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A novel rapamycin analog is highly selective for mTORC1 in vivo

Schreiber, Katherine H., Arriola Apelo, Sebastian I., Yu, Deyang, Brinkman, Jacqueline A., Velarde, Michael C., Syed, Faizan A., Liao, Chen-Yu, Baar, Emma L., Carbajal, Kathryn A., Sherman, Dawn S., Ortiz, Denise, Brunauer, Regina, Yang, Shany E., Tzannis, Stelios T., Kennedy, Brian K., Lamming, Dudley W.·2019·Nature Communications
DOI 10.1038/s41467-019-11174-0PMC PMC6642166
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Abstract

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.

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Figures

Fig. 1 DL001 is a selective inhibitor of mTORC1. a Structure of DL001. b, c PC3 cells were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and b the phosphorylation of S6K1 T389 (a mTORC1 substrate), S6 S240/S244 (a readout for mTORC1 activity), and AKT S473 (a mTORC2 substrate) was determined by western blotting; c the inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; *p < 0.005, Sidak’s test following two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red. d–f The IC50 for rapamycin (Rap) and DL001 against d mTORC1 and e mTORC2 was determined using an in vitro assay to measure the phosphorylation of S6 S240/S244 (mTORC1) and AKT S473 (mTORC2) in PC3 lysates treated for 24 h. Rapamycin data are plotted in black, DL001 data plotted in red. f The selectivity of each compound for mTORC1 was calculated from the IC50 (n = 4 biologically independent replicates, three technical replicates each; IC50 was calculated using Prism 7; *p < 0.05, Student’s t-test). g–i Quantitative proteomic analysis was performed on PC3 cells treated for 24 h with 100 nM Rapamycin (Rap) or DL001, or vehicle, and significantly affected (q < 0.05) proteins were analyzed with gProfiler to identify significantly altered KEGG and Reactome categories, which included g ribosome, h translation initiation, and i macroautophagy and lysosome. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 1 DL001 is a selective inhibitor of mTORC1. a Structure of DL001. b, c PC3 cells were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and b the phosphorylation of S6K1 T389 (a mTORC1 substrate), S6 S240/S244 (a readout for mTORC1 activity), and AKT S473 (a mTORC2 substrate) was determined by western blotting; c the inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; *p < 0.005, Sidak’s test following two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red. d–f The IC50 for rapamycin (Rap) and DL001 against d mTORC1 and e mTORC2 was determined using an in vitro assay to measure the phosphorylation of S6 S240/S244 (mTORC1) and AKT S473 (mTORC2) in PC3 lysates treated for 24 h. Rapamycin data are plotted in black, DL001 data plotted in red. f The selectivity of each compound for mTORC1 was calculated from the IC50 (n = 4 biologically independent replicates, three technical replicates each; IC50 was calculated using Prism 7; *p < 0.05, Student’s t-test). g–i Quantitative proteomic analysis was performed on PC3 cells treated for 24 h with 100 nM Rapamycin (Rap) or DL001, or vehicle, and significantly affected (q < 0.05) proteins were analyzed with gProfiler to identify significantly altered KEGG and Reactome categories, which included g ribosome, h translation initiation, and i macroautophagy and lysosome. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 2 DL001 is an FKBP12-dependent mTORC1 inhibitor. a Decreased protein expression of FKBP12 and FKBP51 by shRNA was verified via western blotting. b–d PC3 cells expressing b a nonspecific control shRNA (shCtrl), c shRNA against FKBP12, or d shRNA against FKBP51 were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and the phosphorylation of S6 S240/S244 (a readout for mTORC1 activity) and AKT S473 (a mTORC2 substrate) was determined by western blotting. e–f The inhibition of e S6 S240/S244 phosphorylation and f The inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; statistics for the overall effects of knockdown of FKBP12 or FKBP51 represent the p-value from a two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red; squares represent cells expressing shCtrl, circles cells expressing shFKBP12, and triangles cells expressing shFKBP51. