title: Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis.
abstract: The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life.
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Strasse 9-b, 50931 Köln, Germany; Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: Jorge Iván
authors.initials: JI
authors.lastname: Castillo-Quan
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: Kerri J
authors.initials: KJ
authors.lastname: Kinghorn
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Dobril K
authors.initials: DK
authors.lastname: Ivanov
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Strasse 9-b, 50931 Köln, Germany.
authors.forename: Luke S
authors.initials: LS
authors.lastname: Tain
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Strasse 9-b, 50931 Köln, Germany.
authors.forename: Cathy
authors.initials: C
authors.lastname: Slack
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Kerr
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Strasse 9-b, 50931 Köln, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Nespital
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Thornton
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bjedov
authors.affiliation: Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Strasse 9-b, 50931 Köln, Germany. Electronic address: l.partridge@ucl.ac.uk.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D031204:Caloric Restriction; D004040:Dietary Carbohydrates; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059165:Hormesis / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects; D008094:Lithium / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000187:drug effects; D015262:Xenobiotics / Q000494:pharmacology
chemical_list: D004040:Dietary Carbohydrates; D029721:Drosophila Proteins; D051267:NF-E2-Related Factor 2; D015262:Xenobiotics; D008094:Lithium; D038362:Glycogen Synthase Kinase 3
keywords: GSK-3; Keap1; NRF-2; aging; dietary restriction; triglycerides; xenobiotic stress