Department of Biology, Loyola University Chicago, 1050 W. Sheridan Rd, Chicago, IL, 60660, USA.
Department of Computer Science, Loyola University, Chicago, 60660, USA.
BMC Genomics. 2019 Jan 7;20(1):14. doi: 10.1186/s12864-018-5401-7.
Circadian 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.
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.
昼夜节律钟存在于从细菌到哺乳动物的几乎所有生物体中，确保行为和生理过程在一天中的最佳时间和正确的时间顺序发生。越来越明显的是，慢性昼夜节律失调（CCM），如发生在轮班工人中，或由于现代社会常见的异常睡眠和饮食时间安排，会产生深远的代谢和认知后果，但将 CCM 与降低生物体健康联系起来的直接机制尚不清楚。此外，很难区分健康影响是直接由失调引起的，还是由于 CCM 通常伴随的睡眠和活动水平的改变引起的。在这里，我们在强大的果蝇模型系统中研究了 CCM 的后果。我们使果蝇每天接受 4 小时的光-暗周期相位延迟，并使用果蝇活动监测（DAM）系统连续跟踪运动活动和睡眠，同时监测果蝇寿命。
与之前的结果一致，我们发现，暴露于 CCM 会导致雌雄果蝇的中位寿命分别降低约 15%。重要的是，我们证明，寿命的缩短与整体睡眠或活动的变化无关。为了揭示 CCM 诱导的寿命缩短的潜在分子机制，我们进行了全基因组 RNA 测序，以评估对照和失配果蝇之间的基因转录差异。CCM 导致基因表达的大规模、渐进变化，表现为参与应对有害物质、衰老和氧化应激的基因上调，以及参与发育和分化、基因表达和生物合成调控的基因下调。
许多这些基因表达的变化与自然衰老时发生的变化相似，这与 CCM 导致生物体过早衰退的观点一致，然而，我们发现，CCM 和衰老差异调控的基因中，涉及脂质代谢的基因被过度表达。这一类基因也是最早表现出 CCM 诱导的表达变化的基因之一，因此强调了脂质代谢的改变可能是 CCM 对健康的负面影响的一个重要中介。
