Identification and functional analysis of regulators of senescence

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H06148
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: Johmura Yoshikazu 東京大学, 医科学研究所, 助教 (40616322)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 老化 / 細胞周期 / 代謝 / がん

Outline of Final Research Achievements

Senolytic removal of senescent cells (senolysis) has been proposed to be beneficial for improving various age-associated pathologies, but effective compounds as well as the molecular pathways for their senolytic activity have not yet emerged. In the present study, genome-wide shRNA screening identified GLS1 as an essential gene for survival of senescent cells. The intracellular pH in senescent cells was lowered by excess protein synthesis-mediated lysosomal membrane damage, and this lowered intracellular pH induced KGA-type GLS1 expression. Enhanced glutaminolysis then caused the production of ammonia which neutralized the lowered pH and improved survival of the senescent cells. GLS1 inhibitor treatment of aged mice eliminated senescent cells and ameliorated age-associated kidney dysfunction. Our results suggest that cells in a senescent state require glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.

Free Research Field

細胞分子生物学

Academic Significance and Societal Importance of the Research Achievements

最近の研究により、加齢に伴う老化細胞の蓄積が老化・老年病発症の大きな要因の一つであることも分かりつつあり、老化細胞除去薬の開発が世界的に注目されている。本研究により、グルタミナーゼ阻害剤により老化細胞を選択的に除去することが可能となった。今後、より臨床に即した形でグルタミナーゼ阻害剤の研究を進めることで、動脈硬化症、腎障害、さらにはがんなどの加齢性疾病の治療・予防の新たな方法論の開発に大きく貢献できるものと考えられる。