Cited by 384Genetics, Aging, and Longevity in Model OrganismsPI3K/AKT/mTOR signaling in cancerAutophagy in Disease and Therapy

Targeting the biology of aging with mTOR inhibitors

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Mannick, Joan B., Lamming, Dudley W.·2023·Nature Aging

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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  • The activity of mTOR in the brain increases with age, substantially inhibiting autophagy, which could explain why pathological proteins are prone to accumulation.

    “The activity of mTOR in the brain increases with age,117 substantially inhibiting autophagy, which could explain why pathological proteins are prone to accumulation.118”

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Authors
Mannick, J. B., & Lamming, D. W.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Lamming, Dudley W.
Venue
Nature Aging
Published
2023-05-04
Volume
3
Issue
6
Pages
642-660
ISSN
2662-8465 (ISSN-L)
OpenAlex
W4368374116
Cited by
372
References
256
Citations by year
2026: 103 · 2025: 135 · 2024: 116 · 2023: 18
FWCI
4.61
Type
journal article
Language
en
Open access
Locations
  • Nature Aging (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG056771, AG062328, AG061635 and AG076941)
  • U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK125859)
  • U.S. Department of Veterans Affairs (BX004031)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mTOR inhibitors, rapamycin, mTORC1, aging, longevity, age-related diseases, clinical trials, mouse model, drug safety
MeSH terms
Mechanistic Target of Rapamycin Complex 1, MTOR Inhibitors, Aging, Animals, Biology, Humans, United States, Sirolimus, Mice, TOR Serine-Threonine Kinases

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