Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone

Abstract

Cells adapt to stressors by activating mechanisms that repair damage and protect them from further injury. Stress-induced damage accumulates with age and contributes to age associated diseases. Increased age attenuates the ability to mount a stress response, but little is known about the mechanisms by which this occurs. To begin addressing this problem, we studied hormesis in the nematode Caenorhabditis elegans. When exposed to a low concentration of the xenobiotic juglone, young worms mount a robust hormetic stress response and survive a subsequent exposure to a higher concentration of juglone that is normally lethal to naïve animals. Old worms are unable to mount this adaptive response. Microarray and RNAi analyses demonstrate that an altered transcriptional response to juglone is responsible in part for the reduced adaptation of old worms. Many genes differentially regulated in young versus old animals are known or postulated to be regulated by the FOXO homologue DAF-16 and the Nrf2 homologue SKN-1. Activation of these pathways is greatly reduced in juglone stressed old worms. DAF-16- and SKN-1-like transcription factors play highly conserved roles in regulating stress resistance and longevity genes. Our studies provide a foundation for developing a molecular understanding of how age affects cytoprotective transcriptional pathways.

A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative-stress adaptation in mammals, C. elegans and D. melanogaster

“…The model organisms C. elegans and D. melanogaster have also been shown to be capable of adaptation to oxidative stresses through mild exposure to heat shock, 100% oxygen or the redox quinone juglone in worms, and heat shock or irradiation in flies (Cypser and Johnson, 2002;Lithgow et al, 1995;Moskalev et al, 2009;Przybysz et al, 2009). The present results demonstrate that both model organisms are capable of such adaptation with H 2 O 2 pre-treatment.…”

“…It has been shown that high doses of H 2 O 2 (10mmoll -1 ) can cause the cytoplasmic to nuclear translocation of SKN-1 fused to GFP (SKN-1::GFP) in C. elegans intestinal cells (An and Blackwell, 2003;An et al, 2005). Also, a report by Przybysz and colleagues has shown that with depletion of SKN-1, worms become more susceptible to the oxidant juglone (Przybysz et al, 2009). The SKN-1::GFP line (An and Blackwell, 2003), was crossed with a glo-1 mutant strain to produce worms with reduced non-specific fluorescence.…”

“…Exposure of the worm to a mild heat shock, or a mild dose of an oxidant (such as brief exposure to 100% oxygen or the quinone juglone), results in increased tolerance to a future, more severe, heat or oxidant assault. Interestingly, such adaptation can also result in an increased lifespan (Cypser and Johnson, 2002;Lithgow et al, 1995;Przybysz et al, 2009). Similarly, in the common fruit fly, Drosophila melanogaster, a mild oxidant pre-treatment, or irradiation, increases the tolerance of the fly to a future, normally toxic oxidant challenge (Moskalev et al, 2009).…”

Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans

“…Some of them generate ROS to extend lifespan. The botanical pesticides juglone and plumbagin are thought to extend lifespan of C. elegans by generating ROS (Hartwig et al, 2009;Hunt et al, 2011;Przybysz et al, 2009). Low concentrations of paraquat, which is toxic at high concentrations, were reported to extend lifespan of C. elegans by generating ROS from mitochondria (Yang and Hekimi, 2010a).…”

Protection or cytotoxicity mediated by a novel quinonoid-polyphenol compound?

“…This results in transcriptional activation and boosting of antioxidant defence, augmentation of detoxification processes or of the protein quality control system (Itoh et al 1997;Itoh et al 1999;DinkovaKostova et al 2001). Naturally occurring quinones (such as juglone, vitamin K, plumbagin) bearing α,β-unsaturated carbonyl moieties represent typical xenohormetics (Shibayama-Imazu et al 2006;Przybysz et al 2009;Son et al 2010). Furthermore, flavonoids might represent precursors of xenohormetic molecules and undergo conversion by oxidative metabolism which involves a two-electron auto-oxidation to an electrophilic quinone-type molecule (Metodiewa et al 1999;Awad et al 2000;Bast and Haenen 2002).…”