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

摘要/项目摘要 认知和行动能力的异常是衰老的常见伴随，通常先于 阿尔茨海默病的发展。在其众多病因中，这些异常与 大脑前额叶区域辅助执行的脑血流调节的变化 功能和步态速度。我们之前已经证明，用可可黄烷醇治疗可以改善血液 老年人对认知任务(神经血管耦合[NVC])和执行功能的反应 NVC受损的人。这些化合物还可以减少衰老细胞的数量和它们的毒性 各种组织中的分泌产物(SASP)。在小鼠身上，黄烷醇和黄烷醇等“感觉性”化合物 酪氨酸激酶抑制剂，已被证明可以减少神经纤维缠绕密度，神经元丢失，以及 脑室扩大，在患有特发性肺纤维化的人类中，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Dasatinib(Q D)将改善NVC以响应执行任务，减少循环SASP 成分，并通过这样做，改善有阿尔茨海默氏症风险的老年人的认知和行动能力 疾病。我们的具体目标是：1)进行为期12周的单臂、开放标签、事前和事后试点研究，以 确定研究间歇剂量的栎素和达沙替尼的可行性和招募挑战 (Q，D)年龄70-90岁，步速慢(&lt；1.0m/s)和轻度认知障碍的老年人12例； 2)获得关于该Q-D方案对：a)静息脑血流量(CBF)和 执行任务期间的神经血管耦合(NVC)，b)步速和执行功能，以及c)其他 身体和认知表现的次级测量；以及3)开发初步证据 关于QD是否与a)血清和尿液中衰老生物标志物的减少有关 和血液中的衰老细胞，以及b)这些生物标志物的减少是否与改善有关 在NVC中，步态速度和执行功能。这项研究将利用 以波士顿胡椒中心和梅奥诊所为基础的翻译老年科学网络。其结果可能识别出一种 改善老年人脑血流调节、灵活性和认知的新方法，以及 防止他们发展为阿尔茨海默病。这项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是由于 衰老的细胞，并可用感觉剂缓解。

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.