An innovative proof-of-concept approach to identify age-modulating drugs capable of reversing inflammation and re-setting the epigenetic clock

一种创新的概念验证方法，用于识别能够逆转炎症和重置表观遗传时钟的年龄调节药物

• 批准号: 10264863
• 负责人: DEAN L KELLOGG
• 金额: $ 19.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264863
• 关键词: Acarbose; Acute; Affect; Age; Aging; Animal Model; Area; Biological Assay; Biological Markers; Blood; Blood Circulation; Bulla; Cells; Clinical Trials; Collection; DNA; DNA Methylation; Dermal; Dose; Drug Controls; Elderly; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Female; Forearm; Future; Human; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intercellular Fluid; Intervention; Liquid substance; Longevity; Measurable; Measures; Metformin; Methods; Methylation; Organism; Outcome; Pathology; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Placebo Control; Placebos; Populations at Risk; Preclinical Testing; Research; Risk; Rodent; Safety; Sex Differences; Sirolimus; Site; Skin; Suction; Surgical Flaps; Surrogate Markers; Techniques; Testing; Therapeutic; Tissues; Topical application; Translating; Treatment Protocols; Validation; age effect; anti aging; arm; base; cohort; cost; cost effective; cytokine; design; drug candidate; drug testing; efficacy evaluation; epigenome; epigenomics; healthspan; healthy aging; human subject; in vivo; innovation; interstitial; keratinocyte; mTOR Inhibitor; male; methylation pattern; minimally invasive; novel; preclinical study; therapeutic candidate; treatment site

ABSTRACT In order to identify drugs and/or interventions with the potential to delay the onset and progression of age- associated pathologies, preclinical studies have used animal models where extension of lifespan could be accurately assessed. Several outstanding candidate therapeutics have been identified over the last decade; these include mTOR inhibitors (like rapamycin), senolytic agents, acarbose, and others. However, translating anti-aging results from animal models into humans has been challenging. For example, measuring extension of lifespan would be impractical in humans, so it is necessary to identify and validate parameters that can serve as surrogate markers of healthy aging. Moreover, the efficacy of age-modulating drugs is often only demonstrable with older individuals where functional deficits are already evident. Thus, testing of potential anti- aging therapeutics should be done in a cohort of human subjects of an advanced age; issues of safe administration would be even more acute in this “at risk” population. To circumvent these limitations, we propose to develop and validate an innovative, minimally invasive, cost-effective assay in human subjects ranging from 65-95 years old. The putative anti-aging test drug will be applied topically to a discrete area of skin on the subject’s forearm while a “vehicle only” (control) is applied in parallel to the opposite arm. Thus, each subject will serve as his/her own control. The pharmacodynamic outcomes at the “test” and placebo sites will be compared in both males and females since the effects of age-modulating agents often differ between the sexes. Ascertaining the efficacy of topically-applied therapeutics requires robust biomarkers of aging that can be measured in skin, but will be generalizable to the intact organism. Towards this end, we have opted to use two independent parameters that are known to be modified with aging both locally (in individual tissues) and systemically: i) the DNA methylation pattern or “epigenetic clock” and ii) biomarkers associated with inflammation. To validate the proposed technique, we have chosen a drug, rapamycin (RAPA), which has already been shown to modulate aging in rodents and which has been tested for safe systemic application in humans [1-4]. After a 6 month treatment phase, suction blisters will be generated at each site to allow collection of skin cells (blister flap) for use in the epigenomic analysis (Aim 1) and interstitial (blister) fluid for use in measuring cytokines and other inflammatory regulators (Aim 2). Once validated, our approach can be used to safely and efficiently screen the age-modulating potential of pharmacological agents in humans to identify those agents that warrant large, expensive human clinical trials with systemic agent administration.

抽象的 为了识别药物和/或干预措施，有可能延迟年龄的发作和进展 相关的病理，临床前研究使用了可以扩展寿命的动物模型 准确评估。在过去的十年中，已经确定了几种出色的候选疗法。 其中包括MTOR抑制剂（如雷帕霉素），塞洛克蛋白剂，acarbose等。但是，翻译 动物模型对人类的抗衰老结果受到挑战。例如，测量扩展 人类的寿命将是不切实际的，因此有必要识别和验证可以服务的参数 作为健康衰老的替代标记。此外，调整药物的效率通常仅是 在功能不足已经证明的老年人中可以证明。那是对潜在抗的测试 衰老治疗应在一个高龄的人类学科中进行；安全问题 在这个“处于危险中”的人群中，行政管理将更加敏锐。为了规避这些限制，我们 在人类受试者中开发和验证创新，微创，具有成本效益的分析的提议 从65-95岁不等。推定的抗衰老测试药物将局部应用于 在“仅车辆”（对照）的同时，与对方平行施加了前臂上的皮肤。那， 每个主题都将充当自己的控制。 “测试”和安慰剂站点的药效结果 在男性和女性中都会比较，因为年龄调节剂的影响通常不同 性别。确定额外应用的疗法的效率需要强大的衰老生物标志物 可以在皮肤中测量，但可以推广到完整的生物体。为此，我们选择了 使用两个独立参数，这些参数已知可以通过局部衰老（在单个组织中）进行修饰 在系统上：i）DNA甲基化模式或“表观遗传钟”和II）与生物标志物相关的生物标志物 炎。为了验证拟议的技术，我们选择了一种药物，雷帕霉素（Rapa），它具有 已经证明已经调节啮齿动物的衰老，并已在 人类[1-4]。经过6个月的治疗阶段，将在每个站点生成任务水泡，以允许 收集用于表观基因组分析（AIM 1）和间质（泡沫）液的皮肤细胞（水泡皮瓣）的收集 用于测量细胞因子和其他炎症调节剂（AIM 2）。一旦验证，我们的方法就可以 用于安全有效地筛选人类药物的年龄调节潜力 确定那些保证具有全身剂给药的大型，昂贵的人类临床试验的代理。