Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis

Jorge Iván Castillo-Quan; Li Li; Kerri J Kinghorn; Dobril K Ivanov; Luke S Tain; Cathy Slack; Fiona Kerr; Tobias Nespital; Janet Thornton; John Hardy; Ivana Bjedov; Linda Partridge

doi:10.1016/j.celrep.2016.03.041

Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis

Cell Rep. 2016 Apr 19;15(3):638-650. doi: 10.1016/j.celrep.2016.03.041. Epub 2016 Apr 7.

Authors

Affiliations

¹ 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.
² 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.
³ European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
⁴ Max Planck Institute for Biology of Ageing, Joseph-Stelzmann Strasse 9-b, 50931 Köln, Germany.
⁵ 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.
⁶ Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
⁷ Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
⁸ 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.
⁹ 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.

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.

Keywords: GSK-3; Keap1; NRF-2; aging; dietary restriction; triglycerides; xenobiotic stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / drug effects
Caloric Restriction
Dietary Carbohydrates
Drosophila Proteins / metabolism
Drosophila melanogaster / drug effects*
Drosophila melanogaster / metabolism
Drosophila melanogaster / physiology*
Female
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / metabolism*
Hormesis / drug effects*
Lipid Metabolism / drug effects
Lithium / pharmacology*
Longevity / drug effects*
Male
Models, Biological
NF-E2-Related Factor 2 / metabolism*
Stress, Physiological / drug effects
Survival Analysis
Transcription, Genetic / drug effects
Xenobiotics / pharmacology

Substances

Dietary Carbohydrates
Drosophila Proteins
NF-E2-Related Factor 2
Xenobiotics
Lithium
Glycogen Synthase Kinase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding