Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis

• Lithium extends Drosophila lifespan independent of sex and genetic background
• Lithium reduces triglycerides and confers stress-resistance
• Genetic or pharmacological inhibition of GSK-3 activates NRF-2
• NRF-2 activation is required for the longevity effects of lithium

SummaryThe 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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