Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice
Hitoshi Inokawa, Yasuhiro Umemura, Akihiro Shimba, Eiryo Kawakami, Nobuya Koike, Yoshiki Tsuchiya, Munehiro Ohashi, Yoichi Minami, Guangwei Cui, T. Asahi, Ryutaro Ono, Yuh Sasawaki, Eiichi Konishi, Seung‐Hee Yoo, Zheng Chen, Satoshi Teramukai, Koichi Ikuta, Kazuhiro Yagita
Abstract
Abstract 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, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, 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 + CD44 high 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. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.