The HIF-1 Hypoxia-Inducible Factor Modulates Lifespan in C. elegans
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During normal development or during disease, animal cells experience hypoxic (low oxygen) conditions, and the hypoxia-inducible factor (HIF) transcription factors implement most of the critical changes in gene expression that enable animals to adapt to this stress. Here, we examine the roles of HIF-1 in post-mitotic aging. We examined the effects of HIF-1 over-expression and of hif-1 loss-of-function mutations on longevity in C. elegans, a powerful genetic system in which adult somatic cells are post-mitotic. We constructed transgenic lines that expressed varying levels of HIF-1 protein and discovered a positive correlation between HIF-1 expression levels and lifespan. The data further showed that HIF-1 acted in parallel to the SKN-1/NRF and DAF-16/FOXO transcription factors to promote longevity. HIF-1 over-expression also conferred increased resistance to heat and oxidative stress. We isolated and characterized additional hif-1 mutations, and we found that each of 3 loss-of-function mutations conferred increased longevity in normal lab culture conditions, but, unlike HIF-1 over-expression, a hif-1 deletion mutation did not extend the lifespan of daf-16 or skn-1 mutants. We conclude that HIF-1 over-expression and hif-1 loss-of-function mutations promote longevity by different pathways. These data establish HIF-1 as one of the key stress-responsive transcription factors that modulate longevity in C. elegans and advance our understanding of the regulatory networks that link oxygen homeostasis and aging.
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The HIF pathway has a role in life span of C. elegans.
“Numerous reports have indicated that the HIF pathway has a role in life span of C. elegans (Chen et al., 2009; Zhang et al., 2009).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Zhang et al., 2009
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- Authors
- Zhang, Y., Shao, Z., Zhai, Z., Shen, C., & Powell-Coffman, J. A.
- Affiliations
- Iowa State University (US)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-07-27
- Volume
- 4
- Issue
- 7
- Pages
- e6348
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2711329
- OpenAlex
- W2076724288
- Cited by
- 211
- References
- 50
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 11 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 14 · 2018: 12 · 2017: 7 · 2016: 16 · 2015: 22 · 2014: 18 · 2013: 9 · 2012: 11
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Iowa State University Digital Repository (Iowa State University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Iowa State University
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM078424)
- National Center for Research Resources
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- HIF-1, hypoxia-inducible factor, lifespan, longevity, Caenorhabditis elegans, DAF-16/FOXO, transcription factors, oxidative stress resistance, heat stress resistance, oxygen homeostasis, stress response, loss-of-function mutations
- MeSH terms
- Animals, Longevity, Mutation, Transcription Factors, Caenorhabditis elegans, Reverse Transcriptase Polymerase Chain Reaction, Caenorhabditis elegans Proteins
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