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

Nat Commun. 2017 Dec 20;8(1):2223. doi: 10.1038/s41467-017-02394-3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / pharmacology*
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / drug effects*
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Line, Tumor
  • Curcumin / pharmacology
  • DNA-Binding Proteins / drug effects*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydralazine / pharmacology*
  • Hypoglycemic Agents / pharmacology
  • In Vitro Techniques
  • Longevity / drug effects*
  • Metformin / pharmacology
  • NF-E2-Related Factor 2 / drug effects*
  • NF-E2-Related Factor 2 / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents
  • Stress, Physiological / drug effects*
  • Tauopathies / metabolism
  • Transcription Factors / drug effects*
  • Transcription Factors / metabolism

Substances

  • Antihypertensive Agents
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Transcription Factors
  • skn-1 protein, C elegans
  • Hydralazine
  • Metformin
  • Curcumin