title: Lifespan extension in hypomorphic daf-2 mutants of Caenorhabditis elegans is partially mediated by glutathione transferase CeGSTP2-2.
abstract: Electrophilic stress caused by lipid peroxidation products such as 4-hydroxynonenal (4-HNE) and/or related compounds may contribute to aging. The major mode of 4-HNE metabolism involves glutathione conjugation catalyzed by specialized glutathione transferases. We have previously shown that glutathione transferase CeGSTP2-2, the product of the Caenorhabditis elegans gst-10 gene, has the ability to conjugate 4-HNE, and that its overexpression extends lifespan of C. elegans. We now demonstrate that the expression level of CeGSTP2-2 correlates highly with lifespan in a series of hypomorphic daf-2 mutants of C. elegans. The overexpression of CeGSTP2-2 in daf-2 is abrogated in daf-16; daf-2 mutants, indicating that expression of the gst-10 gene is modulated by insulin-like growth factor signaling. To determine whether the relationship between CeGSTP2-2 and lifespan is causal, we used RNAi to knock down CeGSTP2-2. Treatment with gst-10-specific dsRNA decreased CeGSTP2-2 protein in wild-type N2 and in daf-2 strains to an approximately equal level. The ability to conjugate 4-HNE was similarly decreased by RNAi, suggesting that the increment of that activity in daf-2 over N2 is due largely to the overexpression of CeGSTP2-2. RNAi-mediated knock-down of CeGSTP2-2 led to an increased susceptibility to 4-HNE, paraquat, and heat shock, and to a shortening of lifespan by 13% in both N2 and daf-2 strains. These results indicate that CeGSTP2-2 significantly contributes to the maintenance of the soma, and that this function is augmented in daf-2 mutants concordantly with other longevity assurance genes, probably via insulin-like growth factor signaling.
authors.affiliation: Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dandapat
authors.forename: Sharda P
authors.initials: SP
authors.lastname: Singh
authors.forename: Helen
authors.initials: H
authors.lastname: Benes
authors.forename: Ludwika
authors.initials: L
authors.lastname: Zimniak
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
authors.forename: Piotr
authors.initials: P
authors.lastname: Zimniak
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D015971:Gene Expression Regulation, Enzymologic; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics*; D034622:RNA Interference; D011972:Receptor, Insulin / Q000235:genetics*; D014157:Transcription Factors
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D005982:Glutathione Transferase; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin