Science特刊:失眠、肥胖、癌症……万能的生物钟如何掌管我们的身体?
2016/12/02
加班、倒班工作,频繁地跨越时区,夜晚玩手机……越来越多人都面临着生物钟紊乱的困扰。11月25日,Science杂志推出了生物钟特刊。用4篇综述阐述了生物钟与健康疾病、免疫系统、睡眠和神经退行性疾病以及代谢的关系。


雄鸡报晓,蜘蛛半夜结网,牵牛花在清晨开放……自然界所有生物的生命活动都存在节律现象,这就是我们常说的生物钟。与地球24小时的光-暗周期保持同步对于生物维持健康的生理状态至关重要。然而现代社会压力使人类的作息时间不再严格遵循于体内的生物钟。加班、倒班工作,频繁地跨越时区,夜晚玩手机……越来越多人都面临着生物钟紊乱的困扰。11月25日,Science杂志推出了生物钟特刊。用4篇综述阐述了生物钟与健康疾病、免疫系统、睡眠和神经退行性疾病以及代谢的关系。

生物钟是如何产生的?

在哺乳动物的大脑中有一个生物节律的起搏器,它位于下丘脑视交叉上核(SCN)。SCN就像一个总司令,根据自然界光-暗周期调控生理和活动节律,并能通过激素和神经信号调节外周生物钟。SCN 被切除之后,动物活动和进食规律将完全被打乱。


生物节律的产生及维持是一系列与生物钟相关的基因调控的结果。这些钟基因包括:BMAL,CLOCK,PER,CRY, REV-ERB-α,ROR-β等。其中,核心钟基因BMAL1-CLOCK形成的异二聚体与PER和CRY及一系列钟控基因(clock-controlled genes,CCGs)上的E-box元件结合,启动这些基因的转录。随着PER和CRY蛋白表达逐渐增多,它们将进入细胞核中,抑制异二聚体的作用。因此,细胞中 PER和 CRY 的蛋白合成开始减少。如此循环,使基因的转录水平呈现出24h的振荡周期。除这个负反馈环路之外,CLOCK和BMAL1蛋白质也调节核受体REV-ERB-α和ROR-β的表达,后者又可反过来抑制或激活BMAL1的转录。在SCN之外, CLOCK的同源物NPAS2也可与BMAL1形成异二聚体,调控钟控基因的表达。


图片来源:参考文献4


1

      生物钟与健康和疾病

Circadian time signatures of fitness and disease

哺乳动物的生物钟包括位于SCN的中枢生物钟(central clock)以及外周组织生物钟(peripheral clock)。在大脑中,生物钟不仅调控着我们睡眠-觉醒周期,也调节着诸多行为,包括学习、奖赏和神经发生。外周生物钟受到中枢生物钟调控,同时也受进食、温度等因素的影响。衰老、轮班工作,时差,营养过剩,肥胖或癌症等原因可能会导致外周生物钟与中枢生物钟不同步。昼夜节律及睡眠紊乱与代谢综合征、肥胖、糖尿病、自身免疫和癌症等疾病密切相关。

在本篇综述中,作者阐述了在基因组动力学水平上昼夜节律对机体生理活动调控的研究进展,以及遵循或扰乱生物节律对机体健康所产生的影响。


生物节律和疾病的关联 图片来源:参考文献1


2

生物钟与免疫

Immunity around the clock

免疫是一把双刃剑,它虽然可抵御病原体侵扰和有害物质的刺激,但过度激活的免疫系统将对宿主造成伤害,甚至导致死亡。由于许多免疫参数都随着一天的时间出现节律性地振荡,生物钟已经成为避免免疫系统过度激活的“闸门”,在保护机体健康中扮演着重要角色。外界环境和免疫细胞内在的生物振荡相互作用,共同优化着机体的免疫反应。

在这篇综述中,作者对生物振荡如何限制免疫系统及免疫反应以增强机体健康进行了阐述。重点讨论了生物节律对免疫反应的“闸门”作用;免疫反应的生物振荡如何产生及维持;免疫细胞中的生物振荡。更好地理解细胞生物钟如何控制免疫反应有助于慢性炎症和免疫失调等疾病中时间治疗学的发展。


