title: Non-linear impact of glutathione depletion on C. elegans life span and stress resistance.
abstract: The redox environment in cells and organisms is set by low-molecular mass and protein-bound thiols, with glutathione (GSH) representing a major intracellular redox buffer. Subtle thiol oxidation elicits signal transduction processes and adaptive responses to cope with stressors, whereas highly oxidizing conditions may provoke cell death. We here tested how thiol depletion affects life span, stress resistance and stress signaling in the model organism Caenorhabditis elegans. Diethyl maleate (DEM), an α,β-unsaturated carbonyl compound that conjugates to GSH and other thiols, decreased C. elegans life span at a concentration of 1mM. In contrast, low and moderate doses of DEM (10-100µM) increased mean and maximum life span and improved resistance against oxidative stress. DEM-induced life span extension was not detectable in worms deficient in either the FoxO orthologue, DAF-16, or the Nrf2 orthologue, SKN-1, pointing to a collaborative role of the two transcription factors in life span extension induced by thiol depletion. Cytoprotective target genes of DAF-16 and SKN-1 were upregulated after at least 3 days of exposure to 100µM DEM, but not 1mM DEM, whereas only 1mM DEM caused upregulation of egl-1, a gene controlled by a p53-orthologue, CEP-1. In order to test whether depletion of GSH may elicit effects similar to DEM, we suppressed GSH biosynthesis in worms by attenuating γ-glutamylcysteine synthetase (gcs-1) expression through RNAi. The decline in GSH levels elicited by gcs-1 knockdown starting at young adult stage did not impair viability, but increased both stress resistance and life expectancy of the worms. In contrast, gcs-1 knockdown commencing right after hatching impaired nematode stress resistance and rendered young adult worms prone to vulval ruptures during egg-laying. Thus, modest decrease in GSH levels in young adult worms may promote stress resistance and life span, whereas depletion of GSH is detrimental to freshly hatched and developing worms.
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Urban
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsitsipatis
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Hausig
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kreuzer
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Erler
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Stein
authors.affiliation: ETH Zurich (Swiss Federal Institute of Technology), Schorenstrasse 16, Building SLA C7, CH-8603 Schwerzenbach-Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Ristow
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Steinbrenner
authors.affiliation: Institute of Nutrition, Department of Nutrigenomics, Friedrich-Schiller-Universität Jena, D-07743 Jena, Germany. Electronic address: lars-oliver.klotz@uni-jena.de.
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Klotz
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004151:Dipeptides / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D005978:Glutathione / Q000096:biosynthesis* / Q000235:genetics; D008298:Maleates / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D004151:Dipeptides; C112486:EGL-1 protein, C elegans; D051858:Forkhead Transcription Factors; D008298:Maleates; D012097:Repressor Proteins; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C108831:daf-16 protein, C elegans; C073702:skn-1 protein, C elegans; D005721:Glutamate-Cysteine Ligase; C014476:diethyl maleate; D005978:Glutathione; C017341:gamma-glutamylcysteine
keywords: Aging; C. elegans; Glutathione; Hormesis; Stress resistance; Thiol; γ-glutamylcysteine synthetase