Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans
Open accessAbstract
Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.
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NRF/SKN-1 is a pro-longevity transcription factor; increasing active NRF/SKN-1 extends lifespan in flies and worms.
“Like FOXO/DAF-16, NRF/SKN-1 is a “pro-longevity” transcription factor. Indeed, increasing the level of active NRF/SKN-1 extends lifespan in flies and worms (Sykiotis and Bohmann, 2008; Tullet et al., 2008).”
From The Aging Epigenome (2016) · cites this paper as Tullet et al., 2008
In C. elegans and Drosophila, Nrf2 activation induces a significant increase in longevity.
“In both C. elegans and Drosophila, Nrf2 activation induces a significant increase in longevity”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Tullet et al., 2008
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- Authors
- Tullet, J. M. A., Hertweck, M., An, J. H., Baker, J., Hwang, J. Y., Liu, S., Oliveira, R. P., Baumeister, R., & Blackwell, T. K.
- Affiliations
- Joslin Diabetes Center (US)
- University of Freiburg (DE)
- Yonsei University (KR)
- Corresponding author
- Blackwell, T. Keith
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-03
- Volume
- 132
- Issue
- 6
- Pages
- 1025-1038
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2367249
- OpenAlex
- W2148242921
- Cited by
- 923
- References
- 43
- Citations by year
- 2026: 42 · 2025: 49 · 2024: 45 · 2023: 48 · 2022: 52 · 2021: 63 · 2020: 55 · 2019: 67 · 2018: 49 · 2017: 49 · 2016: 59 · 2015: 46 · 2014: 63 · 2013: 54 · 2012: 49
- FWCI
- 12.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion)
- PubMed Central (acceptedVersion)
- Americanae (AECID Library) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM062891, F32GM070088)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK 07260, 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 › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SKN-1, longevity, aging, DAF-16, FOXO, AKT1, AKT2, SGK1, protein phosphorylation, oxidative stress resistance, stress tolerance, nuclear accumulation, intestine, Caenorhabditis elegans, transcriptional regulatory networks
- MeSH terms
- Animals, DNA-Binding Proteins, Insulin, Insulin-Like Growth Factor I, Intestines, Longevity, Phosphorylation, Receptor, Insulin, Transcription Factors, Signal Transduction, Caenorhabditis elegans, Oxidative Stress, Caenorhabditis elegans Proteins, Gene Regulatory Networks
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