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: 10040501
• 负责人: DEAN L KELLOGG
• 金额: $ 23.1万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040501
• 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; 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.

摘要 为了确定有可能延缓衰老发生和发展的药物和/或干预措施- 相关的病理学，临床前研究使用了动物模型，在动物模型中，寿命可能会延长 准确评估。在过去的十年里，已经确定了几种优秀的候选疗法； 这些药物包括mTOR抑制剂(如雷帕霉素)、抗衰老药物、阿卡波糖等。然而，翻译 从动物模型到人类的抗衰老结果一直是具有挑战性的。例如，测量的扩展 寿命在人类身上是不切实际的，因此有必要识别和验证可以用于 作为健康衰老的替代标记。此外，调节年龄的药物的疗效往往只有 在那些已经明显存在功能缺陷的老年人身上表现得很明显。因此，测试潜在的反 衰老疗法应在高龄人群中进行；安全问题 政府将在这一“危险”人群中表现得更加尖锐。为了绕过这些限制，我们 建议开发和验证一种创新的、微创的、成本效益高的人体试验方法 年龄从65岁到95岁不等。这种假定的抗衰老试验药物将局部应用于 受试者前臂上的皮肤，而“仅限车辆”(控制)平行地应用于另一只手臂。因此， 每个受试者将充当他/她自己的控制者。“试验”和安慰剂部位的药效学结果 将在男性和女性中进行比较，因为年龄调节剂的效果通常不同于 性别。要确定局部应用疗法的疗效，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有机体。为此，我们选择了 使用两个已知的独立参数，这两个参数在局部(在个别组织中)都会随着年龄的变化而改变 以及系统地：i)DNA甲基化模式或“表观遗传时钟”以及ii)与 发炎。为了验证所提出的技术，我们选择了一种药物雷帕霉素(RapA)，它具有 已经被证明可以调节啮齿动物的衰老，并且已经被测试为安全的全身应用 人类[1-4]。在6个月的治疗阶段后，每个部位都会产生负压水泡，以便 收集用于表观基因组分析(目标1)的皮肤细胞(水泡瓣)和间质(水泡)液 用于测量细胞因子和其他炎症调节因子(目标2)。一旦得到验证，我们的方法可以 用于安全和有效地筛选人类中的药物调节年龄的潜力 确定那些需要通过系统给药进行大规模、昂贵的人体临床试验的药物。