TY - JOUR
T1 - Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders
AU - Johmura, Yoshikazu
AU - Yamanaka, Takehiro
AU - Omori, Satotaka
AU - Wang, Teh Wei
AU - Sugiura, Yuki
AU - Matsumoto, Masaki
AU - Suzuki, Narumi
AU - Kumamoto, Soichiro
AU - Yamaguchi, Kiyoshi
AU - Hatakeyama, Seira
AU - Takami, Tomoyo
AU - Yamaguchi, Rui
AU - Shimizu, Eigo
AU - Ikeda, Kazutaka
AU - Okahashi, Nobuyuki
AU - Mikawa, Ryuta
AU - Suematsu, Makoto
AU - Arita, Makoto
AU - Sugimoto, Masataka
AU - Nakayama, Keiichi I.
AU - Furukawa, Yoichi
AU - Imoto, Seiya
AU - Nakanishi, Makoto
N1 - Funding Information:
This study was supported by MEXT/JSPS KAKENHI under grant numbers JP26250027 (M.N.), JP22118003 (M.N.), JP16K15239 (M.N.), JP18H05026m (Y.J.), JP16H06148 (Y.J.), and JP16K15238 (Y.J.) and by AMED under grant numbers JP17cm0106122 (M.N.), JP17fk0310111 (M.N.), JP17gm5010001 (M.N.), and JP19gm5010003 (Y.S.), as well as by Ono Medical Research Foundation (M.N.), Princess Takamatsu Cancer Research Fund (M.N.), and Relay for Life Japan Cancer Society (M.N.).
Publisher Copyright:
© 2021 The Authors, some rights reserved.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - 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.
AB - 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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U2 - 10.1126/science.abb5916
DO - 10.1126/science.abb5916
M3 - Article
C2 - 33446552
AN - SCOPUS:85099909197
SN - 0036-8075
VL - 371
SP - 265
EP - 270
JO - Science
JF - Science
IS - 6526
ER -