Analysis of circadian misalignment using Mouse Cohort Model

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K22516
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Yagita Kazuhiro 京都府立医科大学, 医学(系)研究科(研究院), 教授 (90324920)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Keywords: 概日リズム / 生体リズム / 体内時計 / 時計遺伝子 / シフトワーク / 未病制御 / 慢性炎症 / 免疫老化

Outline of Final Research Achievements

Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms named “mouse cohort model”, which showed that long-term circadian misalignment induced significant early mortality. We observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1+CD44high CD4 T cells as well as CD95+GL7+ germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation.

Free Research Field

環境生理学、時間生物学

Academic Significance and Societal Importance of the Research Achievements

生物には最適な状況を維持する普遍的なメカニズムがあり、その一つが体内時計による生体リズムによる恒常性維持機構です。単に睡眠覚醒リズムや自律神経リズムなどを生み出す仕組みというよりは、全身の細胞の代謝秩序など生命維持に必須の原理を担うメカニズムが体内時計です。不規則な生活による恒常性破綻の原理解明のため、本研究では環境（明暗周期）の撹乱が様々な疾患発症を再現する動物モデル系を構築しました。本研究により、交替勤務などによる健康問題の本格的な予防法開発が可能になります。