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）可延长健康寿命和寿命 多模型系统。然而，在非药物中不良事件和剂量限制性毒性的潜在可能性未知。 患者群体已经排除了长期预防性使用雷帕霉素类似物作为延长健康寿命的策略 老化。 NIA发布RFA-AG-23-008评估多种药物的药代动力学和药效学（PK/PD） mTOR 抑制剂适用于面临多种老年病风险的老年人。 RFA-AG-23-008 指定了需要 1) 确定老年男性和女性的安全有效剂量，2) 开发评估 mTOR 的新方法 临床研究中应用的活性和 PD 测量。 我们的团队已经证明，抑制 mTOR 复合物 I (mTORC1) 是有益的，并且可以延长 小鼠的健康衰老，而雷帕霉素的许多负面副作用可能是由于“脱靶”造成的 抑制第二个 mTOR 复合物 (mTORC2)。 rapalog 的间歇给药方案（5 毫克/周） 依维莫司能够更选择性地抑制 mTORC1 并提高健康老年人的流感疫苗功效 人类。然而，最高剂量方案（20毫克/周）并没有提高疫苗功效，反而使疫苗效果翻倍。 与低剂量和安慰剂相比不良事件的数量。因此，知识上的一个关键差距是 缺乏 mTOR 抑制剂在老年人中的 PK/PD 数据，无法确定可最大限度发挥作用的安全剂量 通过选择性地靶向 mTORC1，延长健康寿命并最大限度地减少副作用。 该项目的首要目标是建立超越免疫印迹有限数量的新方法 mTOR 底物或组织的免疫沉淀来测定复合物的完整性，这可以很容易地 用于通常只能获得血液和特定组织的人类。本次活动的第二个目标 该项目旨在利用这种新颖的方法来确定 mTOR 抑制剂安全有效的给药方案 可以改变人类衰老的生物学原理。在这里，在目标 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将使我们能够区分 选择性靶向 mTORC1 或同时抑制 mTORC1 和 mTORC2 的给药方案。我们随后将 使用我们的分子特征来测试 rapalogs 是否能有效抑制肌肉中的 mTORC1 或 mTORC2 和/或从我们正在进行的 1) 观察性研究中收集的血液，该研究对人们在标签外服用雷帕霉素类似物 医生的监督和 2) 每天或每周间歇性低剂量的随机安慰剂对照试验 依维莫司治疗。在目标 2 中，我们将确定雷帕霉素的推荐 2 期试验剂量和一种新型药物 通过进行剂量递增研究评估老年男性和女性的 mTORC1 特异性抑制剂 使用传统方法和新颖方法进行 PK/PD、安全性和耐受性以及 mTORC1/2 抑制。 总的来说，我们将结合全面的分子和药理学方法来评估人类的 PK/PD 并确定安全抑制 mTORC1 的给药方案，使我们能够干预衰老生物学。