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

项目摘要 在许多实验研究中，哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，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， 多种年龄依赖性过程。然而，只有有限的临床数据才能知道这些 这些疗法在人类中具有抗衰老作用。mTOR抑制剂作为疾病修饰剂的潜在作用 由于目前缺乏明确有效的治疗方法， 巨大的医疗和社会负担。对药物安全性的担忧，特别是在老年患者中， 为什么临床试验研究mTOR抑制剂的潜在益处， AD/ADRD和其他与衰老相关的结局尚未追踪。然而，随着年龄的增长， mTOR受体相关不良反应的风险因素尚未明确确定。而且大部分 mTOR抑制剂的临床试验表明，副作用在很大程度上是可逆的， 严重。在以下背景下对mTOR抑制剂的潜在获益和风险进行进一步临床研究 因此需要人类衰老。在目前接受这种治疗的患者中，移植受体是 理想的人群，在其中进行大型和纵向观察性研究， mTOR抑制剂。这一群体的优势包括他们的生存期延长，患病率增加， 常见衰老相关疾病（包括AD/ADRD）的发生等原因。最近设立 一个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一个 欢迎有机会在现实世界的队列中研究这些关键的知识差距。在这项研究中，我们将利用 并进一步加强这一关联的医疗保险数据库，以研究mTOR抑制剂对生存的影响。 目标1中老年肾和肝移植受者的医疗保健利用。我们随后将评估 使用该数据源，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 目标2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， 在老年移植受者中进行全面的真实世界药物安全性评估， 退伍军人健康管理局（VA）的电子病历（EMR）数据。在估计mTOR抑制剂时 治疗效果，这项建议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，这种技术在这一研究领域的新应用。我们的发现将带来新的和重要的 关于mTOR抑制剂在老年人中的临床效果和安全性的证据，随后将建立 未来试验mTOR抑制剂作为AD/ADRD治疗和抗衰老治疗的可行性。 其次，所产生的结果将在制定共识指导方面发挥关键作用， 美国老年肾和肝移植受者的个体化治疗方法

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.