Safer mTOR inhibition for human geroprotection

更安全的 mTOR 抑制可促进人类老年保护

• 批准号: 10647339
• 负责人: Adam R Konopka
• 金额: $ 61.82万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647339
• 关键词: Address; Adverse effects; Adverse event; Affect; Age; Aging; Biological Assay; Biological Models; Biology of Aging; Blood; Blood Chemical Analysis; CCI-779; Clinic; Clinical Research; Complex; Data; Diet; Disease; Dose; Dose Limiting; Elderly; FRAP1 gene; Gene Expression; Genetic Transcription; Goals; Hematology; Human; Immunoprecipitation; Immunosuppression; Knowledge; Label; Lipids; Longevity; Measures; Metabolic; Methodology; Methods; Mission; Molecular; Molecular Profiling; Molecular Target; Morbidity - disease rate; Mus; Muscle; Observational Study; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Physiological; Placebos; Population; Protein Kinase; Public Health; Recommendation; Regimen; Research; Risk; SDZ RAD; Safety; Schedule; Scheme; Signal Transduction; Sirolimus; Specific qualifier value; Specificity; Study Subject; Supervision; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Translating; United States; Viral Genes; Western Blotting; age related; cellular targeting; dosage; glucose tolerance; healthspan; healthy aging; influenza virus vaccine; inhibitor; insight; lipidomics; mTOR Inhibitor; mTOR inhibition; mTOR protein; member; metabolomics; mortality; novel; novel strategies; older men; older women; pharmacodynamic model; pharmacokinetics and pharmacodynamics; pharmacologic; phase II trial; prevent; prophylactic; randomized placebo controlled trial; randomized, clinical trials; sex; side effect; transcriptomics; vaccine efficacy

The mTOR inhibitor rapamycin and rapamycin analogs (rapalogs) extend healthspan and lifespan in multiple model systems. However, the unknown potential for adverse events and dose limiting toxicities in non- patient populations have precluded the long-term prophylactic use of rapalogs as a strategy to extend healthy aging. NIA issued RFA-AG-23-008 to evaluate pharmacokinetics and pharmacodynamics (PK/PD) of multiple mTOR inhibitors in older adults at risk for numerous geriatric conditions. RFA-AG-23-008 specified the need to 1) define safe and effective dose(s) in older men and women and 2) develop new methods to assess mTOR activity and PD measures for application in clinical studies. Our team has demonstrated that inhibition of mTOR complex I (mTORC1) is beneficial and extends healthy aging in mice, while many of the negative side effects of rapamycin may result from “off-target” inhibition of a second mTOR complex (mTORC2). Intermittent dosing schedules (5 mg/week) with the rapalog everolimus enable more selective mTORC1 inhibition and increased influenza vaccine efficacy in healthy older humans. However, the highest dosing scheme (20 mg/week) did not improve vaccine efficacy and doubled the number of adverse events compared to low dose and placebo. Therefore, a critical gap in knowledge is the lack of PK/PD data for mTOR inhibitors in older adults to identify a safe dosage that could maximize healthspan extension and minimize adverse effects by selectively targeting mTORC1. The first objective of this project is to establish new methods beyond immunoblotting a limited number of mTOR substrates or immunoprecipitation from tissues to assay complex integrity, which can be readily utilized in humans where only blood and select tissues can usually be obtained. The second objective of this project is to use this novel methodology to identify a safe and effective dosing regimen for mTOR inhibitors that can modify the biology of aging in humans. Here, in Aim 1 we will develop a molecular signature integrating transcriptomics, metabolomics, and lipidomics in mouse blood and muscle that will allow us to discriminate dosing regimens that selectively target mTORC1 or which inhibit both mTORC1 and mTORC2. We will then use our molecular signature to test whether rapalogs are effectively inhibiting mTORC1 or mTORC2 in muscle and/or blood collected from our ongoing 1) observational study of people taking rapalogs off-label under the supervision of their physician and 2) a randomized, placebo control trial of low daily or weekly intermittent everolimus treatment. In Aim 2, we will identify a recommended phase 2 trial dose for rapamycin and a novel mTORC1-specific inhibitor in older men and women by performing a dose escalation study that evaluates PK/PD, safety and tolerability, and mTORC1/2 inhibition using conventional as well as novel approaches. Overall, we will pair comprehensive molecular and pharmacologic approaches to evaluate PK/PD in humans and identify dosing regimens that safely inhibit mTORC1 to allow us to intervene in the biology of aging.

MTOR抑制剂雷帕霉素和雷帕霉素类似物（Rapalogs）扩展了HealthSpan和寿命 多个模型系统。但是，不良事件的未知潜力和剂量限制非 - 患者人口排除了长期的预防用作Rapalogs作为扩展健康的策略 老化。 NIA发行了RFA-AG-23-008，以评估多种的药代动力学和药效学（PK/PD） 老年人的MTOR抑制剂有许多老年疾病的风险。 RFA-AG-23-008指定了需求 到1）在老年男女中定义安全有效的剂量； 2）开发新方法来评估MTOR 在临床研究中应用的活性和PD测量。 我们的团队表明，抑制MTOR Complex I（MTORC1）是有益的，并且扩展 小鼠的健康衰老，而雷帕霉素的许多负面影响可能是由“脱靶”引起的 抑制第二mTOR复合物（MTORC2）。与Rapalog的间歇性给药时间表（5毫克/周） Everolimus启用更具选择性的MTORC1抑制作用，并提高了健康老年人的影响力疫苗效率 人类。但是，最高的给药方案（20 mg/周）并未提高疫苗效率，并将其翻了一番 与低剂量和安慰剂相比，不良事件的数量。因此，知识的关键差距是 老年人缺乏MTOR抑制剂的PK/PD数据，无法确定可以最大化的安全剂量 通过选择性靶向MTORC1，HealthSpan扩展并最小化不良影响。 该项目的第一个目的是建立除了有限数量的免疫印迹之外的新方法 MTOR底物或从组织到测定复杂完整性的免疫沉淀，可以很容易地 通常在人类中使用，通常只能获得血液和选择的组织。第二个目标 项目是使用这种新颖的方法来确定MTOR抑制剂的安全有效给药方案 这可以改变人类衰老的生物学。在这里，在AIM 1中，我们将开发一个分子签名整合 小鼠血液和肌肉中的转录组学，代谢组学和脂质组学，使我们能够歧视 剂量方案有选择地靶向MTORC1或抑制MTORC1和MTORC2。然后我们会 使用我们的分子签名来测试Rapalogs是否有效抑制MTORC1或MTORC2的肌肉中的MTORC2 和/或我们正在进行的血液中收集的血液1）对在标签之外采取Rapalog的观察性研究 对其物理学的监督和2）每日低或每周的随机，安慰剂控制试验 依维莫司治疗。在AIM 2中，我们将确定雷帕霉素的建议2期试验剂量和一种新颖的剂量 老年男性和女性MTORC1特异性抑制剂通过进行剂量升级研究来评估 PK/PD，安全性和耐受性以及MTORC1/2使用常规和新方法抑制。 总体而言，我们将配对全面的分子和药物方法来评估人类的PK/PD 并确定安全抑制MTORC1的剂量方案，使我们能够干预衰老的生物学。