mTOR & Autophagy Modulators (Rapamycin) — References

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Parent Topic: mTOR & Autophagy Modulators (Rapamycin) | References Hub: 02 - Compounds & Molecules References MOC

Landmark Peer-Reviewed Studies

Citation: 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., Pahor, M., Javors, M. A., Fernandez, E., & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392–395.
Identifiers: PMID: 19587680 (PubMed · Europe PMC) | PMCID: PMC2786175 (PMC Full Text) | DOI: 10.1038/nature08221 (DOI · SciDB · Scholar)
Study Design & Sample Size: Three-center (Jackson Lab, Univ. of Michigan, UT Health San Antonio) randomized longevity trial in genetically heterogeneous UM-HET3 mice ( $N = 1, 904$ ) initiated on microencapsulated Rapamycin ( $14 ppm$ in diet) late in life at 600 days of age ( $\approx 60 human years$ ).
Key Quantitative Outcomes: Late-life initiation of Rapamycin increased maximal lifespan (90th percentile survival age) across all three independent test sites ( $p < 0.0001$ ), extending total median lifespan by $+ 9%$ in males and $+ 14%$ in females, which corresponded to an increase in remaining life expectancy from age 600 days of $+ 28%$ in males and $+ 38%$ in females.

Citation: Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., Lonetto, M. A., Maecker, H. T., Kovarik, J., Carson, S., Glass, D. J., & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. Science Translational Medicine, 6(268), 268ra179.
Identifiers: PMID: 25540326 (PubMed · Europe PMC) | DOI: 10.1126/scitranslmed.3009892 (DOI · SciDB · Scholar)
Study Design & Sample Size: Randomized, observer-blind, placebo-controlled trial in elderly volunteers aged $\geq 65 years$ ( $N = 218$ ) treated for 6 weeks with the rapalog RAD001 (Everolimus) at $0.5 mg/day$ , $5 mg/week$ , or $20 mg/week$ , followed by a 2-week drug-free washout and trivalent influenza vaccination.
Key Quantitative Outcomes: Both the $0.5 mg/day$ and $5 mg/week$ intermittent regimens met the primary endpoint, increasing geometric mean hemagglutination inhibition antibody titers by $> 1.2 -fold$ ( $+ 20%$ ) across vaccine strains ( $p < 0.01$ ), expanding broad heterologous cross-reactive antibodies, and reducing the percentage of exhausted $PD-1^{+} CD4^{+}$ and $PD-1^{+} CD8^{+}$ T-lymphocytes by $- 30 to - 36%$ ( $p = 0.01$ ). The $5 mg/week$ intermittent cohort exhibited the lowest rate of drug-related adverse events.

Citation: 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., Guertin, D. A., Sabatini, D. M., & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science, 335(6076), 1638–1643.
Identifiers: PMID: 22461615 (PubMed · Europe PMC) | PMCID: PMC3324089 (PMC Full Text) | DOI: 10.1126/science.1215135 (DOI · SciDB · Scholar)
Study Design & Sample Size: Genetic knockout (Mtor $^{+ / -}$ MLST8 $^{+ / -}$ and hepatic Rictor knockout) and biochemical complex immunoprecipitation study dissecting mTORC1 vs. mTORC2 signaling.
Key Quantitative Outcomes: Proved that chronic daily rapamycin disrupts mTORC2 (Rictor-mTOR) complex assembly in vivo, abolishing insulin-stimulated Akt ( $Ser 473$ ) phosphorylation and causing hepatic gluconeogenesis and glucose intolerance, whereas selective genetic reduction of mTORC1 extended female mouse lifespan by $+ 14.4%$ ( $p = 0.004$ ) while completely preserving normal glucose tolerance and insulin sensitivity.

Citation: Strong, R., Miller, R. A., Cheng, C. J., Nelson, J. F., Gelfond, J., Allani, S. K., Diaz, V., Dorigatti, A. O., Dorigatti, J., Fernandez, E., Galecki, A., … & Harrison, D. E. (2022). Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice. Aging Cell, 21(12), e13724.
Identifiers: PMID: 36179270 (PubMed · Europe PMC) | PMCID: PMC9741502 (PMC Full Text) | DOI: 10.1111/acel.13724 (DOI · SciDB · Scholar)
Study Design & Sample Size: Multi-site randomized longevity trial in UM-HET3 mice ( $N > 900$ ) evaluating combined Rapamycin ( $14.7 ppm$ ) + Acarbose ( $1, 000 ppm$ ) initiated at 9 months or 16 months of age.
Key Quantitative Outcomes: Combining Rapamycin with the postprandial glucose-blunting agent Acarbose Starting at 9 months extended median lifespan by $+ 37%$ in males (pooled $+ 29%$ ) and $+ 28%$ in females ( $p < 0.0001$ ), outperforming every single-agent pharmacological intervention ever tested in the NIA Interventions Testing Program.