Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders

Science. 2021 Jan 15;371(6526):265-270. doi: 10.1126/science.abb5916.


Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (GLS1) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / enzymology
  • Aging / genetics
  • Aging / metabolism*
  • Ammonia / metabolism
  • Animals
  • Cell Survival
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology*
  • Genes, Essential
  • Glutaminase / genetics
  • Glutaminase / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Lung / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Skin / enzymology


  • Ammonia
  • GLS protein, human
  • Glutaminase