Hydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway

Dehghan, Esmaeil; Zhang, Yiqiang; Saremi, Bahar; Yadavali, Sivaramakrishna; Hakimi, Amirmansoor; Dehghani, Maryam; Goodarzi, Mohammad; Tu, Xiaoqin; Robertson, Scott; Lin, Rueyling; Chudhuri, Asish; Mirzaei, Hamid

doi:10.1038/s41467-017-02394-3

Cited by 92Genetics, Aging, and Longevity in Model OrganismsGenomics, phytochemicals, and oxidative stressSirtuins and Resveratrol in Medicine

Hydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway

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Dehghan, Esmaeil, Zhang, Yiqiang, Saremi, Bahar, Yadavali, Sivaramakrishna, Hakimi, Amirmansoor, Dehghani, Maryam, Goodarzi, Mohammad, Tu, Xiaoqin +4 more·2017·Nature Communications

DOI 10.1038/s41467-017-02394-3PMC PMC5738364

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Abstract

Nuclear factor (erythroid-derived 2)-like 2 and its Caenorhabditis elegans ortholog, SKN-1, are transcription factors that have a pivotal role in the oxidative stress response, cellular homeostasis, and organismal lifespan. Similar to other defense systems, the NRF2-mediated stress response is compromised in aging and neurodegenerative diseases. Here, we report that the FDA approved drug hydralazine is a bona fide activator of the NRF2/SKN-1 signaling pathway. We demonstrate that hydralazine extends healthy lifespan (~25%) in wild type and tauopathy model C. elegans at least as effectively as other anti-aging compounds, such as curcumin and metformin. We show that hydralazine-mediated lifespan extension is SKN-1 dependent, with a mechanism most likely mimicking calorie restriction. Using both in vitro and in vivo models, we go on to demonstrate that hydralazine has neuroprotective properties against endogenous and exogenous stressors. Our data suggest that hydralazine may be a viable candidate for the treatment of age-related disorders.

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Hydralazine has anti-neurodegenerative efficacy based on action on antioxidative stress mechanisms, including activation of Nrf2 signaling, increased mitochondrial respiration and ATP production, and activation of autophagy.
“Hydralazine, an FDA-approved antihypertensive, has been chosen for its recently discovered anti-neurodegenerative efficacy based on his action on antioxidative stress mechanisms, such as activation of the Nrf2 signaling pathway, increase of mitochondria respiration capacity and adenosine triphosphate production, activation of autophagy, which facilitates intracellular aggregate clearance [102].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [102]
The Results section ('Hydralazine NRF2/SKN-1 activation provides neuroprotection'; page unavailable) reports protection in rotenone-stressed neurons and improved motility in a C. elegans tauopathy model; the Discussion reports NRF2/SKN-1 activation. The Discussion describes altered mitochondrial respiration only as a possible additional mechanism, citing work in yeast. Our copy does not establish increased respiration or ATP production, or activation of autophagy and aggregate clearance. (LLM, conf=0.88)
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Retracted
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Berberine Extends Lifespan in C. elegans Through Multi-Target Synergistic Antioxidant Effects
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Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response
Chhunchha, B., Kubo, E., Krueger, R. R., & Singh, D. P. (2023) · Antioxidants · doi:10.3390/antiox12010140 · Cited by 18 · see citing works
Tetramethylpyrazine nitrone TBN extends the lifespan of C. elegans by activating the Nrf2/SKN-1 signaling pathway
Wang, T., Jing, M., Zhang, T., Zhang, Z., Sun, Y., & Wang, Y. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.05.009 · Cited by 7 · see citing works
Kynurenine Metabolism Lifespan Extension Mediated by Oxidative Stress Response and Hypoxic Response in C. elegans
Castro-Portuguez, R., Meyers, J., Freitas, S., Dang, H. T. L., Turner, E. A., DeNicola, D., Espejo, L. S., & Sutphin, G. L. (2021) · Innovation in Aging · doi:10.1093/geroni/igab046.2557
Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
Dehghan, E., Goodarzi, M., Saremi, B., Lin, R., & Mirzaei, H. (2019) · Nature Communications · doi:10.1038/s41467-019-12425-w · Cited by 63 · see citing works
The SKN ‐1/Nrf2 transcription factor can protect against oxidative stress and increase lifespan in C. elegans by distinct mechanisms
Tullet, J. M. A., Green, J. W., Au, C., Benedetto, A., Thompson, M. A., Clark, E. H., Gilliat, A. F., Young, A. I. J., Schmeißer, K., & Gems, D. (2017) · Aging Cell · doi:10.1111/acel.12627 · Cited by 193 · see citing works

Authors: Dehghan, E., Zhang, Y., Saremi, B., Yadavali, S., Hakimi, A., Dehghani, M., Goodarzi, M., Tu, X., Robertson, S., Lin, R., Chudhuri, A., & Mirzaei, H.
Affiliations: The University of Texas Southwestern Medical Center (US)
The University of Texas at San Antonio Health Science Center (US)
Corresponding author: Mirzaei, Hamid
ORCID: Dehghan, Esmaeil
Yadavali, Sivaramakrishna
Hakimi, Amirmansoor
Goodarzi, Mohammad
Robertson, Scott
Lin, Rueyling
Mirzaei, Hamid
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2017-12-20
Volume: 8
Issue: 1
Pages: 2223-2223
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/s41467-017-02394-3
PMC: PMC5738364
OpenAlex: W2773555905
Cited by: 92
References: 61
Citations by year: 2026: 3 · 2025: 14 · 2024: 13 · 2023: 13 · 2022: 11 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 7
FWCI: 3.26
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature Communications (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Cancer Prevention and Research Institute of Texas (R1121)
National Institutes of Health (HEK293, P40OD010440)
National Institute on Aging (R03AG045504)
National Institute of General Medical Sciences (R01GM084198)
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
Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords: hydralazine, Caenorhabditis elegans, lifespan extension, aging, oxidative stress response, tauopathy, neuroprotection, anti-aging drugs, age-related neurodegenerative diseases
MeSH terms: Animals, Antihypertensive Agents, Curcumin, Disease Models, Animal, DNA-Binding Proteins, Enzyme Inhibitors, Humans, Hydralazine, Hypoglycemic Agents, Longevity, Metformin, Neurons, Stress, Physiological, Transcription Factors, Caenorhabditis elegans, Neuroprotective Agents, Tauopathies, Caenorhabditis elegans Proteins, Cell Line, Tumor, NF-E2-Related Factor 2, In Vitro Techniques

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Hydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway

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