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 2 DL001 is an FKBP12-dependent mTORC1 inhibitor. a Decreased protein expression of FKBP12 and FKBP51 by shRNA was verified via western blotting. b–d PC3 cells expressing b a nonspecific control shRNA (shCtrl), c shRNA against FKBP12, or d shRNA against FKBP51 were treated with rapamycin or DL001 at 0.3–100 nM for 48 h and the phosphorylation of S6 S240/S244 (a readout for mTORC1 activity) and AKT S473 (a mTORC2 substrate) was determined by western blotting. e–f The inhibition of e S6 S240/S244 phosphorylation and f The inhibition of AKT S473 phosphorylation was plotted (n = 3 biologically independent experiments; statistics for the overall effects of knockdown of FKBP12 or FKBP51 represent the p-value from a two-way ANOVA). Rapamycin data are plotted in black, DL001 data plotted in red; squares represent cells expressing shCtrl, circles cells expressing shFKBP12, and triangles cells expressing shFKBP51. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 3 DL001 selectively inhibits mTORC1 in vivo. a–d Protein lysates were prepared from the a liver, b gastrocnemius, and c heart of female C57BL/6J mice treated with vehicle or 13 mg kg−1 DL001 every other day for 20 days, and the phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting. d The activity of DL001 and rapamycin against mTORC1 and mTORC2 was determined by quantification of the western blots above and from mice treated in parallel with 8 mg kg−1 rapamycin 30 using NIH ImageJ (n = 4 biologically independent animals per group, *p < 0.05, Tukey–Kramer test following one-way ANOVA). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. e, f C57BL/6J mice were treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks. e Quantification of phosphorylated liver proteins in vehicle, rapamycin, and DL001-treated mice (n = 17 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals for quantification of phosphorylated S6 and S6K1, 12 vehicle, 10 rapamycin, and 6 DL0001-treated biologically independent animals for quantification of phosphorylated ULK1; Dunnett’s test following one-way ANOVA, *p < 0.05). f The integrity of mTORC2 was determined by immunoprecipitation of Rictor from liver lysate; the immunoprecipitate and lysate were probed with antibodies against the indicated proteins and quantified with NIH ImageJ. mTOR(IP) and RICTOR(IP) refer to the quantification of the mTOR and RICTOR immunoblots from the RICTOR immunoprecipitate (n = 6 vehicle, 5 rapamycin, and 3 DL001-treated biologically independent animals, *p < 0.05, Tukey–Kramer test following one-way ANOVA). e, f Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 3 DL001 selectively inhibits mTORC1 in vivo. a–d Protein lysates were prepared from the a liver, b gastrocnemius, and c heart of female C57BL/6J mice treated with vehicle or 13 mg kg−1 DL001 every other day for 20 days, and the phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting. d The activity of DL001 and rapamycin against mTORC1 and mTORC2 was determined by quantification of the western blots above and from mice treated in parallel with 8 mg kg−1 rapamycin 30 using NIH ImageJ (n = 4 biologically independent animals per group, *p < 0.05, Tukey–Kramer test following one-way ANOVA). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. e, f C57BL/6J mice were treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks. e Quantification of phosphorylated liver proteins in vehicle, rapamycin, and DL001-treated mice (n = 17 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals for quantification of phosphorylated S6 and S6K1, 12 vehicle, 10 rapamycin, and 6 DL0001-treated biologically independent animals for quantification of phosphorylated ULK1; Dunnett’s test following one-way ANOVA, *p < 0.05). f The integrity of mTORC2 was determined by immunoprecipitation of Rictor from liver lysate; the immunoprecipitate and lysate were probed with antibodies against the indicated proteins and quantified with NIH ImageJ. mTOR(IP) and RICTOR(IP) refer to the quantification of the mTOR and RICTOR immunoblots from the RICTOR immunoprecipitate (n = 6 vehicle, 5 rapamycin, and 3 DL001-treated biologically independent animals, *p < 0.05, Tukey–Kramer test following one-way ANOVA). e, f Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 4 Unlike rapamycin, DL001 does not cause metabolic disruption. a–i C57BL/6J mice were treated with vehicle, 8 mg kg−1 rapamycin, or 12 mg kg−1 DL001 every other day. a Glucose and b pyruvate tolerance tests were performed after 2 or 3 weeks, respectively (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals; for GTT/PTT, Tukey–Kramer test following two-way repeated-measures ANOVA, a = p < 0.006 vs. vehicle, b = p < 0.006 vs. DL001. For AUC, means with the same letter are not significantly different from each other (Tukey–Kramer test following one-way ANOVA, p < 0.0007)). For GTT/PTT, data from Vehicle-treated mice are plotted with white squares, Rapamycin-treated mice with black