Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders

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.

Automated summary

Research has shown that senescent cells rely on glutaminolysis for survival, and inhibiting this process can induce senolysis. Lysosomal membrane damage lowers intracellular pH in senescent cells, inducing KGA expression, leading to glutaminolysis, and ultimately producing ammonia to neutralize low pH and improve cell survival.