Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice
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ABSTRACT:
PROVIDER: PRJNA596388 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10729657_1.fastq.gz | Fastqsanger.gz | |||
| SRR10729657_2.fastq.gz | Fastqsanger.gz | |||
| SRR10729658_1.fastq.gz | Fastqsanger.gz | |||
| SRR10729658_2.fastq.gz | Fastqsanger.gz | |||
| SRR10729659_1.fastq.gz | Fastqsanger.gz |
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Project description: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+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. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.
2020-02-27 | GSE142248 | GEO
Project description: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+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. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.
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Project description:Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation nor elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes, where misaligned mice undergo an 8-hour phase advance every week for 15 weeks. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected against the cardiometabolic impact of circadian disruption seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice. In the UK biobank, female shiftworkers showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males. Thus we show that female mice are resilient to chronic circadian misalignment, and that these differences are conserved in humans.
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Project description:Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation nor elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes, where misaligned mice undergo an 8-hour phase advance every week for 15 weeks. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected against the cardiometabolic impact of circadian disruption seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice. In the UK biobank, female shiftworkers showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males. Thus we show that female mice are resilient to chronic circadian misalignment, and that these differences are conserved in humans.
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Project description:Circadian misalignment, such as in shift work, has been associated with obesity and type 2 diabetes, however, direct effects of circadian misalignment on skeletal muscle insulin sensitivity and muscle molecular circadian clock have never been investigated in humans. Here we investigated insulin sensitivity and muscle metabolism in fourteen healthy young lean men (age 22.4 ± 2.8 years; BMI 22.3 ± 2.1 kg/m2 [mean ± SD]) after a 3-day control protocol and a 3.5-day misalignment protocol induced by a 12-h rapid shift of the behavioral cycle. We show that circadian misalignment results in a significant decrease in peripheral insulin sensitivity due to a reduced skeletal muscle non-oxidative glucose disposal (Rate of disappearance: 23.7 ± 2.4 vs. 18.4 ± 1.4 mg/kg/min; control vs. misalignment; p=0.024). Fasting glucose and FFA levels as well as sleeping metabolic rate were higher during circadian misalignment. Molecular analysis of skeletal muscle biopsies revealed that the molecular circadian clock was not aligned to the new behavourial rhythm, and microarray analysis revealed the human PPAR pathway as a key player in the disturbed energy metabolism upon circadian misallignement. Our findings may provide a mechanism underlying the increased risk of type 2 diabetes among shift workers.
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Project description:We obtained early-senescence (ES)- and late-senescence (LS)-type F7 plants from a cross between a hybrid (Glycine max × Glycine soja) and the Glycine max cultivar. The ES-type plants presented the reproductive (R2) growth stage at 50 days after sowing (DAS) and the R7 growth stage at 95 DAS, whereas the LS-type plants presented the beginning of the R1 and R6 growth stages at 50 and 95 DAS, respectively. To understand the molecular mechanisms underlying this senescence, we performed transcriptome analysis of leaves from 50 and 95 DAS of ES- and LS-type plants. A total of 2,414 and 2,471 genes at 50 and 95 DAS, respectively, were differentially expressed between ES-type and LS-type plants. Twenty-three candidate genes associated with the circadian clock, chlorophyll biosynthesis, phytohormones, and protein kinases were identified, and their expression levels were analyzed. In addition, we analyzed the expression patterns of circadian clock-related genes such as CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), LATE ELONGATED HYPOCOTYL (LHY), CONSTANS-LIKE 9 (COL9), EARLY FLOWERING 3 (ELF3) and pseudo response regulator 5 (PRR5) in ES- and LS-type plants under light and dark conditions. The expression patterns of circadian clock-related genes were similar in the ES- and LS-type plants. However, the transcription levels of these genes were compared between ES- and LS-type plants, and the expression of these genes was greater than that in LS-type plants during the period when expression increased. Therefore, each set of candidate genes regulated senescence in each plant by regulating their expression level.
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Project description:We investigated the consequences of chronic circadian misalignment (CCM) in the powerful model system of the fruit fly, Drosophila melanogaster. We subjected flies to daily 4-hr phase delays in the light-dark schedule and used the Drosophila Activity Monitoring (DAM) system to continuously track locomotor activity and sleep while simultaneously monitoring fly lifespan. Consistent with previous results, we find that exposing flies to CCM leads to a ~15% reduction in median lifespan in both male and female flies. Importantly, we demonstrate that the reduced longevity occurs independent of changes in overall sleep or activity. To uncover potential molecular mechanisms of CCM-induced reduction in lifespan, we conducted whole body RNA-sequencing to assess differences in gene transcription between control and misaligned flies. CCM caused progressive, large-scale changes in gene expression characterized by upregulation of genes involved in response to toxic substances, aging and oxidative stress, and downregulation of genes involved in regulation of development and differentiation, gene expression and biosynthesis. Many of these gene expression changes mimic those that occur during natural aging, consistent with the idea that CCM results in premature organismal decline, however, we found that genes involved in lipid metabolism are overrepresented among those that are differentially regulated by CCM and aging. This category of genes is also among the earliest to exhibit CCM-induced changes in expression, thus highlighting altered lipid metabolism as a potentially important mediator of the negative health consequences of CCM.
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