# Safer mTOR inhibition for human geroprotection

> **NIH NIH U01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $610,352

## Abstract

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 ide...

## Key facts

- **NIH application ID:** 10837717
- **Project number:** 5U01AG081482-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Adam R Konopka
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $610,352
- **Award type:** 5
- **Project period:** 2023-05-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837717

## Citation

> US National Institutes of Health, RePORTER application 10837717, Safer mTOR inhibition for human geroprotection (5U01AG081482-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10837717. Licensed CC0.

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