Development of a novel anti-aging strategy by elucidating the mechanisms regulating aging through a muscle centric organ network

2019 Fiscal Year Final Research Report

• Project/Area Number: 15H05789
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: Ueki Kohjiro 東京大学, 医学部附属病院, 客員研究員 (00396714)
• Co-Investigator(Kenkyū-buntansha): 笹子 敬洋 東京大学, 医学部附属病院, 助教 (20550429) ; 小林 直樹 国立研究開発法人国立国際医療研究センター, その他部局等, 上級研究員 (80750728)
• Project Period (FY): 2015-05-29 – 2020-03-31
• Keywords: 老化 / シグナル伝達 / 糖尿病

Outline of Final Research Achievements

We established skeletal muscle-specific Akt1/2 double knockout (mAktDKO) mice, as a mouse model mimicking premature sarcopenia in humans, and revealed that they exhibited accelerated muscle volume reduction, locomotive dysfunction, insulin resistance, and systemic senescence. In skeletal muscle of the mAktDKO mice, decreased mitochondria and mitophagy failure were observed, and the former was attributed to the mTOR pathway, a key pathway downstream of Akt, whereas the latter was to the FoxO pathway, the other key pathway. Inhibition of FoxO activity was sufficient in the maintenance of muscle volume. The mAktDKO mice showed osteoporosis and shortened lifespan mainly due to debilitation, which mimicked aging and frailty in humans. We also generated a model of sarcopenic obesity by feeding the mAktDKO mice with high-fat diet, which exhibited shortened lifespan mainly due to tumor death, suggesting that skeletal muscle could be involved in the regulation of systemic tumor resistance.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

サルコペニア形成の分子メカニズムを解明するとともに、骨格筋を中心とする全身の老化制御機構の存在を明らかにした。ヒトにおけるサルコペニア・フレイルの新たな予防法の開発につながるとともに、骨格筋介入による抗老化・抗腫瘍療法の開発に道を開くものと考えられる。