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. 2023 Oct;45(5):2769-2783.
doi: 10.1007/s11357-023-00935-x. Epub 2023 Oct 6.

Blazing a trail for the clinical use of rapamycin as a geroprotecTOR

Adam R Konopka  1   2   3 , Dudley W Lamming  4   5 ; RAP PAC Investigators; EVERLAST Investigators
Collaborators, Affiliations

Blazing a trail for the clinical use of rapamycin as a geroprotecTOR

Adam R Konopka et al. Geroscience. 2023 Oct.

Abstract

Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.

Keywords: Aging; Everolimus; Metabolism; Muscle; Sirolimus; mTOR.

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Conflict of interest statement

DWL has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. Aeovian Pharmaceutical mTOR inhibitors will not be used in the clinical trials discussed within this manuscript.

Figures

Fig. 1
Fig. 1
Age is one of the greatest risk factors for nearly every chronic condition. Rapamycin is the most repeatable and effective pharmacological approaches to extend lifespan and delay or treat many age-related pathologies in diverse model systems. A critical translational gap in knowledge is whether rapamycin or rapamycin analogs (rapalogs) can safely maintain or improve healthy aging in humans. CVD, cardiovascular disease; T2DM, type 2 diabetes mellitus; ADRD, Alzheimer’s disease and related dementias. Figure adapted from Kaeberlein et al. [3]
Fig. 2
Fig. 2
Rapamycin acutely and potently inhibits mTORC1 while prolonged exposure to high, daily doses of rapamycin can lead to off-target inhibition of mTORC2. We propose to test the model that inhibition of mTORC1 is geroprotective, while inhibition of mTORC2 mediates metabolic side effects of rapamycin. Rapalog strategies that safely exploit the potent geroprotective effects of mTORC1 inhibition may warrant further testing for the treatment and prevention of age-related diseases in larger phase 3 clinical trials
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