squares, and DL001-treated mice with red triangles. c Fasting blood glucose was measured in mice after 4 weeks of treatment (n = 14 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). d–f Blood was collected after 5 weeks of treatment and plasma levels of d cholesterol, e triglycerides, and f free fatty acids were determined (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). g–i Flow cytometry analysis (expressed as percent of total live cells) of splenocytes collected and isolated after 5 weeks of treatment (n = 18 vehicle, 17 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). a–i Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 4 Unlike rapamycin, DL001 does not cause metabolic disruption. a–i C57BL/6J mice were treated with vehicle, 8 mg kg−1 rapamycin, or 12 mg kg−1 DL001 every other day. a Glucose and b pyruvate tolerance tests were performed after 2 or 3 weeks, respectively (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals; for GTT/PTT, Tukey–Kramer test following two-way repeated-measures ANOVA, a = p < 0.006 vs. vehicle, b = p < 0.006 vs. DL001. For AUC, means with the same letter are not significantly different from each other (Tukey–Kramer test following one-way ANOVA, p < 0.0007)). For GTT/PTT, data from Vehicle-treated mice are plotted with white squares, Rapamycin-treated mice with black squares, and DL001-treated mice with red triangles. c Fasting blood glucose was measured in mice after 4 weeks of treatment (n = 14 vehicle, 16 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). d–f Blood was collected after 5 weeks of treatment and plasma levels of d cholesterol, e triglycerides, and f free fatty acids were determined (n = 18 vehicle, 18 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). g–i Flow cytometry analysis (expressed as percent of total live cells) of splenocytes collected and isolated after 5 weeks of treatment (n = 18 vehicle, 17 rapamycin, and 9 DL001-treated biologically independent animals, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). a–i Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central
Fig. 5 DL001 corrects mTORC1-mediated signaling and metabolic defects of TSC1−/− cells. a Immortalized mouse embryonic fibroblasts (MEFs) expressing or lacking TSC1 were treated with varying doses of rapamycin or DL001 for 24 h. The phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting of protein lysate. b–d MEFs expressing (T1+/+) or lacking TSC1 (TSC1−/−) were treated with vehicle, 100 nM rapamycin, or 100 nM DL001 for 24 h, and the expression of mTORC1 responsive genes involved in b glycolysis, c sterol biosynthesis, and d fatty acid biosynthesis were determined by qPCR (n = 4 biologically independent experiments per condition, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). e Protein lysates were prepared from the brain of C57BL/6J mice treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks, and the phosphorylation of S240/S244 S6 was determined by western blotting (n = 3 vehicle, 4 rapamycin, and 4 DL001-treated biologically independent animals, Tukey–Kramer test following one-way ANOVA, *p < 0.05). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data file
Fig. 5 DL001 corrects mTORC1-mediated signaling and metabolic defects of TSC1−/− cells. a Immortalized mouse embryonic fibroblasts (MEFs) expressing or lacking TSC1 were treated with varying doses of rapamycin or DL001 for 24 h. The phosphorylation of S240/S244 S6 (a readout for mTORC1 activity) and Akt S473, an mTORC2 substrate, was determined by western blotting of protein lysate. b–d MEFs expressing (T1+/+) or lacking TSC1 (TSC1−/−) were treated with vehicle, 100 nM rapamycin, or 100 nM DL001 for 24 h, and the expression of mTORC1 responsive genes involved in b glycolysis, c sterol biosynthesis, and d fatty acid biosynthesis were determined by qPCR (n = 4 biologically independent experiments per condition, means with the same letter are not significantly different from each other, Tukey–Kramer test following one-way ANOVA, p < 0.05). e Protein lysates were prepared from the brain of C57BL/6J mice treated with either vehicle, 8 mg kg−1 rapamycin or 12 mg kg−1 DL001 every other day for 5 weeks, and the phosphorylation of S240/S244 S6 was determined by western blotting (n = 3 vehicle, 4 rapamycin, and 4 DL001-treated biologically independent animals, Tukey–Kramer test following one-way ANOVA, *p < 0.05). Data from Vehicle-treated mice are plotted with white bars, rapamycin-treated mice with black bars, and DL001-treated mice with red bars. Error bars represent standard error. Source data are provided as a Source Data fileCC BY · PubMed Central

