成分，并在这样做，改善认知和流动性的老年人谁是阿尔茨海默氏症的风险 疾病我们的具体目标是：1）进行一项为期12周的单组、开放标签、前后试验性研究， 确定研究间歇剂量槲皮素和达沙替尼的可行性和招募挑战 （Q+D）12例70 ~ 90岁的老年人，步态速度慢（<1.0 m/sec），轻度认知功能障碍; 2)为了获得Q+D方案对以下方面影响的初步数据：a）静息脑血流量（CBF）和 执行任务期间的神经血管耦合（NVC），B）步态速度和执行功能，以及c）其他 身体和认知表现的次要指标;以及3）开发初步证据 关于Q+D是否与a）血清和尿液中衰老生物标志物的减少有关 以及B）这些生物标志物的减少是否与血液中的衰老细胞的改善相关， 步态速度和执行功能。这项研究将利用 波士顿胡椒中心和马约诊所为基础的翻译老年科学网络。其结果可能会确定一个 改善老年人脑血流调节、活动性和认知的新方法，以及 防止他们发展成老年痴呆症该研究还可能有助于建立概念验证， 老年人的认知和功能障碍可能部分来自于 衰老细胞，并通过衰老清除剂减轻。

Abstract/Project Summary Abnormalities in cognition and mobility are common accompaniments of aging that often precede the development of Alzheimer’s disease. Among their many etiologies, these abnormalities are associated with alterations in the regulation of cerebral blood flow to frontal regions of the brain that subserve executive functions and gait speed. We have previously shown that treatment with cocoa flavanols can improve blood flow in response to a cognitive task (neurovascular coupling [NVC]), as well as executive function in older people with impaired NVC. These compounds can also reduce the number of senescent cells and their toxic secretory products (SASP) in a variety of tissues. In mice, “senolytic” compounds such as flavanols and tyrosine kinase inhibitors, have been shown to reduce neurofibrillary tangle density, neuron loss, and ventricular enlargement, and in humans with idiopathic pulmonary fibrosis, improve gait speed and other functional abilities. Based on these findings, we hypothesize that the flavanol, Quercetin, and tyrosine kinase inhibitor, Dasatinib, (Q+D) will improve NVC in response to an executive task, reduce circulating SASP components, and in so doing, improve cognition and mobility in older adults who are at risk of Alzheimer’s disease. Our specific aims are: 1) To conduct a 12-week single arm, open label, pre-post pilot study to determine the feasibility and recruitment challenges of studying intermittent doses of Quercetin and Dasatinib (Q+D) in 12 older adults aged 70 to 90 years with slow gait speed (<1.0 m/sec) and Mild Cognitive Impairment; 2) To obtain preliminary data on the effect of this Q+D regimen on: a) resting cerebral blood flow (CBF) and neurovascular coupling (NVC) during an executive task, b) gait speed and executive function, and c) other secondary measures of physical and cognitive performance; and 3) To develop preliminary evidence concerning whether Q+D is associated with a) a reduction in biomarkers of senescence in serum and urine and senescent cells in blood, and b) whether reductions in these biomarkers are associated with improvements in NVC, gait speed, and executive function. This research will leverage the expertise and resources of the Boston Pepper Center and Mayo Clinic-based Translational Geroscience Network. Its results may identify a novel approach for improving cerebral blood flow regulation, mobility, and cognition in older adults, and preventing their progression to Alzheimer’s disease. The study may also help establish proof-of-concept that the cognitive and functional disabilities of older age may arise, in part, from the secretory products of senescent cells and be alleviated by senolytic agents.