| Budget Amount *help |
¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000)
Fiscal Year 2018: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2017: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2016: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
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| 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.
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