Botanicals for functional resilience to aging: identifying in vivo biomarkers of the effects of Centella asiatica (Project 1)

具有抗衰老功能的植物药：识别积雪草作用的体内生物标志物（项目 1）

• 批准号: 10424465
• 负责人: Nora Gray
• 金额: $ 54.84万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424465
• 关键词: Aging; Biological Markers; Botanicals; Gotu kola; Neurologic; in vivo; resilience

PROJECT SUMMARY_PROJECT 1 Resilience to aging-related challenges can be the difference between physical and mental decline and a longer, healthier life. The increased prevalence of sleep disturbances, mood alterations and cognitive impairment observed in the elderly population can have substantial effects on quality of life and overall health. Traditional medicine systems have identified numerous botanicals that support health in older adults. Many of these botanicals have compelling preclinical evidence supporting their potential efficacy in humans yet few have been evaluated in well-designed clinical trials. This is due in part to a failure of these preclinical studies to focus on translationally relevant endpoints and biomarkers of efficacy. This project proposes to establish the experimental framework necessary to evaluate a botanical agent with promising in vitro mechanistic results in a mammalian system, in order to generate the data necessary to inform a well-designed clinical trial. This proposal will focus on the resilience-promoting effects of the plant Centella asiatica (L.) Urban. This herb is used in Ayurvedic and traditional Chinese medicine as a nerve tonic and to improve cognitive function. Our lab and others have shown that low doses of the water extract of Centella asiatica (CAW) can improve cognitive function in rodent models of aging and Alzheimer’s disease. Anxiolytic effects and improvement in insomnia as a result of administering the extract have also been reported. However, few clinical trials have attempted to validate these effects and each has suffered from severe methodological flaws such as lack of controls, being underpowered and assessing appropriate biomarkers of efficacy. In this study we will address critical knowledge gaps hindering the clinical development of CAW including proper dosage, optimal product formulation and identification of translational biomarkers. Using aged mice we will explore the effects of a range of CAW doses on cognitive impairment, sleep and resilience to sleep deprivation, and anxiety and depression. Brain imaging, sleep phenotype, as well as circulating hormone levels and blood DNA methylation patterns will all be evaluated as biomarkers for target engagement. We will also determine the effects of constituent compounds from the CAW extract on the same behavioral endpoints in order to inform product formulation to be used in a clinical trial. These experiments will determine the efficacy of CAW as a botanical agent to promote functional resilience to age-related challenges and thereby facilitate its translation to a clinical trial in older adults. Additionally, this study will establish a methodological platform that can be used in future studies with any promising botanical to provide the necessary in vivo testing to move towards clinical testing.

项目摘要_项目 1 对与衰老相关的挑战的适应能力可能是身体和精神衰退与衰老之间的区别。 寿命更长、更健康。睡眠障碍、情绪改变和认知障碍的患病率增加 在老年人群中观察到的损害可能会对生活质量和整体健康产生重大影响。 传统医学系统已经发现了许多支持老年人健康的植物药。许多 这些植物药有令人信服的临床前证据支持其对人类的潜在功效，但很少有 已在精心设计的临床试验中进行了评估。部分原因是这些临床前研究未能 重点关注转化相关的终点和功效生物标志物。本项目拟设立 评估具有前景的体外机制结果的植物制剂所必需的实验框架 哺乳动物系统，以便生成为精心设计的临床试验提供信息所需的数据。 该提案将重点关注植物 Centella asiatica (L.) Urban 的恢复力促进作用。这 草药在阿育吠陀和传统中医中用作神经滋补品并改善认知功能。 我们的实验室和其他实验室已经表明，低剂量的积雪草水提取物 (CAW) 可以改善 衰老和阿尔茨海默病啮齿动物模型中的认知功能。抗焦虑作用和改善 也有因服用提取物而导致失眠的报道。然而，很少有临床试验表明 试图验证这些效果，但每一个都存在严重的方法论缺陷，例如缺乏 控制、动力不足并评估适当的功效生物标志物。 在这项研究中，我们将解决阻碍 CAW 临床发展的关键知识差距，包括 适当的剂量、最佳的产品配方和转化生物标志物的鉴定。我们使用老年小鼠 将探讨一系列 CAW 剂量对认知障碍、睡眠和睡眠恢复能力的影响 剥夺、焦虑和抑郁。脑成像、睡眠表型以及循环激素水平 血液 DNA 甲基化模式都将作为目标参与的生物标志物进行评估。我们还将 确定 CAW 提取物中的成分化合物对相同行为终点的影响 以便告知用于临床试验的产品配方。 这些实验将确定 CAW 作为植物制剂促进功能恢复的功效 应对与年龄相关的挑战，从而促进其转化为老年人的临床试验。另外，这 研究将建立一个方法平台，可用于未来任何有前景的植物学研究 提供必要的体内测试以进行临床测试。