Journal Article

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

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

2017

Overview

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. Hydralazine is an FDA approved drug for the treatment of hypertension. Here, Dehghan et al. report that hydralazine triggers the cellular oxidative stress response by activating NRF2/SKN-1 signaling and extends C. elegans healthy lifespan, suggesting hydralazine may have potential to treat age-associated diseases more broadly.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 14/34 / 14/35 / 14/63 / 631/154/436/2388 / 631/443/7 / 64/11 / 82/1 / 82/58 / Aging / Animals / Antihypertensive Agents - pharmacology / Caenorhabditis elegans / Caenorhabditis elegans Proteins - drug effects / Caenorhabditis elegans Proteins - metabolism / Cell Line, Tumor / Curcumin / Curcumin - pharmacology / Disease Models, Animal / DNA-Binding Proteins - drug effects / DNA-Binding Proteins - metabolism / Enzyme Inhibitors - pharmacology / Homeostasis / Humanities and Social Sciences / Humans / Hydralazine - pharmacology / Hypoglycemic Agents - pharmacology / In Vitro Techniques / Life span / Longevity - drug effects / Metformin / Metformin - pharmacology / Mimicry / multidisciplinary / Nematodes / Neurodegenerative diseases / Neurological diseases / Neurons - drug effects / Neurons - metabolism / Neuroprotection / Neuroprotective Agents / NF-E2-Related Factor 2 - drug effects / NF-E2-Related Factor 2 - metabolism / Nutrient deficiency / Oxidative stress / Science / Science (multidisciplinary) / Signal transduction / Signaling / Stress response / Stress, Physiological - drug effects / Tau protein / Tauopathies - metabolism / Transcription factors / Transcription Factors - drug effects / Transcription Factors - metabolism