15 BEDREST Effects of bed rest on the circadian organisation of the human transcriptome as a model for temporal dysregulation in an ageing population

行为和生理的昼夜节律(大约一天)使我们的活动与外界同步。健康、同步的昼夜节律的重要性从时差或睡眠不足期间所经历的负面影响以及在航天期间发生的睡眠和昼夜节律中断中可见一斑。在太空飞行和衰老期间，昼夜节律信号的强度和时间会减少和中断，这可能是观察到宇航员和老年人睡眠/清醒活动发生许多变化的原因。人体周围的生物钟调节大多数生理过程，如新陈代谢、心血管功能和免疫系统，长时间的太空飞行和衰老都可能扰乱这些过程的生物钟调节，并与相关的负面健康结果相关。生物钟还调节激素，如褪黑激素(在夜间达到峰值)和皮质醇(在醒来时达到峰值)。皮质醇是一种重要的循环信号，调节许多基因的表达，包括那些制造参与免疫和炎症的蛋白质的基因。在太空飞行和衰老过程中，皮质醇的分泌也会受到干扰，这可能会改变许多基因的表达调控。血液在人体内循环，越来越多地被视为了解全身状态的窗口。例如，血液生物标记物现在被用来诊断和监测从阿尔茨海默氏症到癌症的许多不同疾病的疾病进展。制造蛋白质的基因表达的时间组织很重要--某些蛋白质需要在白天或晚上的特定时间合成--在任何给定的组织中，大约6%-10%的基因都是按昼夜节律表达的，包括在血液中。在两项单独的人类研究中，我们已经表明，一周的睡眠不足或错时睡眠(如在时差中发生的)会导致血液基因表达的昼夜节律发生戏剧性的扰乱(包括时间和幅度)。这包括对白天正常表达的基因(免疫反应、炎症、氧化应激)和夜间正常表达的基因(蛋白质合成的调节)的干扰，以及对昼夜节律性产生本身至关重要的核心时钟基因的干扰。航天及其卧床模式导致褪黑激素和皮质醇的昼夜节律中断。这种昼夜节律的干扰很可能延伸到血液中基因表达的时间中断，尽管到目前为止还没有人对此进行研究。因此，在卧床休息时，昼夜节律信号会受到干扰，循环皮质醇升高，血液循环发生变化，心血管功能发生变化，包括免疫功能受到抑制，所有这些都在衰老过程中出现。因此，在宇航员和老年人身上发现的许多负面健康影响可能直接与血液中基因表达的昼夜节律被暂时扰乱有关。这里提出的研究的主要目的是对正在进行卧床休息方案的人的血液中的基因表达进行仔细的研究。通过将卧床休息期间不同阶段昼夜采集的一系列血液样本与在基线和恢复期间收集的类似定时样本进行比较，我们将能够识别其中断影响特定生物过程的基因网络，其中可能包括免疫系统和尚未显示出受卧床休息影响的其他过程。很难在长时间的航天飞行期间或在长时间的老化过程中直接研究这些影响，而卧床休息方案提供了一种实用的手段来探索确定的实验室条件的变化。假设卧床休息是衰老的模型，我们还将使用这一模型来评估血液采样是否是监测老龄化时间中断的影响和评估对策效果的可行方法。

Circadian (about a day) rhythms in behaviour and physiology synchronise our activity to the outside world. The importance of robust, well-synchronised circadian rhythms is evident from the negative effects experienced during jet lag or sleep deprivation, and also disruption of sleep and circadian rhythms that occurs during spaceflight. The strength and the timing of circadian signals become reduced and disrupted during spaceflight and ageing and may account for many changes observed with sleep/wake activity in astronauts and the elderly. Circadian clocks around the body regulate most physiological processes such as metabolism, cardiovascular function, and the immune system and both long duration spaceflight and ageing may disrupt the circadian regulation of these processes and be associated with related negative health outcomes.Circadian clocks also regulate hormones such as melatonin (which peaks in the night) and cortisol (which peaks on awakening). Cortisol is an important circulating signal that regulates the expression of many genes, including those that make proteins involved in immunity and inflammation. Cortisol secretion is also disrupted during spaceflight and ageing and could change the regulation of the expression of many genes.Blood circulates around the body and is increasingly viewed as a 'window' on the whole-body state. For example, blood biomarkers are now used to diagnose and to monitor disease progression in many different diseases ranging from Alzheimer's to cancer. Temporal organisation in the expression of genes to make proteins is important - certain proteins need to be made at particular times of day or night - and in any given tissue around 6-10% of all genes are expressed with a circadian rhythm, including in blood. In two separate human studies, we have shown that one-week of insufficient sleep or mistimed sleep (as occurs in jet lag) leads to dramatic disruption (both timing and amplitude) to the circadian rhythms of blood gene expression. This included disruption to genes normally expressed during the day (immune response, inflammation, oxidative stress) and those normally expressed during the night (regulation of protein synthesis), as well as core clock genes central to the generation of circadian rhythmicity itself.Spaceflight and its bed rest model result in circadian disruption to melatonin and cortisol. This circadian disruption likely extends to the temporal disruption of gene expression in blood, although nobody has investigated this to date. Thus, during bed rest there is disruption to circadian signals, elevated circulating cortisol, changes in blood circulation, changes to cardiovascular function, including suppressed immune function, all of which are also found in ageing. Therefore, many of the negative health effects found in astronauts and the elderly could be directly associated with temporal disruption to the circadian regulation of gene expression in blood. The main aim of the research proposed here is to perform a careful study of gene expression in blood of people who are undertaking a bed rest protocol. By comparing a series of blood samples collected through the day and night at different stages during the bed rest period with similar timed samples collected at baseline and during recovery, we will be able to identify networks of genes whose disruption affects specific biological processes, which may include the immune system and other processes not yet shown to be affected by bed rest. It is difficult to study these effects directly during long duration spaceflight or during ageing over extended time periods and the bed rest protocol provides a practical means to explore changes in defined laboratory conditions. It is assumed that bed rest models ageing and we will also use this model to assess the methodological aspects of whether blood sampling is a viable approach to monitor effects of temporal disruption in ageing and to assess the effects of countermeasures.