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Cites

Research works printed but not linked: 59

  1. Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010). · DOI · Paper page
  2. Powers, R. W. 3rd, Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006). · DOI · Paper page
  3. Majumder, S. et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell 11, 326–335 (2012). · DOI
  4. Dai, D. F. et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13, 529–539 (2014). · DOI
  5. Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012). · DOI · Paper page
  6. Urfer, S. R. et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39, 117–127 (2017). · DOI · Paper page
  7. Lelegren, M., Liu, Y., Ross, C., Tardif, S. & Salmon, A. B. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol. Aging Age Relat. Dis. 6, 31793 (2016). · DOI
  8. Trelinska, J. et al. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anti-cancer drugs 26, 437–442 (2015). · DOI · Paper page
  9. Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest 123, 980–989 (2013). · DOI · Paper page
  10. Kennedy, B. K. & Lamming, D. W. The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging. Cell Metab. 23, 990–1003 (2016). · DOI · Paper page
  11. Verges, B. & Cariou, B. mTOR inhibitors and diabetes. Diabetes Res Clin. Pr. 110, 101–108 (2015). · DOI
  12. Kaplan, B., Qazi, Y. & Wellen, J. R. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant. Rev. 28, 126–133 (2014). · DOI
  13. Hurvitz, S. A. et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 16, 816–829 (2015). · DOI
  14. Yao, J. C. et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387, 968–977 (2016). · DOI
  15. Arriola Apelo, S. I., Pumper, C. P., Baar, E. L., Cummings, N. E. & Lamming, D. W. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J. Gerontol. A Biol. Sci. Med Sci. 71, 876–881 (2016). · DOI
  16. Kraig, E. et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp. Gerontol. 105, 53–69 (2018). · DOI · Paper page
  17. Miller, R. A. et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13, 468–477 (2014). · DOI
  18. Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 5, e16351 (2016). · DOI · Paper page
  19. Dumas S. N., Lamming D. W. Next generation strategies for geroprotection via mTORC1 inhibition. J. Gerontol. A Biol. Sci. Med. Sci. glz056 https://doi.org/10.1093/gerona/glz056 (2019). [Epub ahead of print] · DOI
  20. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004). · DOI · Paper page
  21. Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012). · DOI · Paper page
  22. Zeng, Z. et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109, 3509–3512 (2007). · DOI
  23. Schreiber, K. H. et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14, 265–273 (2015). · DOI
  24. Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006). · DOI · Paper page
  25. Liang, J., Choi, J. & Clardy, J. Refined structure of the FKBP12-rapamycin-FRB ternary complex at 2.2 A resolution. Acta Crystallogr D. Biol. Crystallogr 55, 736–744 (1999). · DOI · Paper page
  26. Marz, A. M., Fabian, A. K., Kozany, C., Bracher, A. & Hausch, F. Large FK506-binding proteins shape the pharmacology of rapamycin. Mol. Cell Biol. 33, 1357–1367 (2013). · DOI · Paper page
  27. Harrington, L. S. et al. The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223 (2004). · DOI
  28. Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332, 1317–1322 (2011). · DOI · Paper page
  29. Tang, Y. et al. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat. Commun. 7, 11365 (2016). · DOI
  30. Kumar, A. et al. Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity. Mol. Cell Biol. 28, 61–70 (2008). · DOI
  31. Kumar, A. et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59, 1397–1406 (2010). · DOI
  32. Lamming, D. W. et al. Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 13, 911–917 (2014). · DOI · Paper page
  33. de Wit, D. et al. Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer. Cancer Chemother. Pharm. 78, 63–71 (2016). · DOI
  34. Kovarik, J. M. et al. Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure. J. Heart Lung Transpl. 22, 1117–1125 (2003). · DOI
  35. Lamming, D. W. et al. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell 12, 712–718 (2013). · DOI
