Lithium promotes longevity through GSK3/NRF2-dependent hormesis

Jorge Ivan 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

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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 languageEnglish
Pages (from-to)638–650
Number of pages13
JournalCell Reports
Volume15
Issue number3
Early online date7 Apr 2016
DOIs
Publication statusPublished - Apr 2016

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Hormesis
Lithium
Glycogen Synthase Kinase 3
NF-E2 Transcription Factor
Aging of materials
Chemical activation
Health
Drosophila
Economics
Pharmacology
Pharmaceutical Preparations
Proteins
Therapeutics

Keywords

  • lithium
  • Drosophila
  • Alzheimer’s disease
  • bipolar disorder
  • neuroscience

Cite this

Castillo-Quan, J. I., Li, L., Kinghorn, K. J., Ivanov, D. K., Tain, L. S., Slack, C., ... Partridge, L. (2016). Lithium promotes longevity through GSK3/NRF2-dependent hormesis. Cell Reports, 15(3), 638–650. https://doi.org/10.1016/j.celrep.2016.03.041
Castillo-Quan, Jorge Ivan ; Li, Li ; Kinghorn, Kerri J. ; Ivanov, Dobril K. ; Tain, Luke S. ; Slack, Cathy ; Kerr, Fiona ; Nespital, Tobias ; Thornton, Janet ; Hardy, John ; Bjedov, Ivana ; Partridge, Linda. / Lithium promotes longevity through GSK3/NRF2-dependent hormesis. In: Cell Reports. 2016 ; Vol. 15, No. 3. pp. 638–650.
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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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Castillo-Quan, JI, Li, L, Kinghorn, KJ, Ivanov, DK, Tain, LS, Slack, C, Kerr, F, Nespital, T, Thornton, J, Hardy, J, Bjedov, I & Partridge, L 2016, 'Lithium promotes longevity through GSK3/NRF2-dependent hormesis', Cell Reports, vol. 15, no. 3, pp. 638–650. https://doi.org/10.1016/j.celrep.2016.03.041

Lithium promotes longevity through GSK3/NRF2-dependent hormesis. / Castillo-Quan, Jorge Ivan; Li, Li; Kinghorn, Kerri J.; Ivanov, Dobril K.; Tain, Luke S. ; Slack, Cathy; Kerr, Fiona; Nespital, Tobias; Thornton, Janet; Hardy, John; Bjedov, Ivana; Partridge, Linda.

In: Cell Reports, Vol. 15, No. 3, 04.2016, p. 638–650.

Research output: Contribution to journalArticle

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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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Castillo-Quan JI, Li L, Kinghorn KJ, Ivanov DK, Tain LS, Slack C et al. Lithium promotes longevity through GSK3/NRF2-dependent hormesis. Cell Reports. 2016 Apr;15(3):638–650. https://doi.org/10.1016/j.celrep.2016.03.041