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Targeting the biology of aging with mTOR inhibitors

Nature Aging volume 3, pages 642–660 (2023)Cite this article

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Abstract

Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.

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Fig. 1: Potential healthspan targets of rapamycin.
Fig. 2: An overview of the mTORC1 signaling pathway with areas of potential pharmaceutical inhibition highlighted.
Fig. 3: The known and unknown effects of rapalog-dosing regimens on metabolic health, the immune system, healthspan and longevity in humans and mice.

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Acknowledgements

We thank M. Simons for suggesting additional references to include in our tables of rapamycin lifespan and survival studies, A. Salmon for sharing information about his in-progress studies and many of our colleagues for providing additional information about their published studies and current and future plans. The Lamming laboratory is supported in part by the NIH–NIA (AG056771, AG062328, AG061635 and AG076941), the NIH–NIDDK (DK125859) and startup and other funds from the University of Wisconsin—Madison School of Medicine and Public Health and the Department of Medicine to D.W.L. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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  1. Tornado Therapeutics, New York, NY, USA

    Joan B. Mannick

  2. Department of Medicine, University of Wisconsin—Madison, Madison, WI, USA

    Dudley W. Lamming

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  1. Joan B. Mannick
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  2. Dudley W. Lamming
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J.B.M. and D.W.L. wrote the manuscript and prepared the figures.

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Correspondence to Dudley W. Lamming.

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Competing interests

J.B.M. is CEO and cofounder of Tornado Therapeutics, which is developing safer, more effective mTOR inhibitors to extend human healthspan, and a former CMO of resTORbio. D.W.L. has received funding from and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop new, selective mTOR inhibitors for the treatment of various diseases.

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Nature Aging thanks Troy Merry and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Mannick, J.B., Lamming, D.W. Targeting the biology of aging with mTOR inhibitors. Nat Aging 3, 642–660 (2023). https://doi.org/10.1038/s43587-023-00416-y

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