Clinical evaluation of mTORC1 inhibition for geroprotection.

mTORC1 抑制对老年保护的临床评估。

• 批准号: 10654621
• 负责人: Adam R Konopka
• 金额: $ 135万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654621
• 关键词: Address; Adult; Adverse event; Age of Onset; Aging; Bioenergetics; Biological Markers; Biological Models; Biology of Aging; Biopsy Specimen; Blood; Blood Chemical Analysis; C-Peptide; CCI-779; Cardiovascular Diseases; Chronic; Chronic Disease; Clinical Trials; Complex; DNA Methylation; Dementia; Disease; Dose; Double-Blind Method; Elderly; Ensure; FDA approved; FRAP1 gene; Funding; Glucose; Goals; Hematology; Human; Hyperactivity; Immunosuppression; Incidence; Individual; Insulin; Insulin Resistance; Intervention; Knowledge; Lead; Lipids; Longevity; Metabolic; Mitochondria; Molecular; Molecular Target; Morbidity - disease rate; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phenotype; Physical Function; Physiological; Population; Prevention; Protein Kinase; Proteomics; Resources; Risk; Role; SDZ RAD; Safety; Schedule; Scientist; Signal Transduction; Sirolimus; Skeletal Muscle; Specific qualifier value; Specificity; Techniques; Testing; Tissues; United States; United States National Institutes of Health; Universities; Whole Blood; Wisconsin; age related; aging population; cellular targeting; cognitive function; comorbidity; epigenomics; frailty; healthspan; healthy aging; heart function; high risk; holistic approach; immune function; immunosenescence; improved; influenza virus vaccine; inhibitor; innovation; insight; lipidomics; member; metabolomics; middle age; mortality; multiple omics; pharmacologic; predict clinical outcome; prevent; prophylactic; randomized placebo-controlled clinical trial; research clinical testing; senescence; side effect; transcriptomics; vaccine efficacy

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.

NIA发布了RFA-AG-22-011，以测试化合物在人类中“通过调节基本的衰老相关机制来预防、延迟或治疗衰老相关疾病”。RFA-AG-22-011规定需要进行临床试验，以确定对1）临床结局预测因子的影响，2）分子靶点与脱靶效应的特异性，以及3）安全性。在不同的模型系统中，雷帕霉素（mTOR）机制靶点的药理学抑制已被反复证明可延长寿命并预防或延迟几种年龄相关疾病。然而，迄今为止，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年龄相关疾病的治疗。因此，一个关键的知识缺口是雷帕霉素或雷帕霉素类似物（雷帕霉素类似物）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（mTORC 1）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对第二个mTOR复合物（mTORC 2）的“脱靶”抑制。我们和其他人已经系统地确定了间歇给药方案和替代雷帕霉素类似物，使mTORC 1抑制更具选择性。本项目的目的是确定24周的每日低剂量（0.5 mg/天）或每周间歇（5 mg/周）的雷帕霉素依维莫司治疗是否可以安全地改善中老年胰岛素抵抗成人的生理和分子衰老标志，这些人几乎面临着各种年龄相关疾病的高风险。使用双盲，随机，安慰剂对照临床试验，我们将执行一组金标准和创新技术来测试假设，即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血生化、血液学、血脂、血糖、胰岛素和C肽相对于基线的变化。为了全面研究依维莫司的分子靶点特异性和对衰老机制的影响，我们将评估mTORC 1和mTORC 2信号传导，评估线粒体生物能量学，并在血液和肌肉活检样本中进行多组学方法（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的分泌表型、DNA甲基化时钟和衰老生物标志物的作用。为了完成这种整体方法，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，并将利用多个NIH资助的资源，以确保安全，严格和有效的研究执行。通过完成这项研究，我们希望了解依维莫司是否可以安全地利用mTORC 1抑制剂的有效老年保护作用来治疗和预防人类年龄相关疾病。