  36. Lamming, D. W. & Sabatini, D. M. A Central role for mTOR in lipid homeostasis. Cell Metab. 18, 465–469 (2013). · DOI
  37. Peterson, T. R. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408–420 (2011). · DOI
  38. Soliman, G. A., Acosta-Jaquez, H. A. & Fingar, D. C. mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes. Lipids 45, 1089–1100 (2010). · DOI
  39. Chakrabarti, P. et al. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol. Cell Biol. 33, 3659–3666 (2013). · DOI
  40. Mahe, E. et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 79, 476–482 (2005). · DOI
  41. Goldberg, E. L. et al. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14, 130–138 (2015). · DOI
  42. Goldberg, E. L., Smithey, M. J., Lutes, L. K., Uhrlaub, J. L. & Nikolich-Zugich, J. Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J. Immunol. 193, 757–763 (2014). · DOI · Paper page
  43. Wang, Y. et al. Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice. J. Immunol. 186, 2809–2818 (2011). · DOI
  44. Makki, K. et al. Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice. PLoS ONE 9, e92684 (2014). · DOI
  45. Kwiatkowski, D. J. & Manning, B. D. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet 14(Spec No. 2), R251–R258 (2005). · DOI · Paper page
  46. Yang, J. et al. Renal tumours in a Tsc2( + /-) mouse model do not show feedback inhibition of Akt and are effectively prevented by rapamycin. Oncogene 34, 922–931 (2015). · DOI
  47. Krueger, D. A. et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 80, 574–580 (2013). · DOI
  48. Kwiatkowski, D. J. et al. Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2. Eur. J. Hum. Genet. : EJHG 23, 1665–1672 (2015). · DOI
  49. Bissler, J. J. et al. Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. PLoS One 12, e0180939 (2017). · DOI · Paper page
  50. Krueger, D. A. et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology 87, 2408–2415 (2016). · DOI · Paper page
  51. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010). · DOI · Paper page
  52. Li, K. et al. Rheb1 deletion in myeloid cells aggravates OVA-induced allergic inflammation in mice. Sci. Rep. 7, 42655 (2017). · DOI
  53. Yang, W. et al. Genetic deletion of Rheb1 in the brain reduces food intake and causes hypoglycemia with altered peripheral metabolism. Int J. Mol. Sci. 15, 1499–1510 (2014). · DOI
  54. Tian, Q. et al. RHEB1 insufficiency in aged male mice is associated with stress-induced seizures. Geroscience 39, 557–570 (2017). · DOI
  55. Frey, J. W., Jacobs, B. L., Goodman, C. A. & Hornberger, T. A. A role for Raptor phosphorylation in the mechanical activation of mTOR signaling. Cell Signal 26, 313–322 (2014). · DOI
  56. Crino, P. B. Focal brain malformations: a spectrum of disorders along the mTOR cascade. Novartis Found. Symp. 288, 260–272 (2007). discussion 272–281. · DOI
  57. Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M. & Baur, J. A. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front Genet 3, 177 (2012). · DOI
  58. Cummings, N. E. et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J. Physiol. 596, 623–645 (2018). · DOI
  59. Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43, e47 (2015). · DOI · Paper page

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Metadata

Authors
Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., Liao, C.-Y., Baar, E. L., Carbajal, K. A., Sherman, D. S., Ortiz, D., Brunauer, R., Yang, S. E., Tzannis, S. T., Kennedy, B. K., & Lamming, D. W.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-07-19
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-11174-0
PMC
PMC6642166
Cited by
177
References
11
Language
en
Licence
Funders
  • American Diabetes Association (1-16-PMF-001)
  • American Heart Association (17PRE33410983)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30CA014520)
  • U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (UL1TR002373)
  • UW | School of Medicine and Public Health, University of Wisconsin-Madison
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG056771, R01AG062328)
  • Aeonian Pharmaceuticals

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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