Pathological roles of senometabolites in cardiovascular disorders

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03650
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Juntendo University (2021); Niigata University (2019-2020)
• Principal Investigator: Shimizu Ippei 順天堂大学, 医学部, 准教授 (60444056)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 老化促進代謝物質（セノメタボライト） / 加齢同期 / 心不全 / サルコペニア

Outline of Final Research Achievements

Mechanisms contributing for the synchronization of aging (sync-aging) are yet to be defined. Here, we define “senometabolite” as circulating metabolites having causal roles for the synchronization and progression of aging. We did metabolomics studies in aged individuals or patients with heart failure and found oxidized choline increased under these conditions compared to respective controls. We generated murine left ventricular (LV) pressure overload model and found oxidized choline increased both in plasma and failing heart. Proteomic study showed that oxidized choline reduced the expression of cytochrome c oxidase subunit1, and this was causal for mitochondrial dysfunction. Administration of oxidized choline also reduced muscle strength, induced fibrosis in skeletal muscle. In aged wild type mice, metabolomic study showed oxidized choline increased in plasma. Our findings indicate that suppression of circulating senometabolite would become therapies for age related disorders.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

本研究課題により老化促進代謝物質を介して加齢が同期する可能性が強く示唆された。我々が同定した老化促進代謝物質はミトコンドリア障害を惹起し、心不全やサルコペニアの病態を促進する作用を有していた。本代謝物質は心不全に加え老化で上昇することがわかった。他の研究グループの報告により、アルツハイマー病患者でも上昇するという報告がある。心不全やサルコペニア、アルツハイマー病といった加齢及びミトコンドリア障害に関連する疾患を「老化促進代謝物質関連疾患」と包括的に定義し検討を行うことで、疾患横断的治療法を開発できる可能性が高い。