Safer mTOR inhibition for human geroprotection
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The mTOR inhibitor rapamycin and rapamycin analogs (rapalogs) extend healthspan and lifespan in multiple model systems. However, the unknown potential for adverse events and dose limiting toxicities in non- patient populations have precluded the long-term prophylactic use of rapalogs as a strategy to extend healthy aging. NIA issued RFA-AG-23-008 to evaluate pharmacokinetics and pharmacodynamics (PK/PD) of multiple mTOR inhibitors in older adults at risk for numerous geriatric conditions. RFA-AG-23-008 specified the need to 1) define safe and effective dose(s) in older men and women and 2) develop new methods to assess mTOR activity and PD measures for application in clinical studies. Our team has demonstrated that inhibition of mTOR complex I (mTORC1) is beneficial and extends healthy aging in mice, while many of the negative side effects of rapamycin may result from “off-target” inhibition of a second mTOR complex (mTORC2). Intermittent dosing schedules (5 mg/week) with the rapalog everolimus enable more selective mTORC1 inhibition and increased influenza vaccine efficacy in healthy older humans. However, the highest dosing scheme (20 mg/week) did not improve vaccine efficacy and doubled the number of adverse events compared to low dose and placebo. Therefore, a critical gap in knowledge is the lack of PK/PD data for mTOR inhibitors in older adults to identify a safe dosage that could maximize healthspan extension and minimize adverse effects by selectively targeting mTORC1. The first objective of this project is to establish new methods beyond immunoblotting a limited number of mTOR substrates or immunoprecipitation from tissues to assay complex integrity, which can be readily utilized in humans where only blood and select tissues can usually be obtained. The second objective of this project is to use this novel methodology to identify a safe and effective dosing regimen for mTOR inhibitors that can modify the biology of aging in humans. Here, in Aim 1 we will develop a molecular signature integrating transcriptomics, metabolomics, and lipidomics in mouse blood and muscle that will allow us to discriminate dosing regimens that selectively target mTORC1 or which inhibit both mTORC1 and mTORC2. We will then use our molecular signature to test whether rapalogs are effectively inhibiting mTORC1 or mTORC2 in muscle and/or blood collected from our ongoing 1) observational study of people taking rapalogs off-label under the supervision of their physician and 2) a randomized, placebo control trial of low daily or weekly intermittent everolimus treatment. In Aim 2, we will identify a recommended phase 2 trial dose for rapamycin and a novel mTORC1-specific inhibitor in older men and women by performing a dose escalation study that evaluates PK/PD, safety and tolerability, and mTORC1/2 inhibition using conventional as well as novel approaches. Overall, we will pair comprehensive molecular and pharmacologic approaches to evaluate PK/PD in humans and identify dosing regimens that safely inhibit mTORC1 to allow us to intervene in the biology of aging.
