Impact of mammalian target of rapamycin inhibitor therapy on aging-related outcomes

雷帕霉素抑制剂治疗哺乳动物靶标对衰老相关结果的影响

• 批准号: 10564036
• 负责人: Therese Bittermann
• 金额: $ 41.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564036
• 关键词: Adverse drug effect; Adverse effects; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapy; Animal Model; Animals; Area; Benefits and Risks; Biological Models; Caring; Clinical; Clinical Data; Clinical Trials; Computerized Medical Record; Consensus; Data; Data Sources; Databases; Dimensions; Disease; Dose; Effectiveness; Elderly; Evaluation; FRAP1 gene; Feasibility Studies; Future; General Population; Genetic; Healthcare; Hospitals; Human; Immunosuppression; Impaired cognition; Incidence; Individual; K-Series Research Career Programs; Kidney Transplantation; Knowledge; Link; Longevity; Longitudinal Studies; Longitudinal cohort; Longitudinal, observational study; Malignant Neoplasms; Medicare; Medicare claim; Modernization; Modification; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Neurodegenerative Disorders; Oncology; Organ; Organ Transplantation; Outcome; Pathway interactions; Patients; Physiological; Play; Population; Prevalence; Prevention; Process; Property; Reporting; Research; Resources; Risk; Risk Factors; Role; Safety; Signal Transduction; Sirolimus; Techniques; Therapeutic; Therapy Clinical Trials; Time; Transplant Recipients; Transplantation; United Network for Organ Sharing; Veterans Health Administration; age effect; age related; aged; analog; anti aging; bench to bedside; body system; cancer therapy; care burden; clinical application; clinical effect; clinical investigation; cohort; comorbidity; data registry; effective therapy; experience; experimental study; health care service; health care service utilization; human old age (65+); improved; individualized medicine; inhibitor; inhibitor therapy; interest; liver transplantation; medication safety; novel; older patient; post-transplant; pre-clinical; prevent; safety and feasibility; side effect; symptomatology; transplant database; transplant registry; treatment effect; tumor progression

PROJECT SUMMARY In numerous experimental studies, mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, prolong lifespan, prevent the progression of Alzheimer's disease and related dementias (AD/ADRD) and improve multiple other age-dependent processes. However, there are limited clinical data to know whether these therapies have anti-aging effects in humans. The potential role of mTOR inhibitors as disease-modifying treatment for AD/ADRD is of particular significance given the ongoing lack of clearly effective therapies and their immense healthcare and societal burden. Concern over drug safety, particularly in older patients, has remained a key reason as to why clinical trials investigating the potential benefits of mTOR inhibitors with respect to AD/ADRD and other aging-related outcomes have not been pursued. Yet, the significance of increasing age as a risk factor for mTOR inhibitor-associated adverse effects is not clearly established. Moreover, the majority of clinical trials of mTOR inhibitors suggest that side effects are largely reversible with dose modification and rarely severe. Further clinical investigation into the potential benefits and risks of mTOR inhibitors in the context of human aging is therefore needed. Among patients currently receiving this therapy, transplant recipients are the ideal population in whom to conduct a large and longitudinal observational study on the aging-related effects of mTOR inhibitors. Advantages of this group include their prolonged survival, increasing prevalence and frequent occurrence of common aging-related diseases (including AD/ADRD), among other reasons. The recent creation of a comprehensive database linking national transplant registry data to Medicare claims by the PI represents a welcome opportunity to study these critical knowledge gaps in a real-world cohort. In this study, we will leverage and further enhance this linked Medicare database to investigate the effect of mTOR inhibitors on the survival and healthcare utilization of older kidney and liver transplant recipients in Aim 1. We will subsequently evaluate the effect of mTOR inhibitor therapy and its interaction with age on the risk of AD/ADRD using this data source in Aim 2. Then, in Aim 3, we will establish the independent predictors of mTOR inhibitor adverse effects and perform a comprehensive assessment of real-world drug safety in older transplant recipients using detailed electronic medical record (EMR) data from the Veterans Health Administration (VA). In estimating mTOR inhibitor treatment effects, this proposal will employ modern statistical techniques that draw upon the multidimensional nature of Medicare claims data to strengthen confounder adjustment while applying a time-dependent framework, a novel application of this technique in this research area. Our findings will bring new and important evidence on the clinical effects and safety of mTOR inhibitors in older persons, which will subsequently establish the feasibility of future trials of mTOR inhibitors as treatment for AD/ADRD and as anti-aging therapeutics. Secondarily, the results generated will play a key role in developing consensus guidance that allow for an individualized treatment approach for older kidney and liver transplant recipients in the U.S.

项目概要 在许多实验研究中，哺乳动物雷帕霉素靶点（mTOR）抑制剂，例如雷帕霉素， 延长寿命，预防阿尔茨海默病和相关痴呆症（AD/ADRD）的进展并改善 多个其他与年龄相关的过程。然而，目前尚无足够的临床数据来了解这些药物是否有效。 疗法对人类具有抗衰老作用。 mTOR 抑制剂缓解疾病的潜在作用 鉴于持续缺乏明确有效的治疗方法及其疗效，AD/ADRD 的治疗尤为重要 巨大的医疗保健和社会负担。对药物安全性的担忧，特别是老年患者的安全性，仍然存在 临床试验调查 mTOR 抑制剂在以下方面的潜在益处的一个关键原因 AD/ADRD 和其他与衰老相关的结果尚未得到研究。然而，增加年龄的意义 mTOR 抑制剂相关不良反应的危险因素尚未明确确定。此外，大多数 mTOR 抑制剂的临床试验表明，副作用在很大程度上可以通过剂量调整来逆转，但很少见 严重。进一步临床研究 mTOR 抑制剂在以下情况下的潜在益处和风险 因此，人类的衰老是必要的。在目前接受这种治疗的患者中，移植受者是 对衰老相关影响进行大规模纵向观察研究的理想人群 mTOR 抑制剂。该群体的优点包括生存期长、患病率增加和频繁 常见的衰老相关疾病（包括 AD/ADRD）的发生等原因。最近的创作 将国家移植登记数据与 PI 的医疗保险索赔联系起来的综合数据库代表了 欢迎有机会在现实世界中研究这些关键知识差距。在本研究中，我们将利用 并进一步增强此链接的医疗保险数据库，以研究 mTOR 抑制剂对生存的影响 目标 1 中老年肾移植和肝移植接受者的医疗保健利用率。我们随后将评估 使用此数据源研究 mTOR 抑制剂治疗及其与年龄的相互作用对 AD/ADRD 风险的影响 在目标 2 中。然后，在目标 3 中，我们将建立 mTOR 抑制剂不良反应的独立预测因子和 使用详细信息对老年移植受者的现实世界药物安全性进行全面评估 来自退伍军人健康管理局 (VA) 的电子病历 (EMR) 数据。评估 mTOR 抑制剂 治疗效果，该提案将采用现代统计技术，利用多维 医疗保险索赔数据的性质，以加强混杂因素调整，同时应用时间依赖性 框架，该技术在该研究领域的新颖应用。我们的发现将带来新的、重要的 mTOR 抑制剂对老年人的临床效果和安全性的证据，随后将确定 mTOR 抑制剂未来试验作为 AD/ADRD 治疗和抗衰老疗法的可行性。 其次，产生的结果将在制定共识指导方面发挥关键作用，从而允许 美国老年肾移植和肝移植受者的个体化治疗方法