Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders

Yoshikazu Johmura, Takehiro Yamanaka, Satotaka Omori, Teh Wei Wang, Yuki Sugiura, Masaki Matsumoto, Narumi Suzuki, Soichiro Kumamoto, Kiyoshi Yamaguchi, Seira Hatakeyama, Tomoyo Takami, Rui Yamaguchi, Eigo Shimizu, Kazutaka Ikeda, Nobuyuki Okahashi, Ryuta Mikawa, Makoto Suematsu, Makoto Arita, Masataka Sugimoto, Keiichi I. NakayamaYoichi Furukawa, Seiya Imoto, Makoto Nakanishi

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)265-270
Number of pages6
JournalScience
Volume371
Issue number6526
DOIs
Publication statusPublished - 2021 Jan 15

ASJC Scopus subject areas

  • General

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