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Park, SK, Tedesco, PM and Johnson, TE (2009) Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1. Aging Cell 8:258-69
Oxidative stress has been hypothesized to play a role in normal aging. The response to oxidative stress is regulated by the SKN-1 transcription factor, which also is necessary for intestinal development in Caenorhabditis elegans. Almost a thousand genes including the antioxidant and heat-shock responses, as well as genes responsible for xenobiotic detoxification were induced by the oxidative stress which was found using transcriptome analysis. There were also 392 down-regulated genes including many involved in metabolic homeostasis, organismal development, and reproduction. Many of these oxidative stress-induced transcriptional changes are dependent on SKN-1 action; the induction of the heat-shock response is not. When RNAi to inhibit genes was used, most had no effect on either resistance to oxidative stress or longevity; however two SKN-1-dependent genes, nlp-7 and cup-4, that were up-regulated by oxidative stress were found to be required for resistance to oxidative stress and for normal lifespan. nlp-7 encodes a neuropeptide-like protein, expressed in neurons, while cup-4 encodes a coelomocyte-specific, ligand-gated ion channel. RNAi of nlp-7 or cup-4 increased sensitivity to oxidative stress and reduced lifespan. Among down-regulated genes, only inhibition of ent-1, a nucleoside transporter, led to increased resistance to oxidative stress; inhibition had no effect on lifespan. In contrast, RNAi of nhx-2, a Na(+)/H(+) exchanger, extended lifespan significantly without affecting sensitivity to oxidative stress. These findings showed that a transcriptional shift from growth and maintenance towards the activation of cellular defense mechanisms was caused by the oxidative stress; many of these transcriptional alterations are SKN-1 dependent.
Animals; Antioxidants/metabolism; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/antagonists & inhibitors; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/physiology; DNA-Binding Proteins/antagonists & inhibitors; DNA-Binding Proteins/genetics; DNA-Binding Proteins/physiology; Homeostasis/genetics; Longevity/genetics; Neuropeptides/antagonists & inhibitors; Neuropeptides/genetics; Oxidative Stress/genetics; RNA Interference; Reproduction/genetics; Sodium-Hydrogen Antiporter/physiology; Transcription Factors/antagonists & inhibitors; Transcription Factors/genetics; Transcription Factors/physiology
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