Clinical evaluation of mTORC1 inhibition for geroprotection.

NIA发布了RFA-AG-22-011，以测试化合物“通过调节人类基本的衰老相关机制来预防、延缓或治疗与衰老相关的疾病”。RFA-AG-22-011规定需要进行临床试验，以确定以下方面的影响：1)临床结果的预测因素；2)分子靶标与脱靶效应的特异性；3)安全性。在不同的模型系统中，药理抑制雷帕霉素的机制靶点（mTOR）已被反复证明可以延长寿命，预防或延缓几种与年龄相关的疾病。然而，到目前为止，对人类潜在严重副作用的风险阻止了长期使用mTOR抑制剂雷帕霉素作为衰老和与年龄有关的疾病的治疗方法。因此，一个关键的知识缺口是雷帕霉素或雷帕霉素类似物（rapalogs）是否可以安全地改善人类的健康衰老。我们的团队已经证明，抑制mTOR复合物1 （mTORC1）是有益的，并延长了小鼠的健康衰老；然而，雷帕霉素的许多负面副作用是由于在多个组织中“脱靶”抑制第二mTOR复合物（mTORC2）。我们和其他人已经系统地确定了间歇性给药方案和替代rapalogs，使mTORC1抑制更具选择性。该项目的目的是确定24周每日低剂量（0.5 mg/天）或每周间歇性（5mg /周）的拉帕洛依维莫司治疗是否可以安全地改善几乎所有年龄相关疾病的高风险中年至老年胰岛素抵抗成人的生理和分子衰老特征。通过一项双盲、随机、安慰剂对照的临床试验，我们将采用一系列金标准和创新技术来验证每日低剂量或每周依维莫司治疗将改善生理衰老的五个相关领域：代谢、心脏、认知、身体和免疫功能。我们还将评估不良事件的发生率以及基线血液化学、血液学、血脂、葡萄糖、胰岛素和c肽的变化。为了全面研究依维莫司的分子靶标特异性和对衰老机制的影响，我们将在血液和肌肉活检样本中评估mTORC1和mTORC2信号，评估线粒体生物能量学，并采用多组学方法（表观基因组学、转录组学、蛋白质组学、脂质组学和代谢组学）。我们还将探讨依维莫司对衰老相关秘书表型、DNA甲基化时钟和提出的衰老生物标志物的作用。为了完成这一整体方法，科学家和临床医生组成的团队都位于威斯康星大学麦迪逊分校，并将利用美国国立卫生研究院资助的多种资源来确保安全、严格和有效的研究执行。通过这项研究的完成，我们希望了解依维莫司是否可以安全地利用mTORC1抑制的有效老年保护作用来治疗和预防人类年龄相关疾病。

NIA issued RFA-AG-22-011 to test compounds to “prevent, delay, or treat aging-related conditions by modulating fundamental aging-related mechanisms” in humans. RFA-AG-22-011 specified the need for clinical trials to determine the effects on 1) predictors of clinical outcomes, 2) the specificity of molecular target versus off-target effects, and 3) safety. Pharmacological inhibition of mechanistic target of rapamycin (mTOR) has been repeatedly demonstrated to extend lifespan and prevent or delay several age-related diseases in diverse model systems. However, the risk of potentially serious side effects in humans have thus far prevented the long-term use of the mTOR inhibitor rapamycin as a therapy for aging and age-related diseases. Therefore, a critical gap in knowledge is whether rapamycin or rapamycin analogs (rapalogs) can safely improve healthy aging in humans. Our team has demonstrated that inhibition of mTOR complex 1 (mTORC1) is beneficial and extends healthy aging in mice; however, many of the negative side effects of rapamycin result from “off-target” inhibition of a second mTOR complex (mTORC2) in multiple tissues. We and others have systematically identified intermittent dosing schedules and alternative rapalogs that enable more selective mTORC1 inhibition. The objective of this project is to determine if 24 weeks of daily low dose (0.5 mg/day) or weekly intermittent (5 mg/week) treatment with the rapalog everolimus can safely improve physiological and molecular hallmarks of aging in middle-aged to older insulin resistant adults who are at high risk for nearly every age-related condition. Using a double-blinded, randomized, placebo-controlled clinical trial, we will perform a battery of gold standard and innovative techniques to test the hypothesis that daily low dose or weekly everolimus treatment will improve five interrelated domains of physiological aging: metabolic, cardiac, cognitive, physical, and immune function. We will also assess the incidence of adverse events and changes from baseline blood chemistry, hematology, lipids, glucose, insulin, and c-peptide. To comprehensively examine the molecular target specificity and the impact on mechanisms of aging by everolimus, we will evaluate mTORC1 and mTORC2 signaling, assess mitochondrial bioenergetics, and perform a multi-omics approach (epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics) in blood and muscle biopsy samples. We will also explore the role of everolimus on the senescence-associated secretary phenotype, the DNA methylation clock, and proposed biomarkers of aging. To complete this holistic approach, the assembled team of scientists and clinicians are all located at the University of Wisconsin-Madison and will leverage multiple NIH-funded resources to ensure safe, rigorous, and efficient study execution. By completion of this study, we expect to understand if everolimus can safely exploit the potent gero-protective effects of mTORC1 inhibition for the treatment and prevention of age-related diseases in humans.