Abstract Aging is the time-dependent functional decline responsible for increased susceptibility to chronic disease, frailty, and disability. Aging is a substantial public health concern, and new therapeutic interventions intended to mitigate its effects are needed. While preclinical evidence supports the crucial role of mTOR inhibitors in slowing aging processes, the lack of pharmacokinetic (PK) and pharmacodynamic (PD) data in older adults presents a substantial challenge in designing clinical trials. Sirolimus and everolimus are well-studied mTOR inhibitors commonly used in transplantation. However, both age and severe illness can significantly alter drug PK, and there is currently limited data in older adults without underlying, confounding illnesses. Additionally, there is a lack of data to inform the selection of PD biomarkers that optimally demonstrate improvement in age-related processes. Without well-defined PK characterization and identification of robust PD biomarkers, future clinical trials will lack the statistical power needed to establish evidence of effectiveness. To lay the foundation for future studies, we assembled a multidisciplinary team of clinical pharmacologists and epidemiologists, as well as experts in geriatrics, gerontology, and immunosuppression. The primary goal of this research is to precisely estimate fundamental PK/PD parameters of sirolimus and everolimus in older adults without confounding illness. We will first validate measurement techniques and quantify the in vitro exposure-response relationship for two different biomarkers: S6K activity and mitochondrial function (Aim 1). We will then conduct a clinical study to characterize the PK/PD of sirolimus and everolimus in older adults (Aim 2). Lastly, the biomarkers will be evaluated for their ability to demonstrate the magnitude of treatment response over an intermediate term follow-up (Aim 3). We anticipate that our research will address the existing knowledge gaps related to mTOR inhibitor PK/PD, leading to a transformative shift in the field of aging research.