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

项目摘要_项目1 对衰老相关挑战的恢复力可能是身体和精神衰退与 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。 传统医学系统已经确定了许多支持老年人健康的植物药物。许多. 这些植物药有令人信服的临床前证据支持它们对人类的潜在疗效，但很少有 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 重点关注翻译上相关的终点和疗效的生物标记物。本项目建议建立 评估一种具有良好体外机制结果的植物制剂所需的实验框架 哺乳动物系统，以便产生必要的数据，为设计良好的临床试验提供信息。 这项建议将重点放在植物积雪草(Centella asiatica(L.)城市。这 草本植物在阿育吠陀和传统中医中被用作神经补充剂和改善认知功能。 我们的实验室和其他实验室已经证明，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的认知功能。安慰剂的抗焦虑作用及其改善 也有因服用这种提取物而导致失眠的报道。然而，很少有临床试验 我试图验证这些影响，但每种方法都存在严重的方法缺陷，例如缺乏 控制、动力不足和评估适当的疗效生物标记物。 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 合适的剂量，最佳的产品配方和翻译生物标志物的鉴定。我们用衰老的小鼠 将探索一系列CAW剂量对认知障碍、睡眠和睡眠弹性的影响 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甲基化模式都将被评估为靶点接触的生物标志物。我们还将 确定从CAW提取物中提取的成分对小鼠相同行为终点的影响 通知将在临床试验中使用的产品配方。 这些实验将确定CAW作为一种植物制剂促进功能弹性的有效性 以应对与年龄相关的挑战，从而促进将其转化为老年人的临床试验。此外，这一点 研究将建立一个方法学平台，可以用于未来的研究，任何有希望的植物学到 提供必要的体内测试，以进入临床测试。

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.