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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	638-650
Number of pages	13
Journal	Cell Reports
Volume	15
Issue number	3
Early online date	7 Apr 2016
DOIs	https://doi.org/10.1016/j.celrep.2016.03.041
Publication status	Published - 19 Apr 2016

Bibliographical note

Keywords

aging
dietary restriction
GSK-3
keap1
NRF-2
triglycerides
xenobiotic stress

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10.1016/j.celrep.2016.03.041Licence: CC BY 3.0

Lithium promotes longevity through GSK3 NRF2-dependent hormesis
© 2016 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 2.26 MBLicence: CC BY 3.0

Cite this

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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.",

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AU - Kinghorn, Kerri J.

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AU - Tain, Luke S.

AU - Slack, Cathy

AU - Kerr, Fiona

AU - Nespital, Tobias

AU - Thornton, Janet

AU - Hardy, John

AU - Bjedov, Ivana

AU - Partridge, Linda

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AB - 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.

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Lithium promotes longevity through GSK3/NRF2-dependent hormesis

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Keywords

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