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

项目概要_项目1 对与衰老有关的挑战的适应力可能是身体和精神衰退与衰老之间的区别。 更长寿更健康的生活睡眠障碍、情绪改变和认知障碍的患病率增加， 在老年人口中观察到的损伤可对生活质量和总体健康产生重大影响。 传统医学系统已经确定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 已经在精心设计的临床试验中进行了评估。这部分是由于这些临床前研究未能 重点关注与疗效相关的终点和生物标志物。该项目建议建立 必要的实验框架，以评估具有有希望的体外机制结果的植物制剂， 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。 本研究将重点探讨植物积雪草（Centella asiatica（L.）城市。这 草药在阿育吠陀和传统中医中用作神经滋补剂和改善认知功能。 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 认知功能在啮齿动物模型的老化和阿尔茨海默氏病。溶瘤作用和改善 也已经报道了由于施用该提取物而导致的失眠。然而，很少有临床试验 试图验证这些影响，每个都遭受了严重的方法缺陷，如缺乏 控制，动力不足，并评估适当的生物标志物的疗效。 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 合适的剂量、最佳的产品配方和翻译生物标志物的鉴定。使用老年小鼠， 将探索一系列CAW剂量对认知障碍、睡眠和睡眠恢复力的影响 剥夺、焦虑和抑郁。脑成像，睡眠表型，以及循环激素水平 和血液DNA甲基化模式都将被评估为目标接合的生物标志物。我们还将 确定来自CAW提取物的组成化合物对相同行为终点的影响， 以告知临床试验中使用的产品配方。 这些实验将确定CAW作为植物剂促进功能恢复的功效 与年龄相关的挑战，从而促进其转化为老年人的临床试验。而且这个 这项研究将建立一个方法学平台，可用于未来的研究与任何有前途的植物， 提供必要的体内测试，以走向临床测试。

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.