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

Senolytics 可改善有阿尔茨海默病风险的老年人的认知和活动能力

• 批准号: 10287509
• 负责人: LEWIS LIPSITZ
• 金额: $ 20万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287509
• 关键词: Activities of Daily Living; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; American; Biological; Biological Markers; Blood; Blood Vessels; Blood flow; Boston; Brain; Brain region; Capsicum; Cells; Cerebrovascular Circulation; Chronic Disease; Clinic; Cocoa Powder; Cognition; Cognitive; Cognitive deficits; Consumption; Dasatinib; Data; Development; Disease; Dose; Elderly; Etiology; Flavanol; Future; Gait; Gait speed; Geroscience; Goals; Human; Impaired cognition; Impairment; Interruption; Intervention; Joints; Lead; Measures; Mus; Neurofibrillary Tangles; Outcome; Phenotype; Physical Performance; Pilot Projects; Plants; Process; Quercetin; Randomized Controlled Trials; Regimen; Regulation; Research; Research Personnel; Resources; Rest; Risk; Rodent; Serum; Testing; Therapeutic Agents; Tissues; Trail Making Test; Tyrosine Kinase Inhibitor; Urine; Ventricular; Work; age related; aged; arm; base; cognitive disability; cognitive function; cognitive performance; cognitive task; density; executive function; exercise capacity; experience; falls; frailty; frontal lobe; functional disability; healthspan; human data; idiopathic pulmonary fibrosis; improved; middle cerebral artery; mild cognitive impairment; neural circuit; neuron loss; neurovascular coupling; novel strategies; open label; prevent; randomized controlled design; recruit; response; senescence; tau phosphorylation; vascular risk factor

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.

摘要/项目摘要 认知和流动性异常是衰老的共同安排，通常是在 阿尔茨海默氏病的发展。在他们的许多病因中，这些异常与 调节脑血流到大脑额叶区域的调节改变了高管 功能并获得速度。我们以前已经表明，用可可黄烷醇治疗可以改善血液 响应认知任务（神经血管耦合[NVC]）的流量以及较旧的执行功能 NVC受损的人。这些化合物还可以减少感觉细胞的数量及其有毒 各种组织中的分泌产物（SASP）。在小鼠中，“鼻溶剂”化合物，例如黄烷醇和 酪氨酸激酶抑制剂已被证明可降低神经原纤维缠结密度，神经元丧失和 心室膨胀，以及具有特发性肺纤维化的人，改善了对齐的速度和其他 功能能力。基于这些发现，我们假设黄素，槲皮素和酪氨酸激酶 抑制剂Dasatinib（Q+D）将对执行任务改善NVC，减少循环SASP 组成部分，这样做，改善了有阿尔茨海默氏症风险的老年人的认知和流动性 疾病。我们的具体目的是：1）进行12周的单臂，开放标签，前试验前研究 确定研究槲皮素和达沙替尼的间歇性剂量的可行性和招聘挑战 （Q+D）在12名70至90岁的老年人中，收集速度缓慢（<1.0 m/sec）和轻度的认知障碍； 2）获得有关此Q+D方案对以下效果的初步数据：a）静止的脑血流（CBF）和 在执行任务期间，神经血管耦合（NVC），b）满足速度和执行功能，c）其他 物理和认知表现的次要测量； 3）发展初步证据 关于Q+D是否与a）血清和尿液中感应生物标志物的降低有关 和血液中的感觉细胞，b）这些生物标志物中的降低是否与改进有关 在NVC中，获得速度和执行功能。这项研究将利用 波士顿胡椒中心和基于梅奥诊所的转化Geroscience网络。它的结果可能会确定 改善老年人脑血流调节，活动性和认知的新方法，以及 防止他们发展为阿尔茨海默氏病。该研究还可能有助于确定概念证明 老年的认知和功能障碍可能部分来自 感觉细胞，并被塞溶剂剂减轻。