SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans
Open accessAbstract
The mammalian Nrf/CNC proteins (Nrf1, Nrf2, Nrf3, p45 NF-E2) perform a wide range of cellular protective and maintenance functions. The most thoroughly described of these proteins, Nrf2, is best known as a regulator of antioxidant and xenobiotic defense, but more recently has been implicated in additional functions that include proteostasis and metabolic regulation. In the nematode Caenorhabditis elegans, which offers many advantages for genetic analyses, the Nrf/CNC proteins are represented by their ortholog SKN-1. Although SKN-1 has diverged in aspects of how it binds DNA, it exhibits remarkable functional conservation with Nrf/CNC proteins in other species and regulates many of the same target gene families. C. elegans may therefore have considerable predictive value as a discovery model for understanding how mammalian Nrf/CNC proteins function and are regulated in vivo. Work in C. elegans indicates that SKN-1 regulation is surprisingly complex and is influenced by numerous growth, nutrient, and metabolic signals. SKN-1 is also involved in a wide range of homeostatic functions that extend well beyond the canonical Nrf2 function in responses to acute stress. Importantly, SKN-1 plays a central role in diverse genetic and pharmacologic interventions that promote C. elegans longevity, suggesting that mechanisms regulated by SKN-1 may be of conserved importance in aging. These C. elegans studies predict that mammalian Nrf/CNC protein functions and regulation may be similarly complex and that the proteins and processes that they regulate are likely to have a major influence on mammalian life- and healthspan.
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NRF/SKN-1 activates cellular protection genes in response to ROS, toxins, nutrient/metabolic changes via mTOR and insulin/IGF signaling.
“In response to elevated levels of reactive oxygen species (ROS) and environmental toxins or to nutrient and metabolic changes through mTOR signaling and insulin/IGF signaling, NRF/SKN-1 activates the expression of genes involved in cellular protection (Blackwell et al., 2015; Tebay et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Blackwell et al., 2015
NRF/SKN-1 is implicated in general detoxification, proteostasis, and immunity.
“Classically considered to control the transcriptional response to oxidative stress, NRF/SKN-1 has also been implicated in general detoxification, proteostasis, and immunity (Blackwell et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Blackwell et al., 2015
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The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
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Epigenetic changes during aging and their reprogramming potential
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Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension
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Defining the functional targets of cap'n'collar transcription factors NRF1, NRF2, and NRF3
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- Authors
- Blackwell, T. K., Steinbaugh, M. J., Hourihan, J. M., Ewald, C. Y., & Isik, M.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- Blackwell, T. Keith
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 88
- Issue
- Pt B
- Pages
- 290-301
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC4809198
- OpenAlex
- W1013361806
- Cited by
- 622
- References
- 160
- Citations by year
- 2026: 58 · 2025: 72 · 2024: 82 · 2023: 65 · 2022: 72 · 2021: 63 · 2020: 45 · 2019: 62 · 2018: 47 · 2017: 27 · 2016: 28 · 2015: 1
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH to TKB (R01GM062891, R01GM094398, R21AG043949)
- MJS (T32DK007260)
- Swiss National Science funding to CYE (P300P3_154633)
- Diabetes Research Center award to the Joslin Diabetes Center (P30DK036836)
- 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 › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- SKN-1, Nrf2, Caenorhabditis elegans, aging, longevity, stress response, antioxidant defense, proteostasis, metabolic regulation, nutrient signaling, DNA binding, functional conservation, healthspan
- MeSH terms
- Aging, Animals, DNA-Binding Proteins, Longevity, Stress, Physiological, Transcription Factors, Caenorhabditis elegans, Caenorhabditis elegans Proteins
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