Duration of Rapamycin Treatment Has Differential Effects on Metabolism in Mice
Open accessAbstract
The evolutionarily conserved target of rapamycin (TOR) signaling controls growth, metabolism, and aging. In the first robust demonstration of pharmacologically-induced life extension in mammals, longevity was extended in mice treated with rapamycin, an inhibitor of mechanistic TOR (mTOR). However, detrimental metabolic effects of rapamycin treatment were also reported, presenting a paradox of improved survival despite metabolic impairment. How rapamycin extended lifespan in mice with such paradoxical effects was unclear. Here we show that detrimental effects of rapamycin treatment were only observed during the early stages of treatment. These effects were reversed or diminished in mice treated for 20 weeks, with better metabolic profiles, increased oxygen consumption and ketogenesis, and markedly enhanced insulin sensitivity. Thus, prolonged rapamycin treatment lead to beneficial metabolic alterations, consistent with life extension previously observed. Our findings provide a likely explanation of the "rapamycin paradox" and support the potential causal importance of these metabolic alterations in longevity.
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Compensatory pathways are activated in response to chronic rapamycin treatment.
“Specifically, compensatory pathways are activated in response to chronic rapamycin treatment [66, 67].”
From AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma (2021) · cites this paper as [66]
The Results section (“Both mTORC1 and mTORC2 were Involved in Metabolic Alterations”; page not available) reports that 20 weeks of rapamycin reversed several signaling responses seen after shorter treatment. The Discussion says prolonged treatment no longer inhibited phosphorylation of several signaling proteins, but explicitly leaves the mechanism unclear; it does not establish that compensatory pathways were activated. (LLM, conf=0.83)
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- Authors
- Fang, Y., Westbrook, R., Hill, C., Boparai, R. K., Arum, O., Spong, A., Wang, F., Javors, M. A., Chen, J., Sun, L. Y., & Bartke, A.
- Affiliations
- SIU Medicine (US)
- Southern Illinois University Carbondale (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Fang, Yimin
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 17
- Issue
- 3
- Pages
- 456-462
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3658445
- OpenAlex
- W2001399616
- Cited by
- 195
- References
- 23
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 13 · 2021: 20 · 2020: 11 · 2019: 21 · 2018: 14 · 2017: 15 · 2016: 18 · 2015: 26 · 2014: 20 · 2013: 10
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Office of Public Affairs
- National Institute on Aging (AG031736, R21AG038850, R01AG019899, AG038850, P01AG031736, AG019899)
- National Institute of General Medical Sciences (R01GM089771)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR048914)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- rapamycin, mTOR signaling, longevity, lifespan extension, metabolic effects, insulin sensitivity, oxygen consumption, ketogenesis, treatment duration, aging
- MeSH terms
- Animals, Blood Chemical Analysis, Body Composition, Calorimetry, Indirect, Energy Metabolism, Enzyme-Linked Immunosorbent Assay, Insulin Resistance, Longevity, Oxygen Consumption, Time Factors, Blotting, Western, Sirolimus, Mice, TOR Serine-Threonine Kinases
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