Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice

TLDR

Modern 24/7 lifestyles cause chronic circadian misalignment, which is linked to adverse health outcomes, though the underlying mechanisms remain unclear. In mice, long‑term jet‑lag accelerated mortality and triggered immune senescence, marked by increased PD‑1⁺ CD44^high CD4⁺ T cells, GL7⁺ germinal‑center B cells, liver steatohepatitis, and activation of immune‑related gene pathways, highlighting immune homeostasis as a key therapeutic target.

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.