Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis

Publication date: Available online 7 April 2016
Source:Cell Reports
Author(s): 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
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.

Graphical abstract

Teaser

The mood stabilizer lithium has been shown to extend lifespan in organisms ranging from yeast to flies. Castillo-Quan et al. show that lithium promotes longevity through GSK-3 inhibition and subsequent NRF-2 activation, suggesting that GSK3 is a possible drug target that might affect aging.


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