生物钟对免疫系统的“闸门”作用。图片来源:参考文献2


3

生物钟与睡眠和神经退行性疾病

Mechanisms linking circadian clocks,sleep, and neurodegeneration

生物节律及睡眠周期的紊乱往往随着衰老出现,严重危害着人类的健康。许多研究表明,节律及睡眠紊乱不仅是多种神经退行性疾病的临床症状,还会推动着这些疾病早期的进展。

在这篇综述中,作者阐述了生物节律紊乱及失眠与神经退行性疾病在细胞及分子机制上的关联,其中重点阐述了阿尔茨海默病。此外,作者还考察了中央和外周生物节律的相互作用,生物钟基因功能及睡眠在维持大脑稳态中的作用,并阐述了潜在的治疗意义。生物钟和睡眠可以影响神经退行性疾病的一些关键过程,这意味着调控这一系统可以促进更加健康的大脑老化。


阿尔茨海默病中,失眠、β-淀粉样蛋白与神经变性之间的关联。图片来源:参考文献3


4

生物钟与代谢

Circadian physiology of metabolism

除了自然界的光-暗周期变化,进食也是一个重要的授时因子。生物体内很多器官生理功能的运行需要进食喝水的信号刺激。因此,对于动物来说,“什么时候吃”和“吃什么”同样重要。同时,生物节律也控制着机体的代谢过程,与器官吸收营养、动员营养及处理代谢垃圾有关的一系列基因都受到节律调控。规律的饮食及禁食对于维持正常的生物节律十分重要,而频繁扰乱日常活动-休息及饮食-禁食节律或利用基因工程破坏实验小鼠的生物钟基因,都将导致代谢疾病。

在这篇综述中,作者阐述了代谢通路、代谢产物与生物钟系统的相互作用,以及光、摄食、环境温度等授时因子对睡眠和代谢的影响。理解生物节律与代谢相互作用机制有助于人们选择一个更健康的生活方式,并为代谢疾病寻求更佳的治疗方法。


生物节律调控代谢途径及代谢途径影响生物钟的实例。图片来源:参考文献4

结语

本杰明•富兰克林曾说“早睡早起使人健康、富裕又聪明。”无数的研究证明,这句格言确实有科学道理。遵循自然界的昼夜节律有益人们身心健康。但是,现代人类的生活方式使人们不得不常常面临着生物节律紊乱的亚健康状态。长期失眠、倒时差、夜班加重了抑郁症、癌症、认知障碍、糖尿病等一系列疾病的风险。理解生物钟的重要性及其生理机制不仅帮助我们调整生活作息,提升健康状况,同时也利于时间治疗学的发展,使临床治疗能达到更加理想的治疗效果。

参考文献

1.Circadian time signatures of fitness and disease

2.Immunity around the clock

3.Mechanisms linking circadian clocks, sleep, and neurodegeneration

4.Circadian physiology of metabolism

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • Circadian time signatures of fitness and disease

    Biological clocks are autonomous anticipatory oscillators that play a critical role in the organization and information processing from genome to whole organisms. Transformative advances into the clock system have opened insight into fundamental mechanisms through which clocks program energy transfer from sunlight into organic matter and potential energy, in addition to cell development and genotoxic stress response. The identification of clocks in nearly every single cell of the body raises questions as to how this gives rise to rhythmic physiology in multicellular organisms and how environmental signals entrain clocks to geophysical time. Here, we consider advances in understanding how regulatory networks emergent in clocks give rise to cell type–specific functions within tissues to affect homeostasis.

    展开 收起
  • Immunity around the clock

    Immunity is a high-cost, high-benefit trait that defends against pathogens and noxious stimuli but whose overactivation can result in immunopathologies and sometimes even death. Because many immune parameters oscillate rhythmically with the time of day, the circadian clock has emerged as an important gatekeeper for reducing immunity-associated costs, which, in turn, enhances organismal fitness. This is mediated by interactions between extrinsic environmental cues and the intrinsic oscillators of immune cells, which together optimize immune responses throughout the circadian cycle. The elucidation of these clock-controlled immunomodulatory mechanisms might uncover new approaches for treating infections and chronic inflammatory diseases.

    展开 收起
  • Mechanisms linking circadian clocks, sleep, and neurodegeneration

    Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer’s disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.

    展开 收起
  • Circadian physiology of metabolism

    A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test