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

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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.