TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO
Open accessAbstract
The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity.
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Animal models have determined that rapamycin and rapalogs can extend lifespan.
“Animal models exploring the effect of rapamycin and rapalogs on longevity have determined their ability to extend lifespan167-169.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [168]
Metformin, like rapamycin, is known to inhibit mTOR signaling.
“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [223]
Inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster.
“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [223]
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Anisimova, A. S., Alexandrov, A. I., Makarova, N. E., Gladyshev, V. N., & Dmitriev, S. E. (2018) · Aging · doi:10.18632/aging.101721 · Cited by 172 · see citing works
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<scp>TOR</scp>‐mediated regulation of metabolism in aging
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“Another connection between TOR signaling and DAF-16/FOXO is AAK-2/AMPK, which is required for the synergistic lifespan extension by daf-2/INSR and rsks-1/S6K1 double mutants (Chen et al., 2013), and could thus be a mediator of TOR signaling to DAF-16/ FOXO.”
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The road ahead for health and lifespan interventions
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- Authors
- Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., Sabatini, D. M., & Blackwell, T. K.
- Affiliations
- Joslin Diabetes Center (US)
- Broad Institute (US)
- Hiroshima University (JP)
- Corresponding author
- Blackwell, T. Keith
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 15
- Issue
- 5
- Pages
- 713-724
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3348514
- OpenAlex
- W2038120788
- Cited by
- 648
- References
- 68
- Citations by year
- 2026: 26 · 2025: 41 · 2024: 60 · 2023: 52 · 2022: 49 · 2021: 60 · 2020: 37 · 2019: 40 · 2018: 39 · 2017: 52 · 2016: 43 · 2015: 46 · 2014: 46 · 2013: 45 · 2012: 12
- FWCI
- 15.45
- 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)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Elsevier eBooks
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science (24580142)
- National Institute on Aging (F32AG032833)
- National Cancer Institute (CA129105, R01CA103866, R01CA129105)
- National Institute of General Medical Sciences (R01GM062891, GM 62891)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007260)
- 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
- TOR signaling, TORC1, TORC2, rapamycin, longevity, aging, SKN-1, NRF, DAF-16, FOXO, stress tolerance, insulin/IGF-1 signaling, growth signals, Caenorhabditis elegans, feedback loops
- MeSH terms
- Animals, DNA-Binding Proteins, Insulin-Like Growth Factor I, Longevity, Male, Transcription Factors, Transcription, Genetic, Signal Transduction, Trans-Activators, Caenorhabditis elegans, Sirolimus, Caenorhabditis elegans Proteins, Mice, Forkhead Transcription Factors, TOR Serine-Threonine Kinases
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