Short-term mTOR inhibition by rapamycin improves cardiac and endothelial function in older men: a proof-of concept pilot study

Rapamycin (RAPA) and related mTOR-inhibitors have been shown to enhance healthy aging in animal models (2-10) and to be generally safe and tolerable in older people (11-13). However, studies to assess their effects on specific age-related pathologies in humans are limited. Since improvements in cardiovascular function with RAPA treatment have been reported in preclinical studies (5, 9, 10, 14-17), we posited that RAPA could be similarly efficacious in humans. Towards this end, we performed a pilot "proof of concept" trial to examine RAPA's effects on cardiovascular and endothelial functions that are known to decline with age (18, 19). We hypothesized that RAPA would elicit beneficial cardiovascular effects in men. A cohort of older male subjects with no known cardiac disease (ages 70-76 years) were enrolled in the open-label study and received 1 mg RAPA/day for 8 weeks. To assess cardiovascular function, cardiac MRI (CMR) was performed twice: prior to initiation of the intervention and again after 8 weeks of treatment. Endothelial function was examined using laser-Doppler flowmetry (LDF) by measuring cutaneous, endothelium-dependent, local thermal hyperemic responses pre-intervention and after 4 and 8 weeks of RAPA (1). In all 6 subjects, transmitral blood flow, peak flow rate, and maximal blood acceleration showed statistically significant improvements while endothelial function also improved over the 8-week course of RAPA treatment. Thus, cardiac and endothelial function improvements with RAPA were found and support future placebo-controlled studies in larger cohorts of healthy older persons as well as in patients with compromised diastolic and endothelial function (20, 21).