Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice

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. From the cellular to the organismal levels, circadian clocks regulate various essential biological processes to enable anticipation of and adaptation to the daily environmental changes from Earth rotation 1. Modernization of our society is accompanied by a dramatic change in human lifestyle, with unprecedented increases in, for example, night shift work and nocturnal feeding/recreational activities 2. Recent epidemiological studies have revealed shift workers as being at a higher risk of various diseases, such as mood disorders, metabolic syndrome, cardiovascular disease, and some types of cancers, suggesting that the misalignment between environmental cycles and endogenous circadian clocks exacerbates systemic pathological consequences 3-8. However, the pathophysiological mechanisms underlying the deleterious effects of long-term circadian misalignment in health and healthspan remain unclear. Recent studies have investigated the perturbation of circadian systems by environmental and/or genetic manipulation in animal models 9,10. For example, Davidson et al. reported that an experimental model of environmental perturbation induced by the scheduled shifts of light-dark cycles-called chronic jet-lag (CJL)-for 8 weeks using aged mice (27-31 months old) showed the mortality rate to be higher in the phase advance condition (6-hour phase advance every 7 days) than in the phase delay (6-hour phase delay every 7 days) condition or control LD condition 9. These studies principally investigated the acute or subacute (for up to a few months) effects of circadian misalignment; it thus remains uncertain how long-term perturbation of environmental light-dark cycle induces physiological transformation and pathological consequences.

Dim Light at Night Disturbs Molecular Pathways of Lipid Metabolism

“…Hepatic metabolic homeostasis is maintained in accordance with circadian oscillations; therefore, circadian misalignment induced by disturbed LD cycles can impair the homeostasis and result in ectopic accumulation of lipids in the liver [ 20 , 27 , 30 ]. In our study, we examined this link in rats, which were exposed to dLAN for 2 or 5 weeks.…”

“…The ectopic accumulation of lipids in the liver has been experimentally demonstrated following a chronic exposure to disrupted LD cycles, especially by phase shifts [ 20 , 39 ] and constant light [ 30 ]. The same effect resulted from dLAN in a rat model of essential hypertension [ 27 ] and here, we evidenced that 5-week dLAN exposure can trigger abnormal hepatic lipid accumulation in healthy animals.…”

“…Although the day–night light intensity difference is not completely lost under dLAN conditions, dLAN has been shown to disturb the circadian clock function, as evidenced by suppressed nighttime melatonin levels [ 14 , 15 ], low-amplitude rhythms in locomotor activity and cardiovascular parameters [ 14 , 16 ], and an altered rhythmic variation of clock genes in the hypothalamus and the liver [ 16 , 17 ]. Circadian disruption in response to diverse environmental or endogenous perturbations can misalign metabolic homeostasis and thereby contribute to the development of metabolic disorders [ 18 , 19 , 20 ]. Accordingly, a growing number of epidemiological and experimental studies have reported an association between dLAN exposure and metabolic dysfunction, leading to an increased risk of obesity [ 21 , 22 ], type 2 diabetes mellitus [ 23 ], and cardiovascular disease [ 24 , 25 ].…”

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

“…By inhibiting Bmal1 [ 100 , 101 ], YY1 will also contribute to how circadian dysregulation induces immune suppression, in association with an increase in PD-1 in cytolytic cells [ 102 ]. As pineal melatonin requires Bmal1 to drive the conversion of pyruvate to acetyl-CoA by PDC, YY1 and its potentiation by O-GlcNAcylation will modulate mitochondrial metabolism and its interactions, via acetyl-CoA, with glycolysis, thereby increasing key factors in these cells that regulate immune suppression and cytolytic cell ‘exhaustion’.…”

Circadian Clock and Complement Immune System—Complementary Control of Physiology and Pathology?

“…schedule is often compromised, resulting in sleep deprivation and circadian disruption in the form of “social jet-lag” (Brisbare-Roch et al, 2007 ; Yao et al, 2015 ; Pagel et al, 2017 ; Gupta, 2019 ; Walker et al, 2020 ). There is evidence that circadian disruption may alter the proper temporal regulation of proinflammatory cytokines, which can induce uncontrolled complement activation, resulting in neuropathological disorders, autoimmune diseases, and shortened life expectancy (Petersen et al, 1986 ; Ricklin, 2012 ; Gomez-Gonzalez et al, 2013 ; Hurtado-Alvarado et al, 2013 ; Brodsky, 2015 ; Oster et al, 2017 ; Jasim et al, 2019 ; Inokawa et al, 2020 ).…”