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The HIF-1 Hypoxia-Inducible Factor Modulates Lifespan in C. elegans
Open accessAbstract
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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“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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Cites
A C. elegans mutant that lives twice as long as wild type
Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993) · Nature · doi:10.1038/366461a0 · Cited by 3,387
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · cited 1×
“HIF stability and activity are influenced by reactive oxygen species, citric acid cycle intermediates, Fe(II) availability, and intracellular signaling events [1,3].”
BackgroundKimura, K. D., Tissenbaum, H. A., Liu, Y., & Ruvkun, G. (1997) · Science · doi:10.1126/science.277.5328.942 · Cited by 2,250
Ogg, S., Paradis, S., Gottlieb, S., Patterson, G. I., Lee, L., Tissenbaum, H. A., & Ruvkun, G. (1997) · Nature · doi:10.1038/40194 · Cited by 1,935
Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
Tissenbaum, H. A., & Guarente, L. (2001) · Nature · doi:10.1038/35065638 · Cited by 1,603
Regulation of aging and age-related disease by DAF-16 and heat-shock factor
Hsu, A.-L., Murphy, C. T., & Kenyon, C. (2003) · Science · doi:10.1126/science.1083701 · Cited by 1,513
Hypoxia-inducible factor 1: master regulator of O2 homeostasis
Semenza, G. L. (1998) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(98)80016-6 · Cited by 1,092
Lin, K., Hsin, H., Libina, N., & Kenyon, C. J. (2001) · Nature Genetics · doi:10.1038/88850 · Cited by 1,027
Henderson, S. T., & Johnson, T. E. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00594-2 · Cited by 949
Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans
Tullet, J. M. A., Hertweck, M., An, J. H., Baker, J., Hwang, J. Y., Liu, S., Oliveira, R. P., Baumeister, R., & Blackwell, T. K. (2008) · Cell · doi:10.1016/j.cell.2008.01.030 · Cited by 923
Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging
Morimoto, R. I. (2008) · Genes & Development · doi:10.1101/gad.1657108 · Cited by 872
Creation of Low-Copy Integrated Transgenic Lines in Caenorhabditis elegans
Praitis, V., Casey, E., Collar, D. C., & Austin, J. (2001) · Genetics · doi:10.1093/genetics/157.3.1217 · Cited by 817
The role of hypoxia-inducible factors in tumorigenesis
Rankin, E. B., & Giaccia, A. J. (2008) · Cell Death & Differentiation · doi:10.1038/cdd.2008.21 · Cited by 806 · cited 1×
“There is also great interest in pharmaceuticals that can inhibit HIF and may be effective in combinatorial treatments for certain cancers [46].”
BackgroundSKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress responsePreprint
An, J. H., & Blackwell, T. K. (2003) · Genes & Development · doi:10.1101/gad.1107803 · Cited by 741
Regulation of Longevity in Caenorhabditis elegans by Heat Shock Factor and Molecular Chaperones
Morley, J. F., & Morimoto, R. I. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-07-0532 · Cited by 741
EGG-LAYING DEFECTIVE MUTANTS OF THE NEMATODE CAENORHABDITIS ELEGANS
Trent, C., Tsung, N., & Horvitz, H. R. (1983) · Genetics · doi:10.1093/genetics/104.4.619 · Cited by 729
Paradis, S., & Ruvkun, G. (1998) · Genes & Development · doi:10.1101/gad.12.16.2488 · Cited by 710
Semenza, G. L. (2007) · Science · doi:10.1126/science.1147949 · Cited by 706
PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans
Panowski, S. H., Wolff, S., Aguilaniu, H., Durieux, J., & Dillin, A. G. (2007) · Nature · doi:10.1038/nature05837 · Cited by 538
Lee, R., Hench, J., & Ruvkun, G. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00595-4 · Cited by 499
McElwee, J. J., Schuster, E. F., Blanc, E., Thomas, J. H., & Gems, D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406207200 · Cited by 411
Hertweck, M., Göbel, C., & Baumeister, R. (2004) · Developmental Cell · doi:10.1016/s1534-5807(04)00095-4 · Cited by 368
Lethal paralysis of Caenorhabditis elegans by Pseudomonas aeruginosa
Darby, C., Cosma, C. L., Thomas, J. H., & Manoil, C. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.15202 · Cited by 314
Jiang, H., Guo, R. J., & Powell‐Coffman, J. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141234698 · Cited by 296
Self-citationHIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans
Chen, D., Thomas, E. L., & Kapahi, P. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000486 · Cited by 250
Regulation of Hypoxic Death in C. elegans by the Insulin/IGF Receptor Homolog DAF-2
Scott, B. A., Avidan, M. S., & Crowder, C. M. (2002) · Science · doi:10.1126/science.1072302 · Cited by 247
Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans
Mehta, R., Steinkraus, K. A., Sutphin, G. L., Ramos, F. J., Shamieh, L. S., Huh, A., Davis, C., Chandler-Brown, D. B., & Kaeberlein, M. R. (2009) · Science · doi:10.1126/science.1173507 · Cited by 242
