The DOI matches its Crossref record; 22 of the 23 references it cites were found in a registry or an index.
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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“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]
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1 retracted
Bonkowski, M. S., Dominici, F. P., Arum, O., Rocha, J. S., Al-Regaiey, K., Westbrook, R., Spong, A., Panici, J. A., Masternak, M. M., Kopchick, J. J., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004567 · Cited by 125
Self-citationRetractedTOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766
Self-citationProlonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,365
mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex
Cunningham, J. T., Rodgers, J. T., Arlow, D. H., Vazquez, F., Mootha, V. K., & Puigserver, P. (2007) · Nature · doi:10.1038/nature06322 · Cited by 1,488
Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity
Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., Davis, J. G., Salmon, A. B., Richardson, A., Ahima, R. S., et al. (2012) · Science · doi:10.1126/science.1215135 · Cited by 1,199
Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
Selman, C., Tullet, J. M. A., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., et al. (2009) · Science · doi:10.1126/science.1177221 · Cited by 1,120
The Critical Role of Metabolic Pathways in Aging
Barzilai, N., Huffman, D. M., Muzumdar, R. H., & Bartke, A. (2012) · Diabetes · doi:10.2337/db11-1300 · Cited by 803
Self-citationPende, M., Um, S. H., Mieulet, V., Sticker, M., Goss, V. L., Mestan, J., Mueller, M., Fumagalli, S., Kozma, S. C., & Thomas, G. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.8.3112-3124.2004 · Cited by 766
Li, S., Brown, M. S., & Goldstein, J. L. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914798107 · Cited by 733 · cited 2×
“…and hypertriglyceridemia occur (Matsumoto et al., 2006). mTORC1 is required for insulin-induced stimulation of lipogenesis but not for inhibition of gluconeogenesis (Li et al., 2010), and 2 weeks of rapamycin treatment inhibited lipogenesis and upregulated gluconeogenesis (Houde et al., 2010).”
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Rapamycin: one drug, many effects
Li, J., Kim, S. G., & Blenis, J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.001 · Cited by 1,287
Autophagy—a key player in cellular and body metabolism
Kim, K. H., & Lee, M. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2014.35 · Cited by 972
Metabolic Control of Longevity
López-Otín, C., Galluzzi, L., Freije, J. M. P., Madeo, F., & Kroemer, G. (2016) · Cell · doi:10.1016/j.cell.2016.07.031 · Cited by 753
Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism
Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., Caples, K., Bradley, L., Beaver, L. M., Ho, E., et al. (2017) · Aging Cell · doi:10.1111/acel.12587 · Cited by 360
Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases
Perl, A. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.172 · Cited by 348
Metadata
- 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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