title: Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila.
abstract: Lifespan of laboratory animals can be increased by genetic, pharmacological, and dietary interventions. Increased expression of genes involved in xenobiotic metabolism, together with resistance to xenobiotics, are frequent correlates of lifespan extension in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila, and mice. The Green Theory of Aging suggests that this association is causal, with the ability of cells to rid themselves of lipophilic toxins limiting normal lifespan. To test this idea, we experimentally increased resistance of Drosophila to the xenobiotic dichlordiphenyltrichlorethan (DDT), by artificial selection or by transgenic expression of a gene encoding a cytochrome P450. Although both interventions increased DDT resistance, neither increased lifespan. Furthermore, dietary restriction increased lifespan without increasing xenobiotic resistance, confirming that the two traits can be uncoupled. Reduced activity of the insulin/Igf signaling (IIS) pathway increases resistance to xenobiotics and extends lifespan in Drosophila, and can also increase longevity in C. elegans, mice, and possibly humans. We identified a nuclear hormone receptor, DHR96, as an essential mediator of the increased xenobiotic resistance of IIS mutant flies. However, the IIS mutants remained long-lived in the absence of DHR96 and the xenobiotic resistance that it conferred. Thus, in Drosophila IIS mutants, increased xenobiotic resistance and enhanced longevity are not causally connected. The frequent co-occurrence of the two traits may instead have evolved because, in nature, lowered IIS can signal the presence of pathogens. It will be important to determine whether enhanced xenobiotic metabolism is also a correlated, rather than a causal, trait in long-lived mice.
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany;
authors.forename: Sonita
authors.initials: S
authors.lastname: Afschar
authors.affiliation: Laboratorio de Genética Bioquímica, Departamento de Anatomía, Embriología y Genética Animal, Facultad de Veterinaria, Instituto Agroalimentario de Aragón, Instituto de Investigación Sanitaria Aragón, Universidad de Zaragoza, 50013 Zaragoza, Spain;
authors.forename: Janne M
authors.initials: JM
authors.lastname: Toivonen
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany;
authors.forename: Julia Marianne
authors.identifier: http://orcid.org/0000-0002-9619-6292
authors.initials: JM
authors.lastname: Hoffmann
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany;
authors.forename: Luke Stephen
authors.initials: LS
authors.lastname: Tain
authors.affiliation: Wellcome Trust Genome Campus, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, United Kingdom;
authors.forename: Daniela
authors.initials: D
authors.lastname: Wieser
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany;
authors.forename: Andrew John
authors.initials: AJ
authors.lastname: Finlayson
authors.affiliation: Department of Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Vlaams Instituut voor Biotechnologie, Zwijnaarde, B-9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde, B-9052, Ghent, Belgium;
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Driege
authors.affiliation: University College London Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Nazif
authors.initials: N
authors.lastname: Alic
authors.affiliation: University College London Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Sahar
authors.initials: S
authors.lastname: Emran
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Stinn
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany;
authors.forename: Jenny
authors.initials: J
authors.lastname: Froehlich
authors.affiliation: University College London Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Piper
authors.affiliation: Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; University College London Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom partridge@age.mpg.de.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000818:Animals; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000502:physiology*; D004351:Drug Resistance; D007328:Insulin / Q000235:genetics*; D008017:Life Expectancy; D009154:Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014158:Transcription, Genetic; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D029721:Drosophila Proteins; C096796:Hr96 protein, Drosophila; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D015262:Xenobiotics
keywords: DHR96; IIS; lifespan; nuclear hormone receptor; xenobiotic resistance