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

Esmaeil Dehghan, Yiqiang Zhang, Bahar Saremi, Sivaramakrishna Yadavali, Amirmansoor Hakimi, Maryam Dehghani, Mohammad Goodarzi, Xiaoqin Tu, Scott Robertson, Rueyling Lin, Asish Chudhuri and Hamid Mirzaei ()
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Esmaeil Dehghan: UT Southwestern Medical Center
Yiqiang Zhang: UT Science Center at San Antonio
Bahar Saremi: UT Southwestern Medical Center
Sivaramakrishna Yadavali: UT Southwestern Medical Center
Amirmansoor Hakimi: UT Southwestern Medical Center
Maryam Dehghani: UT Southwestern Medical Center
Mohammad Goodarzi: UT Southwestern Medical Center
Xiaoqin Tu: UT Southwestern Medical Center
Scott Robertson: UT Southwestern Medical Center
Rueyling Lin: UT Southwestern Medical Center
Asish Chudhuri: UT Southwestern Medical Center
Hamid Mirzaei: UT Southwestern Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02394-3

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