RESTOR [Rapamycin and Everolimus Study Towards Older Rejuvenation]: An exploratory PK/PD study of mTOR inhibition in older human subjects - Pharmacological mTOR inhibition (mTORi) extends lifespan and healthspan in older mice, suggesting these medications may similarly slow the progression of age-associated deficits in humans. However, older individuals may exhibit greater susceptibility to adverse drug effects. The current RFA seeks pharmacokinetic (PK) and pharmacodynamic (PD) mTORi studies to gain insights into safe dosing strategies for use in older adults. Indeed, reliable PK/PD indicators of mTOR activity for use in clinical studies could lead to optimal, even individualized age-ameliorating treatments. Towards this end, our over-arching goal is to define PK/PD parameters that reflect mTORi activity in otherwise healthy older adults in order to determine an optimal, safe dosing protocol for clinical amelioration of age-associated functional deficits. Aim 1. Assess PK/PD effects of the mTOR inhibitors Rapamycin (RAPA) and Everolimus (EVERO) in healthy elderly persons as a function of agent, dose, dosing schedule, and sex. We will recruit healthy older persons (65-90 yrs) for a short-term (6 week) adaptive, open-label, dose-finding, PK/PD study comparing RAPA and EVERO using both daily and intermittent dosing. We will make detailed PK measurements while also quantifying mTORi effects on PD biomarkers of mTORC1 [phosphorylation of p70S6K, ribosomal protein S6]; mTORC2 [Akt]; and on a potential PD biomarker, soluble ICAM-1. Optimal dosing will be defined as the mTORi dose and drug that best re-established “youthful” PD values in the older adult subjects. Aim 2. Assess the safety/tolerability/adverse effects of PK/PD-optimized doses as determined in AIM1 for daily and intermittent dosing of either RAPA or EVERO in a placebo-controlled trial in healthy elderly persons of both sexes. With the optimal doses from AIM 1, we will perform a longer-term randomized, placebo-controlled trial of daily vs. intermittent mTORi. To this end, 3 older cohorts of 24 older adults each (12/group x 2 sexes) will be recruited and treated for 6 months with either daily (sustained) mTORi, intermittent mTORi, or placebo. Specimens will be collected for PD biomarkers as in AIM1. In addition, PK/PD parameters will be assessed in skeletal muscle (hydrophilic tissue) and fat (lipophilic tissue) biopsies. Maintenance of the mTORi outcomes post-treatment will be assessed during a 6 month follow-up. Throughout the study, safety measures will be incorporated, including glucose tolerance tests. Undertaking a well-controlled PK/PD study to define those PD parameters that best correlate with optimal mTOR pathway inhibition while being safely administered to the target population is a necessary step in development of mTORi as a therapeutic for enhancing healthy human aging. This long-term goal will be further facilitated as follows: i) PD parameters will be optimized across tissues and may identify an easily assayed surrogate mTORi marker; ii) a Repository of blood/tissues will be established for further aging research, and iii) we expect a diverse demographic drawn from our population, which is >50% Hispanic.
