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

项目概要： 认知能力和活动能力的下降是衰老的常见表现， 早于阿尔茨海默病的发展。在他们的许多病因，这些 异常与额叶脑血流调节的改变有关， 大脑中有助于执行功能和步态速度的区域。我们先前已经 可可黄烷醇治疗可以改善血液流动， 任务（神经血管耦合[NVC]），以及执行功能的老年人受损 NVC。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，已被证明可以减少神经系统缠结 密度，神经元丢失和心室扩大，以及在患有特发性肺动脉高压的人中， 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 改进NVC以响应执行任务，减少循环SASP组件，从而 做，改善认知和流动性的老年人谁是在阿尔茨海默氏症的风险。

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.