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发出了RFA-AG-22-011，以测试化合物，以“通过调节与衰老相关的基本机制来预防，延迟或治疗与衰老有关的疾病”。 RFA-AG-22-011指定了对临床试验的需求，以确定对1）临床结局预测的影响，2）分子靶标与脱靶效应的特异性，以及3）安全性。雷帕霉素（MTOR）对机械靶标的药理抑制已被反复证明可以延长寿命并预防或延迟潜水模型系统中的几种与年龄相关的疾病。然而，迄今为止，潜在的严重副作用的风险阻止了MTOR抑制剂雷帕霉素长期使用作为衰老和年龄相关疾病的疗法。因此，知道雷帕霉素或雷帕霉素类似物（Rapalogs）是否可以安全地改善人类健康的衰老。我们的团队表明，抑制MTOR复合物1（MTORC1）是有益的，并且可以扩大小鼠的健康衰老。然而，雷帕霉素的许多负副作用是由于多次对第二mTOR复合物（MTORC2）的“脱靶”抑制引起的。我们和其他人系统地确定了间歇性的给药时间表和替代性Rapalogs，可以抑制更有选择性的MTORC1。该项目的目的是确定每天24周的低剂量（0.5 mg/day）或每周间歇性（5 mg/周）使用Rapalog Everolimus进行治疗，可以安全地改善中年衰老的身体和分子标志，以使年龄较大的年龄较高的疾病高风险。使用双盲，随机，安慰剂对照的临床试验，我们将执行一系列的黄金标准和创新技术，以测试以下假设：每天的低剂量或每周的依依他属治疗将改善五个相互关联的物理衰老领域：代谢，心脏，心脏，认知，物理，物理和免疫学功能。我们还将评估不良事件的事件以及基线血液化学，血液学，脂质，葡萄糖，胰岛素和C肽的变化。为了全面检查分子靶标特异性以及对依维莫司（Everolimus）对衰老机制的影响，我们将评估MTORC1和MTORC2信号传导，评估线粒体生物能学和执行多组学方法（表观基因组学，转录组学，蛋白质组学，蛋白质组学，生物学，脂质组和化学词性）。我们还将探讨依维莫司在感应相关的秘书表型，DNA甲基化时钟以及提出的衰老生物标志物上的作用。为了完成这种整体方法，由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，并将利用多种NIH资助的资源来确保安全，严格且高效的研究执行。通过完成这项研究，我们希望了解Everolimus是否可以安全探索MTORC1抑制对人类治疗和预防年龄相关疾病的潜在Gero保护作用。