TY - JOUR
T1 - Hydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway
AU - Dehghan, Esmaeil
AU - Zhang, Yiqiang
AU - Saremi, Bahar
AU - Yadavali, Sivaramakrishna
AU - Hakimi, Amirmansoor
AU - Dehghani, Maryam
AU - Goodarzi, Mohammad
AU - Tu, Xiaoqin
AU - Robertson, Scott
AU - Lin, Rueyling
AU - Chudhuri, Asish
AU - Mirzaei, Hamid
N1 - Funding Information:
We thank Drs. David Mangelsdorf, Melanie Cobb, Peter Douglas, Nima Sharifi, Marc Diamond and Margaret Phillips for advice on our manuscript. We thank Dr. Marc Diamond for providing us with aggregate-positive and negative HEK293 cells and Dr. James Malter for helping us with primary neuronal cell culture and analysis. All C. elegans strains were provided by the CGC, which is funded by NIH office of Research and Infrastructure Programs (P40OD010440). This work was supported by the National Institutes of Health (grant R03AG045504 to H.M.), Robert A. Welch Foundation (grant I-1850 to H.M.) and the Cancer Prevention and Research Institute of Texas (grant R1121 to H.M.). H.M. is the founder of Neurodaroo LLC and a member of its scientific advisory board.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85038883534&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85038883534&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-02394-3
DO - 10.1038/s41467-017-02394-3
M3 - Article
C2 - 29263362
AN - SCOPUS:85038883534
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2223
ER -