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.


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


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