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.

项目摘要 在许多实验研究中，雷帕霉素（MTOR）抑制剂（例如雷帕霉素）的哺乳动物靶标 延长寿命，防止阿尔茨海默氏病和相关痴呆症（AD/ADRD）的进展并改善 多个其他与年龄有关的过程。但是，有限的临床数据可以知道这些是否 疗法对人类具有抗衰老作用。 MTOR抑制剂作为疾病改良的潜在作用 鉴于持续缺乏明显有效的疗法及其，对AD/ADRD的治疗特别重要 巨大的医疗保健和社会负担。对药物安全的关注，尤其是在老年患者中，仍然存在 为什么临床试验研究MTOR抑制剂在 尚未追求AD/ADRD和其他与衰老有关的结果。然而，年龄增加的意义 MTOR抑制剂相关的不良反应的危险因素尚未明确确定。而且，大多数 MTOR抑制剂的临床试验表明，副作用在很大程度上可通过剂量修饰而可逆，并且很少 严重。进一步研究MTOR抑制剂在 因此，需要人类衰老。在目前接受此疗法的患者中，移植受者是 理想的人群在其中进行大型纵向观察研究，以了解与老龄化相关的影响 mTOR抑制剂。该组的优点包括它们的长期生存，增加患病率和频繁 出现常见的与衰老有关的疾病（包括AD/ADRD），以及其他原因。最近的创作 将国家移植注册表数据与PI的Medicare索赔联系起来的综合数据库代表 在现实世界中研究这些关键知识差距的欢迎机会。在这项研究中，我们将利用 并进一步增强了该连接的Medicare数据库，以研究MTOR抑制剂对生存的影响 AIM 1和AIM 1中较大的肾脏和肝移植受者的医疗保健利用。我们随后将评估 MTOR抑制剂治疗及其与年龄相互作用对使用此数据源的AD/ADRD风险的影响 在AIM 2中。然后，在AIM 3中，我们将建立MTOR抑制剂不良影响和 使用详细的人对老年移植受者的现实药物安全进行全面评估 退伍军人卫生管理局（VA）的电子病历（EMR）数据。在估计MTOR抑制剂时 治疗效果，该建议将采用现代统计技术来利用多维 Medicare索赔数据的性质数据以加强混淆器调整，同时应用时间依赖 框架，该技术在该研究领域的新应用。我们的发现将带来新的重要 关于老年人MTOR抑制剂的临床影响和安全性的证据，这些抑制剂随后将建立 MTOR抑制剂作为AD/ADRD和抗衰老治疗剂的未来试验的可行性。 其次，产生的结果将在制定共识指导中发挥关键作用，以实现 美国较老的肾脏和肝移植接受者的个性化治疗方法