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

项目总结 在众多的实验研究中，哺乳动物靶向雷帕霉素(MTOR)抑制剂，如雷帕霉素， 延长寿命，防止阿尔茨海默病和相关痴呆的进展(AD/ADRD)并改善 多个其他年龄相关的过程。然而，只有有限的临床数据来了解这些 治疗方法对人类有抗衰老的作用。MTOR抑制剂作为疾病修饰剂的潜在作用 AD/ADRD的治疗具有特别重要的意义，因为持续缺乏明显有效的治疗方法和他们的 巨大的医疗保健和社会负担。对药物安全性的担忧，特别是对老年患者的担忧仍然存在。 为什么研究mTOR抑制剂在以下方面的潜在益处的临床试验的关键原因 AD/ADRD和其他与老龄化有关的结果尚未得到追求。然而，增加年龄的意义在于 MTOR抑制剂相关不良反应的危险因素尚未明确确定。此外，大多数人 MTOR抑制剂的临床试验表明，副作用在很大程度上是可逆的，通过剂量调整很少发生。 很严重。进一步临床研究mTOR抑制剂的潜在益处和风险 因此，人类老龄化是必要的。在目前正在接受这种疗法的患者中，移植接受者是 对老年人的老龄化相关影响进行大型纵向观察性研究的理想人群 MTOR抑制剂。这一群体的优势包括生存时间长、患病率增加和频繁 发生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 将国家移植登记数据与联邦医疗保险索赔联系起来的综合数据库代表着 欢迎有机会在现实世界中研究这些关键的知识差距。在本研究中，我们将利用 并进一步加强这个链接的医疗保险数据库，以调查mTOR抑制剂对存活率的影响 目标1中老年肾和肝移植受者的医疗保健利用情况。我们将随后评估 MTOR抑制剂治疗及其与年龄的交互作用对AD/ADRD风险的影响 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实际药物安全性进行全面评估 退伍军人健康管理局(VA)的电子病历(EMR)数据。在评估mTOR抑制剂时 治疗效果，这项建议将使用现代统计技术，利用多维 联邦医疗保险索赔数据的性质，以加强混杂因素调整，同时应用与时间相关的 框架，这是该技术在这一研究领域的一个新的应用。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，随后将确定 MTOR抑制剂作为AD/ADRD治疗药物和抗衰老治疗药物未来试验的可行性。 其次，所产生的结果将在制定协商一致的指导意见方面发挥关键作用，使 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.