Clinical evaluation of mTORC1 inhibition for geroprotection.

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NIA issued RFA-AG-22-011 to test compounds to “prevent, delay, or treat aging-related conditions by modulating fundamental aging-related mechanisms” in humans. RFA-AG-22-011 specified the need for clinical trials to determine the effects on 1) predictors of clinical outcomes, 2) the specificity of molecular target versus off-target effects, and 3) safety. Pharmacological inhibition of mechanistic target of rapamycin (mTOR) has been repeatedly demonstrated to extend lifespan and prevent or delay several age-related diseases in diverse model systems. However, the risk of potentially serious side effects in humans have thus far prevented the long-term use of the mTOR inhibitor rapamycin as a therapy for aging and age-related diseases. Therefore, a critical gap in knowledge is whether rapamycin or rapamycin analogs (rapalogs) can safely improve healthy aging in humans. Our team has demonstrated that inhibition of mTOR complex 1 (mTORC1) is beneficial and extends healthy aging in mice; however, many of the negative side effects of rapamycin result from “off-target” inhibition of a second mTOR complex (mTORC2) in multiple tissues. We and others have systematically identified intermittent dosing schedules and alternative rapalogs that enable more selective mTORC1 inhibition. The objective of this project is to determine if 24 weeks of daily low dose (0.5 mg/day) or weekly intermittent (5 mg/week) treatment with the rapalog everolimus can safely improve physiological and molecular hallmarks of aging in middle-aged to older insulin resistant adults who are at high risk for nearly every age-related condition. Using a double-blinded, randomized, placebo-controlled clinical trial, we will perform a battery of gold standard and innovative techniques to test the hypothesis that daily low dose or weekly everolimus treatment will improve five interrelated domains of physiological aging: metabolic, cardiac, cognitive, physical, and immune function. We will also assess the incidence of adverse events and changes from baseline blood chemistry, hematology, lipids, glucose, insulin, and c-peptide. To comprehensively examine the molecular target specificity and the impact on mechanisms of aging by everolimus, we will evaluate mTORC1 and mTORC2 signaling, assess mitochondrial bioenergetics, and perform a multi-omics approach (epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics) in blood and muscle biopsy samples. We will also explore the role of everolimus on the senescence-associated secretary phenotype, the DNA methylation clock, and proposed biomarkers of aging. To complete this holistic approach, the assembled team of scientists and clinicians are all located at the University of Wisconsin-Madison and will leverage multiple NIH-funded resources to ensure safe, rigorous, and efficient study execution. By completion of this study, we expect to understand if everolimus can safely exploit the potent gero-protective effects of mTORC1 inhibition for the treatment and prevention of age-related diseases in humans.