Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1.
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.
Park
Sang-Kyu
SK
Institute for Behavioral Genetics, University of Colorado, Box 447, Boulder, CO 80309, USA. sangkyu@colorado.edu
Tedesco
Patricia M
PM
Johnson
Thomas E
TE
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics; D008136:Longevity / Q000235:genetics*; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D034622:RNA Interference; D012098:Reproduction / Q000235:genetics; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D000975:Antioxidants; C504071:CUP-4 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C480043:NHX-2 protein, C elegans; D009479:Neuropeptides; C544177:Nlp-7 protein, C elegans; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors; C073702:skn-1 protein, C elegans