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: 10661723
• 负责人: Nora Gray
• 金额: $ 42.84万
• 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/10661723
• 关键词: Acids; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animals; Anti-Anxiety Agents; Antioxidants; Anxiety; Ayurvedic Medicine; Behavior; Behavior assessment; Behavioral; Biological Markers; Blood; Botanicals; Brain; Brain imaging; Chinese Traditional Medicine; Chronic; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; DNA Methylation; Data; Dopamine; Dose; Drug Kinetics; Elderly; Electroencephalography; F2-Isoprostanes; Failure; Food; Formulation; Future; Goals; Gotu kola; Health; Herb; Hormones; Human; Hydrocortisone; Impaired cognition; In Vitro; Knowledge; Learning; Life; Magnetic Resonance Spectroscopy; Measures; Memory; Mental Depression; Methodology; Methods; Mitochondria; Moods; Mus; Nerve; Neurologic; Neurons; Neurotransmitters; Oral Administration; Pathway interactions; Pattern; Perfusion; Phenotype; Plant Extracts; Plants; Plasma; Population; Prevalence; Psyche structure; Quality of life; Rapid screening; Reporting; Rodent Model; Serotonin; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Synapses; System; Testing; Traditional Medicine; Translations; Water; affective disturbance; age related; aged; arterial spin labeling; blood perfusion; clinical development; cognitive change; cognitive enhancement; cognitive function; cognitive performance; density; depressive symptoms; dosage; efficacy evaluation; executive function; experimental study; gamma-Aminobutyric Acid; healthy aging; human subject; improved; improvement on sleep; in vivo; in vivo evaluation; metabolomics; methylation pattern; mouse model; peripheral blood; pre-clinical; pre-clinical research; preclinical study; promote resilience; research clinical testing; resilience; response; sleep spindle; targeted biomarker

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summary_project 1 对与衰老相关的挑战的韧性可能是身体和精神衰落与A之间的差异 更长，更健康的生活。睡眠障碍，情绪改变和认知的患病率增加 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。许多 这些植物药具有令人信服的临床前证据，支持其在人类中的潜在有效性 已在精心设计的临床试验中评估。这部分是由于这些临床前研究未能 专注于效率的翻译相关终点和生物标志物。这个项目提议建立 评估具有承诺在体外机理的植物剂所必需的实验框架中 哺乳动物系统，以生成为精心设计的临床试验提供必要的数据。 该提案将重点介绍Centella Asiatica（L.）Urban植物的弹力促进作用。 草药被用作阿育吠陀和传统中药，用作一种神经滋补品并改善认知功能。 我们的实验室和其他实验室表明，低剂量的Centella Asiatica（CAW）的水提取物可以改善 衰老和阿尔茨海默氏病的啮齿动物模型中的认知功能。抗焦虑作用和改善 由于施用了提取物，也已经报道了失眠。但是，很少有临床试验有 试图验证这些效果，并且每个效果都遭受了严重的方法论缺陷，例如缺乏 对照，功能不足并评估适当的效率生物标志物。 在这项研究中，我们将解决关键知识差距，阻碍CAW的临床发展，包括 适当的剂量，最佳产品配方和转化生物标志物的识别。使用老年小鼠 将探讨一系列CAW剂量对认知障碍，睡眠和韧性的影响 剥夺，焦虑和沮丧。脑成像，睡眠表型以及循环骑马水平 血液DNA甲基化模式将被评估为靶标参与的生物标志物。我们也会 确定CAW提取物对相同行为终点的构成化合物的影响 为了告知产品公式以在临床试验中使用。 这些实验将确定CAW作为植物剂的效率，以促进功能弹性 与年龄有关的挑战，从而将其转化为老年人的临床试验。另外，这个 研究将建立一个方法论平台，可以在未来的研究中使用任何承诺的植物学 提供必要的体内测试，以朝着临床测试迈进。