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Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders

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Science  15 Jan 2021:
Vol. 371, Issue 6526, pp. 265-270
DOI: 10.1126/science.abb5916

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Selective destruction of senescent cells

Senescent cells are associated with a variety of age-related medical conditions and thus have been proposed as potential targets for therapy, but we do not yet have a full understanding of the underlying mechanisms. Johmura et al. used RNA interference to screen for enzymes essential to the survival of senescent cells (see the Perspective by Pan and Locasale). The authors identified a key role for glutamine metabolism, particularly the enzyme glutaminase 1, and demonstrated that inhibition of this pathway induced the death of senescent cells. Glutaminase targeting also ameliorated aging-related organ dysfunction and obesity-related disorders in mouse models, suggesting the potential therapeutic value of this approach.

Science, this issue p. 265; see also p. 234

Abstract

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.

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