Chronic Circadian Misalignment Results in Reduced Longevity and Large-Scale Changes in Gene Expression in Drosophila
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ABSTRACT:
PROVIDER: PRJNA510642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8350400_1.fastq.gz | Fastqsanger.gz | |||
| SRR8350400_2.fastq.gz | Fastqsanger.gz | |||
| SRR8350401_1.fastq.gz | Fastqsanger.gz | |||
| SRR8350401_2.fastq.gz | Fastqsanger.gz | |||
| SRR8350402_1.fastq.gz | Fastqsanger.gz |
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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.
2018-12-19 | GSE124065 | GEO
Project description:BackgroundCircadian clocks are found in nearly all organisms, from bacteria to mammals, and ensure that behavioral and physiological processes occur at optimal times of day and in the correct temporal order. It is becoming increasingly clear that chronic circadian misalignment (CCM), such as occurs in shift workers or as a result of aberrant sleeping and eating schedules common to modern society, has profound metabolic and cognitive consequences, but the proximate mechanisms connecting CCM with reduced organismal health are unknown. Furthermore, it has been difficult to disentangle whether the health effects are directly induced by misalignment or are secondary to the alterations in sleep and activity levels that commonly occur with CCM. Here, we investigated the consequences of CCM in the powerful model system of the fruit fly, Drosophila melanogaster. We subjected flies to daily 4-h 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.ResultsConsistent 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.ConclusionsMany 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.
| S-EPMC6323780 | biostudies-literature
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.
2018-08-10 | GSE106800 | 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.
2020-02-27 | GSE142248 | GEO
Project description:Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pathological progression during the pre-symptomatic stage, prior to the development of irreversible diseases under chronic circadian misalignment, using wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of intrinsic behavioral rhythms was found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contribute to inter-individual variations in pathogenesis of circadian misalignment-induced diseases, and arise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders.
2024-04-03 | GSE245519 | GEO
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.
2023-04-14 | GSE167443 | GEO
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.
2023-04-14 | GSE222789 | GEO
Project description:Reduced sphingolipid biosynthesis modulates proteostasis networks to enhance longevity
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Project description:Sexual dimorphism in the response to chronic circadian misalignment
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Project description:Organisms use endogenous clocks to adapt to the rhythmicity of the environment and to synchronize social activities. Although circadian rhythms have been implicated in multiple aspects of aging, it remains uncertain whether evolutionary selection of circadian cycle gene variants contributes to changes in longevity and aging traits within animal populations. We have sequenced the genomes of Drosophila melanogaster strains with exceptional longevity that were obtained via multiple rounds of selection for reduced senescence from a parental strain. Preservation of youthful muscle gene expression and function is seen during aging in these strains and is primarily due to intergenic polymorphisms rather than to mutations in coding sequences. Expression of transcriptional regulators of the circadian machinery is highly modulated, with higher period and timeless and lower cycle expression in strains with delayed aging compared to the parental strain. These changes in the expression of circadian core components associate with changes in the amplitude and specificity of the circadian transcriptome. Moreover, a muscle-specific increase in timeless expression to levels similar to long-lived lines extends lifespan. Altogether, these findings indicate that circadian clock gene variants contribute to shaping aging traits and to the evolutionarily divergence in longevity within a species.
2019-06-06 | GSE129922 | GEO