The Mito-Frail Trial: Effects of MitoQ on Vasodilation, Mobility and Cognitive Performance in Frail Older Adults

项目总结 这项建议的首要目标是为申请者提供所需的选定附加技能 申请者将成为NIH资助的独立调查员，能够设计和实施早期阶段 老年科学指导的临床试验，有可能通过靶向生物衰老来延长健康寿命。 这一定制设计的学习体验将通过三个独特的组件来增强。首先，帕特森 信托基金资助的研究：Mito-Frail试验：MitoQ对血管扩张、流动性和认知表现的影响 在虚弱的老年人中“将提供一个研究平台。第二，NIA翻译老年科学网络(R33 AG061456)及其老年科学分析设施已同意提供学习经验并提供补贴 生物标志物的测量允许对衰老的生物学特征进行更广泛和更深入的分析。 第三，NIA老年科学教育和培训网络(R25 AG073119)将允许应聘者履行 康涅狄格州大学对老年科学证书的要求，这是该网络目前的五个网站之一。 慢性病和与之相关的身体和认知能力的下降是造成损失的主要原因 随着年龄的增长而独立。除了缺乏有效的运动以外的干预措施来解决 问题是，很少有研究检查针对两种情况的虚弱个体的策略，这些人可能 行走和记忆都有困难。使用老年科学指导的治疗方法使我们能够 衰老与慢性病的共同机制是，衰老是一个主要的风险因素。因此，相反， 一次只关注一种疾病，有可能延缓残疾的发生和发展 涉及多个功能领域，包括由阿尔茨海默病和其他痴呆引起的领域。 我们最近发现MitoQ，一种线粒体靶向的抗氧化剂，已知可以改善内皮功能 和一氧化氮(NO)的生物利用度，也可能恢复虚弱老年人受损的血流介导的血管扩张， 提高步态速度。在Mito-Frail研究中，我们现在希望探索MitoQ延缓衰老的假设- 涉及外周和脑血管的血流介导的血管扩张功能相应下降。同时 时间，我们将获得可行性和试点数据，包括身体活动能力和认知能力的测量 这可能会帮助我们设计并支持未来的临床试验。最终，我们寻求制定战略，以防止 或减缓阿尔茨海默病的进展和血管对痴呆症的影响。 因此，Aim 1将评估外周和大脑中NO的生物利用度和线粒体活性氧 健康的老年人、步行速度慢的虚弱的老年人和那些 符合轻度认知障碍(MCI)标准的患者。目标2将确定MitoQ补充是否可以 通过增强认知功能来改善血管扩张。拟议的研究将为以下方面提供必要的培训 将作为NIA资助的独立调查员建立专业知识的候选人 旨在维持和增强老年人功能独立性的翻译性老年学研究。

PROJECT SUMMARY The overarching goal of this proposal is to provide the applicant with selected additional skills required for an applicant to become an independent NIH-funded investigator capable of designing and implementing early phase geroscience-guided clinical trials that have the potential to extend healthy lifespan by targeting biological aging. This custom-designed learning experience will be enhanced by three unique components. First, a Patterson Trust-funded study “The Mito-Frail Trial: Effects of MitoQ on Vasodilation, Mobility and Cognitive Performance in Frail Older Adults” will provide a research platform. Second, the NIA Translational Geroscience Network (R33 AG061456) and its Facility for Geroscience Analysis has agreed to provide learning experiences and subsidized measurements of biomarkers permitting a much broader and deeper analysis of biological hallmarks of aging. Third, the NIA Geroscience Education and Training Network (R25 AG073119) will permit the candidate to fulfill the requirements for a Certificate in Geroscience at UConn, one of the network's current five sites. Chronic diseases and associated declines in physical and cognitive performance contribute greatly to lost independence with aging. In addition to a lack of effective interventions other than exercise to address either problem, few studies have examined strategies for targeting both conditions in frail individuals who may experience difficulties with both walking and memory. Use of geroscience-guided therapies permits us to target mechanisms shared by aging with chronic conditions for which aging represents a major risk factor. Thus, instead of focusing on one single disease at a time, it may be possible to delay the onset and progression of disability involving multiple functional domains including those caused by Alzheimer's disease and other dementias. We have recently shown that MitoQ, a mitochondria-targeted antioxidant known to improve endothelial function and Nitric Oxide (NO) bioavailability, may also restore impaired flow-mediated vasodilation in frail older adults, enhancing gait speed. In the Mito-Frail study we now wish to explore the hypothesis that MitoQ attenuates aging- related declines in flow-mediated vasodilation involving both peripheral and cerebral blood vessels. At the same time, we will obtain feasibility and pilot data involving measures of physical mobility and cognitive performance that may help us design and power a future clinical trial. Ultimately, we seek to develop strategies for preventing or slowing the progression of Alzheimer's disease and the vascular contribution to dementia. Therefore, Aim 1 will assess peripheral and cerebral NO bioavailability and mitochondrial reactive oxygen species (mtROS) levels in older adults who are healthy, others who are frail with slow walking speed and those who meet criteria for mild cognitive impairment (MCI). Aim 2 will determine whether MitoQ supplementation can improve vasodilation with enhancing cognitive function. The proposed research will provide essential training for the candidate who will establish expertise as an independent NIA-funded investigator conducting cutting-edge translational geroscience research designed to maintain and enhance functional independence in older adults.