Bell, E. L., Klimova, T. A., Eisenbart, J., Schumacker, P. T., & Chandel, N. S. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02265-06 · Cited by 237
Roles of the HIF-1 Hypoxia-inducible Factor during Hypoxia Response in Caenorhabditis elegans
Shen, C., Nettleton, D. S., Jiang, M., Kim, S. K., & Powell‐Coffman, J. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501894200 · Cited by 230
Self-citationHypoxia-Inducible Factor 1 Mediates Upregulation of Telomerase (hTERT)
Nishi, H., Nakada, T., Kyo, S., Inoue, M., Shay, J. W., & Isaka, K. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.13.6076-6083.2004 · Cited by 219
Thermotolerance of a Long-lived Mutant of Caenorhabditis elegans
Lithgow, G. J., White, T. M., Hinerfeld, D. A., & Johnson, T. E. (1994) · Journal of Gerontology · doi:10.1093/geronj/49.6.b270 · Cited by 213
Powell‐Coffman, J. A., Bradfield, C. A., & Wood, W. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.6.2844 · Cited by 188
Self-citationSensing and responding to hypoxia via HIF in model invertebrates
Gorr, T. A., Gassmann, M., & Wappner, P. (2006) · Journal of Insect Physiology · doi:10.1016/j.jinsphys.2006.01.002 · Cited by 173
Padilla, P. A., Nystul, T. G., Zager, R. A., Johnson, A. C. M., & Roth, M. B. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.01-12-0594 · Cited by 153
Bishop, T., Lau, K. W., Epstein, A. C. R., Kim, S. K., Jiang, M., O’Rourke, D., Pugh, C. W., Gleadle, J., Taylor, M. S., Hodgkin, J., et al. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020289 · Cited by 145
Hormesis and aging in Caenorhabditis elegans
Cypser, J. R., Tedesco, P., & Johnson, T. E. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.09.004 · Cited by 143
The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α
Gort, E. H., van Haaften, G. W., Verlaan-Klink, I., Groot, A. J., Plasterk, R. H. A., Shvarts, A., Suijkerbuijk, K. P. M., van Laar, T., van der Wall, E., Raman, V., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1210795 · Cited by 142
Oxidative Stress and Life Span Determination in the Nematode Caenorhabditis elegans
Honda, Y., & Honda, S. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb02117.x · Cited by 124
HIF-1 is required for heat acclimation in the nematode Caenorhabditis elegans
Treinin, M., Shliar, J., Jiang, H., Powell‐Coffman, J. A., Bromberg, Z., & Horowitz, M. (2003) · Physiological Genomics · doi:10.1152/physiolgenomics.00179.2002 · Cited by 124
Self-citationThe trifecta of aging in Caenorhabditis elegans
Wolff, S., & Dillin, A. G. (2006) · Experimental Gerontology · doi:10.1016/j.exger.2006.06.054 · Cited by 115
Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans
Pocock, R., & Hobert, O. (2008) · Nature Neuroscience · doi:10.1038/nn.2152 · Cited by 111
Cytokine-Induced Signaling Networks Prioritize Dynamic Range over Signal Strength
Janes, K. A., Reinhardt, H. C., & Yaffe, M. B. (2008) · Cell · doi:10.1016/j.cell.2008.08.034 · Cited by 99
Chang, A. J., & Bargmann, C. I. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802164105 · Cited by 90
Shen, C., Shao, Z., & Powell‐Coffman, J. A. (2006) · Genetics · doi:10.1534/genetics.106.063594 · Cited by 79
Self-citationMendenhall, A., LaRue, B., & Padilla, P. A. (2006) · Genetics · doi:10.1534/genetics.106.061390 · Cited by 75
Hoogewijs, D., Geuens, E., Dewilde, S., Vierstraete, A. R., Moens, L. J., Vinogradov, S. N., & Vanfleteren, J. R. (2007) · BMC Genomics · doi:10.1186/1471-2164-8-356 · Cited by 51
Jiang, J. C., Kirchman, P. A., Allen, M., & Jazwinski, S. M. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2004.03.026 · Cited by 51
Henderson, S. T., & Johnson, T. E. (2005) · Current Biology · doi:10.1016/j.cub.2005.03.045 · Cited by 8
Flagged first, then by citations
1 of the 50 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
mTOR is a key modulator of ageing and age-related disease
Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013) · Nature · doi:10.1038/nature11861 · Cited by 1,676
Schmidt, E. P., Yang, Y., Janssen, W. J., Gandjeva, A., Perez, M. J., Barthel, L., Zemans, R. L., Bowman, J. C., Koyanagi, D., Yunt, Z. X., et al. (2012) · Nature Medicine · doi:10.1038/nm.2843 · Cited by 842
Mitonuclear communication in homeostasis and stress
Quirós, P. M., Mottis, A., & Auwerx, J. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.23 · Cited by 787
Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1α
Lim, J.-H., Lee, Y.-M., Chun, Y.-S., Chen, J., Kim, J.-E., & Park, J.-W. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.023 · Cited by 758
With TOR, Less Is More: A Key Role for the Conserved Nutrient-Sensing TOR Pathway in Aging
Kapahi, P., Chen, D., Rogers, A. N., Katewa, S. D., Li, P. W.-L., Thomas, E., & Kockel, L. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.05.001 · Cited by 678
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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