生物钟与衰老的相关研究进展

众所周知,从单细胞生物到人,几乎所有生物体在生理和行为上都表现出昼夜节律.内源性生物钟是产生昼夜节律的物质基础,由母钟和子钟组成,母钟位于下丘脑视交叉上核(SCN),子钟位于各个外周组织(肝脏、心脏等).随着机体的逐渐衰老,反应生物钟输出信号的生理昼夜节律在振荡幅度、振荡周期和表达时相等方面发生了相应的变化.另一方面,生物钟控制的生理昼夜节律影响衰老的进程,生物钟功能紊乱会严重加速机体的衰老.本文概述了衰老与生物钟之间的相关研究进展,为进一步认识衰老机制及其对机体的影响提供了线索.     

生物钟与衰老的相关研究进展

众所周知,从单细胞生物到人,几乎所有生物体在生理和行为上都表现出昼夜节律。内源性生物钟是产生昼夜节律的物质基础,由母钟和子钟组成,母钟位于下丘脑视交叉上核（SCN）,子钟位于各个外周组织（肝脏、心脏等）。随着机体的逐渐衰老,反应生物钟输出信号的生理昼夜节律在振荡幅度、振荡周期和表达时相等方面发生了相应的变化。另一方面,生物钟控制的生理昼夜节律影响衰老的进程,生物钟功能紊乱会严重加速机体的衰老。本文概述了衰老与生物钟之间的相关研究进展,为进一步认识衰老机制及其对机体的影响提供了线索。     

生物钟的转录后与翻译后水平调控进展

哺乳动物中的昼夜节律系统由位于下丘脑SCN核内的生物钟主钟和位于多数外周细胞中的子钟组成。在分子水平上,生物钟的节律振荡由生物钟基因及其编码蛋白的转录和翻译形成的自主的反馈环路组成,并接受外界因素的影响与环境周期保持同步。为此,就生物钟的调控机制而言,除了转录水平的基因表达调控外,生物钟转录产物和蛋白质的修饰也可以显著影响生物钟基因的表达时相。讨论了一些转录后与翻译后的修饰作用及其对生物钟的影响,并对其今后的研究方向作了展望。     

人体是如何感知时间的——谈谈“生物钟”

地球上绝大多数生物的生命活动都有与地球自转24h周期相一致的节律,由这些生物自身的计时系统,即生物钟来控制。人体的各种组织都有自己的生物钟,而主控生物钟位于脑中的下丘脑视交叉上核（简称SCN）,协调和统一外周生物钟的节律。生物钟由复杂的反馈回路组成,其中基因的活性周期性地振荡,形成时间信号。人眼中有2类感光细胞,分别接收视觉信号和感知光线强度的周期性变化。其中后一种信号被用来校对生物钟。     

白兰氏鸡精减轻抑郁病症作用的研究

抑郁症是一类以情绪低落、乐趣丧失为核心症状的疾病。目前,临床研究发现,抑郁症往往伴随着昼夜节律的紊乱,但对此类临床表现的产生机制缺乏系统深入的研究。该文建立了慢性温和不可预见性应激(chronic mild unpredictable stimulation,CUMS)抑郁症大鼠模型。在诱导抑郁症模型大鼠过程中通过外源补充白兰氏鸡精(Brand’s essence of chicken,BEC),应用ELISA、荧光定量PCR等方法从生理水平、基因转录水平研究BEC对生物钟系统的影响以及是否具有减轻抑郁症症状的作用。研究结果表明,BEC能有效调控和稳定生物钟母钟[下丘脑视交叉上核(suprachiasmatic nucleus,SCN)]及子钟(肝脏、脂肪组织)中生物钟基因的表达时相,减缓由CUMS引起的探索行为活动下降以及血清中相关激素的分泌紊乱,从而减轻抑郁症相关症状及有效预防抑郁症的发生。     

进食行为调控外周生物钟节律的研究进展

哺乳动物的生物钟包括位于下丘脑视交叉神经上核中的中枢生物钟(central clock)以及外周组织生物钟(peripheral clock)。节律正常时,由中枢时钟决定的外周生物钟同时具有一定程度的独立性。食物牵引实验(food entrainment)证明改变进食时间(白天给食)可以完全逆转外周组织的节律,因此,对于外周组织,进食是一个重要的授时因子(synchronizer)。目前已报道多种进食相关信号调控外周生物钟基因的表达及节律。现就进食行为影响外周生物钟等方面的研究进行综述。     

O-GlcNAc修饰调节生物节律研究进展

生物体的睡眠/觉醒、进食等行为以及各种生理、生化、代谢过程都遵循着大约24 h的周期性变化,称为昼夜节律(circadian rhythms)。昼夜节律与能量代谢之间存在着紧密的联系。位于下丘脑视交叉上核(suprachiasmatic nuclei,SCN)的中枢生物钟与外周组织细胞中的生物钟共同组成了哺乳动物的昼夜节律系统。以CLOCK/BMAL1异二聚体为核心的转录/翻译负反馈环保障了节律系统的正常运行。各种蛋白质翻译后修饰参与了昼夜节律的调控。综述了氧连β-N-乙酰葡糖胺修饰(O-Glc NAcylation)在调节昼夜节律中发挥的重要作用。O-Glc NAc修饰可以增强一些生物钟蛋白的稳定性及转录活性,也可以影响其他一些生物钟蛋白的磷酸化及细胞定位。抑制生物钟蛋白的O-Glc NAc修饰导致细胞节律衰弱和多种节律基因表达下调。研究表明,O-Glc NAc作为机体能量代谢的感受器参与了多条细胞代谢相关信号转导通路的调节,O-Glc NAc修饰为能量代谢影响昼夜节律提供了一条新的途径。     

肾上腺糖皮质激素与生物钟基因表达调控的相关研究进展

由生物体内源性生物钟所产生的昼夜节律是近年来生命科学的研究热点之一。哺乳动物中的昼夜节律系统由位于下丘脑SCN核内的主钟和位于多数外周细胞中的子钟组成。生物钟基因及其编码的蛋白质组成反馈回路,维持振荡系统持续进行并与环境周期保持同步。光照和食物是生物钟重要的授时因子, 光照刺激能引起肾上腺中基因表达变化以及糖皮质激素的分泌, 而肾上腺糖皮质激素能减缓由食物因子引起的外周生物钟时相的移动。可见, 肾上腺糖皮质激素与生物钟有着非常密切的关系。文章综述了两者的相互影响并对今后的研究方向做了展望。     

哺乳动物季节性繁殖的内源年生物钟及光敏神经环路研究进展

生活在温带和寒带的哺乳动物在长期的进化过程中形成了季节性繁殖的生活史特征。哺乳动物的繁殖功能主要受到下丘脑-垂体-性腺轴(hypothalamic-pituitary-gonadal axis,HPGA)的调控。视交叉上核(suprachiasmatic nucleus,SCN)能够自发振荡并响应光周期信号的变化,引发褪黑素分泌的改变,并介导下游通路中下丘脑甲状腺激素、Kisspeptin和RF酰胺相关肽(RF amide-related peptide,RFRP)的节律性表达变化,从而调控哺乳动物的季节性繁殖。本文综述了哺乳动物季节性繁殖的内源年生物钟调控,并强调了光敏通路中包括甲状腺激素、Kisspeptin和RFRP在季节性繁殖调控中的重要作用。     

Identification of the suprachiasmatic nucleus in birds

Circadian rhythms are generated by an internal biological clock. The suprachiasmatic nucleus (SCN) in the hypothalamus is known to be the dominant biological clock regulating circadian rhythms in mammals. In birds, two nuclei, the so-called medial SCN (mSCN) and the visual SCN (vSCN), have both been proposed to be the avian SCN. However, it remains an unsettled question which nuclei are homologous to the mammalian SCN. We have identified circadian clock genes in Japanese quail and demonstrated that these genes are expressed in known circadian oscillators, the pineal and the retina. Here, we report that these clock genes are expressed in the mSCN but not in the vSCN in Japanese quail, Java sparrow, chicken, and pigeon. In addition, mSCN lesions eliminated or disorganized circadian rhythms of locomotor activity under constant dim light, but did not eliminate entrainment under light-dark (LD) cycles in pigeon. However, the lesioned birds became completely arrhythmic even under LD after the pineal and the eye were removed. These results indicate that the mSCN is a circadian oscillator in birds.     

Photoperiod differentially regulates circadian oscillators in central and peripheral tissues of the Syrian hamster

In many seasonally breeding rodents, reproduction and metabolism are activated by long summer days (LD) and inhibited by short winter days (SD). After several months of SD, animals become refractory to this inhibitory photoperiod and spontaneously revert to LD-like physiology. The suprachiasmatic nuclei (SCN) house the primary circadian oscillator in mammals. Seasonal changes in photic input to this structure control many annual physiological rhythms via SCN-regulated pineal melatonin secretion, which provides an internal endocrine signal representing photoperiod. We compared LD- and SD-housed animals and show that the waveform of SCN expression for three circadian clock genes (Per1, Per2, and Cry2) is modified by photoperiod. In SD-refractory (SD-R) animals, SCN and melatonin rhythms remain locked to SD, reflecting ambient photoperiod, despite LD-like physiology. In peripheral oscillators, Per1 and Dbp rhythms are also modified by photoperiod but, in contrast to the SCN, revert to LD-like, high-amplitude rhythms in SD-R animals. Our data suggest that circadian oscillators in peripheral organs participate in photoperiodic time measurement in seasonal mammals; however, circadian oscillators operate differently in the SCN. The clear dissociation between SCN and peripheral oscillators in refractory animals implicates intermediate factor(s), not directly driven by the SCN or melatonin, in entrainment of peripheral clocks.     

Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells

The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus (SCN) of the brain and subsidiary oscillators in most peripheral cell types. While oscillators in SCN neurons are known to function in a self-sustained fashion, peripheral oscillators have been thought to damp rapidly when disconnected from the control exerted by the SCN. Using two reporter systems, we monitored circadian gene expression in NIH3T3 mouse fibroblasts in real time and in individual cells. In conjunction with mathematical modeling and cell co-culture experiments, these data demonstrated that in vitro cultured fibroblasts harbor self-sustained and cell-autonomous circadian clocks similar to those operative in SCN neurons. Circadian gene expression in fibroblasts continues during cell division, and our experiments unveiled unexpected interactions between the circadian clock and the cell division clock. Specifically, the circadian oscillator gates cytokinesis to defined time windows, and mitosis elicits phase shifts in circadian cycles.     

Retinal circadian clocks and control of retinal physiology

Retinas of all classes of vertebrates contain endogenous circadian clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis, and cellular events such as rod disk shedding, intracellular signaling pathways, and gene expression. The vertebrate retina is an example of a "peripheral" oscillator that is particularly amenable to study because this tissue is well characterized, the relationships between the various cell types are extensively studied, and many local clock-controlled rhythms are known. Although the existence of a photoreceptor clock is well established in several species, emerging data are consistent with multiple or dual oscillators within the retina that interact to control local physiology. A prominent example is the antiphasic regulation of melaton in and dopamine in photoreceptors and inner retina, respectively. This review focuses on the similarities and differences in the molecular mechanisms of the retinal versus the SCN oscillators, as well as on the expression of core components of the circadian clockwork in retina. Finally, the interactions between the retinal clock(s) and the master clock in the SCN are examined.     

Effects of restricted feeding on daily fluctuations of hepatic functions including p450 monooxygenase activities in rats

Hepatic P450 monooxygenase activities, assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) activities, show obvious daily fluctuations in male rats with high values during the dark period and low values during the light period. We have already confirmed that the ACD activities are controlled by the suprachiasmatic nucleus (SCN), which is well known as the oscillator of circadian rhythm. Recently, it is reported that circadian oscillators exist not only in the SCN but also in peripheral organs. To date, it is unclear which circadian oscillators predominantly drive the daily fluctuations of hepatic ACD activities. To address this question, we examined the effects of restricted feeding, which uncouples the circadian oscillators in the liver from the central pacemaker in the SCN, on the daily fluctuations in hepatic ACD activities in male rats. Here we show that restricted feeding inverts the oscillation phase of the daily fluctuations in hepatic ACD activities. Regarding the hepatic P450 content, there were no fluctuations between the light and dark periods under ad libitum and restricted feeding conditions. Therefore, it is considered that the daily fluctuations in hepatic ACD activities are predominantly driven by the circadian factors in peripheral organs rather than by the oscillator in the SCN directly.     

The in vitro real-time oscillation monitoring system identifies potential entrainment factors for circadian clocks

Background  

Circadian rhythms are endogenous, self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes. The circadian organization of these processes in mammals is governed by the master oscillator within the suprachiasmatic nuclei (SCN) of the hypothalamus. Recent findings revealed that circadian oscillators exist in most organs, tissues, and even in immortalized cells, and that the oscillators in peripheral tissues are likely to be coordinated by SCN, the master oscillator. Some candidates for endogenous entrainment factors have sporadically been reported, however, their details remain mainly obscure.