Universitat Pompeu Fabra

在两项新的研究中，来自西班牙庞培法布拉大学和巴塞罗那生物医学研究所的研究人员揭示了中枢生物钟（central circadian clock）和外周生物钟（peripheral circadian clock）之间的协调作用，不仅可以维持日常生理节律，更能防衰减龄。这两种生物钟之间的协调保证了50%的昼夜节律功能，包括细胞周期、DNA修复、线粒体活动和新陈代谢等重要过程。大脑中枢生物钟与外周生物钟同步可防止肌肉过早衰老并改善肌肉功能，这为通过调节生物钟来解决与年龄有关的衰退问题提出了新的策略。自20世纪70年代生物钟机制的发现以来，科学家们不断探索着这一人体内部时钟如何调控着日常生物进程。每24小时的生物钟摆动，确保了细胞与外界环境的完美同步，从睡眠到代谢，无一不漏。昼夜节律由大脑中的中枢生物钟协调，并与不同外周组织中的生物钟（即外周生物钟）沟通，影响着从睡眠模式到食物代谢能力等许多功能。在这两项新的研究中，这些作者描述了中枢生物钟与肌肉和皮肤中的外周生物钟之间的精准同步，以及两者如何确保组织的正确功能以及防止与衰老相关的退化过程。他们的发现突显了这种协调对维持肌肉和皮肤最佳功能的重要性。他们的研究还描述了外周生物钟非凡的自主程度，在外周生物钟缺失的情况下，外周生物钟可以维持24小时周期并管理大约15%的昼夜节律功能。庞培法布拉大学医学与生命科学系研究员Pura Muñoz-Cánoves博士解释说，“我们的研究揭示了，只有两种组织时钟（一种是中枢生物钟，另一种是外周生物钟）之间存在最低限度的相互作用，才能维持肌肉和皮肤等组织的最佳功能，避免其退化和老化。如今，下一步是确定参与这种相互作用的信号因子，并考虑潜在的治疗应用。”与肌肉外周生物钟协调可保持肌肉功能并防止过早衰老第一项关于大脑与肌肉之间沟通的研究证实中枢生物钟与外周生物钟之间的协调对于维持日常肌肉功能和防止肌肉组织过早衰老至关重要。恢复这种昼夜节律可减少肌肉质量和力量的损失，从而改善实验小鼠模型中退化的运动功能。这些研究结果还证实限时进食（time-restricted feeding, TRF），即只在一天中的活跃期进食，可以部分取代中枢生物钟，增强肌肉外周生物钟的自主性。更有意义的是，通过限时进食恢复昼夜节律可减轻老龄小鼠的肌肉损失、代谢和运动功能衰退以及肌肉力量的丧失。这些发现对开发抗肌肉衰老疗法和提高老年体能具有重要意义。皮肤外周生物钟整合并调节大脑信号在第二项研究中，这些作者证实皮肤外周生物钟在协调该组织的日常生理机能方面起着关键作用。这种协调通过整合大脑信号，有时还通过修改这些信号，确保皮肤的正常功能。一项令人惊讶的发现是，在外周生物钟缺失的情况下，大脑中枢生物钟仍能维持皮肤的昼夜节律，但其工作方式与往常相反（即作息时间相反）。例如，他们观察到，如果仅由中枢生物钟调节，DNA 复制将发生在白天，而此时皮肤暴露在紫外线下，这将增加积累突变的风险。图片来自Cell Stem Cell, 2024, doi:10.1016/j.stem.2024.04.013总而言之，这两大研究不仅为生物钟的协调性描绘了生动画面，更揭示了其在防衰逆龄、维护肌肉与皮肤健康中的关键角色，为未来抗老医学与健康老龄化干预提供了全新的靶标靶点。参考资料：Arun Kumar et al. Brain–muscle communication prevents muscle aging by maintaining daily physiology. Science, 2024, doi:10.1126/science.adj8533.Thomas Mortimer et al. The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis. Cell Stem Cell, 2024, doi:10.1016/j.stem.2024.04.013.Synchronisation between the central circadian clock and the circadian clocks of tissues preserves their functioning and prevents ageinghttps://www.irbbarcelona.org/en/news/scientific/synchronisation-between-central-circadian-clock-and-circadian-clocks-tissues本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

Two complementary research articles reveal that central and peripheral circadian clocks coordinate to regulate the daily activity of skin and muscles. The coordination between the two clocks (central and peripheral) guarantees 50% of the circadian functions of tissues, including vital processes such as the cell cycle, DNA repair, mitochondrial activity, and metabolism. Synchronization between the central brain clock and peripheral ones prevents premature muscle aging and improves muscle function, suggesting new strategies to tackle age-related decline through circadian rhythm modulation. Discovered in the 1970s, circadian clocks are essential for the regulation of biological time in most cells in the human body. These internal mechanisms adjust biological processes to a 24-hour cycle, allowing the synchronisation of cellular functions with daily variations in the environment. Circadian rhythms, which are coordinated by a central clock in the brain that communicates with clocks in different peripheral tissues, influence many functions, from our sleep patterns to our ability to metabolise food. A team led by Dr. Salvador Aznar Benitah, an ICREA researcher at IRB Barcelona, and Dr. Pura Muñoz-Cánoves, an ICREA researcher in the Department of Medicine and Life Sciences at the Pompeu Fabra University (UPF), has described how the synchronisation between the central clock and peripheral clocks in muscle and skin plays a key role in ensuring the correct function of these tissues, as well as preventing degenerative processes associated with ageing. The results of this work have been published in two articles in high-impact journals. In this regard, the research on the synchronisation between the central and peripheral clocks appears in Science, while the work on the coordination between the central clock and skin peripheral clock has been released in Cell Stem Cell. Both studies reveal the common mechanisms that underscore the importance of this coordination to uphold the optimal functionality of muscle and skin. The work also describes the remarkable degree of autonomy of the peripheral clocks, which can maintain 24-h cycles and manage approximately 15% of circadian functions in the absence of the central clock. "It is fascinating to see how synchronisation between the brain and peripheral circadian clocks plays a critical role in skin and muscle health, while peripheral clocks alone are autonomous in carrying out the most basic tissue functions," says Dr. Aznar Benitah, head of the Stem Cell and Cancer laboratory at IRB Barcelona. "Our study reveals that minimal interaction between only two tissue clocks (one central and the other peripheral) is needed to maintain optimal functioning of tissues like muscles and skin and to avoid their deterioration and ageing. Now, the next step is to identify the signalling factors involved in this interaction, with potential therapeutic applications in mind," explains Dr. Muñoz-Cánoves, a UPF Professor who is now a Principal Investigator at Altos Labs (San Diego, US). Coordination with the muscle peripheral clock maintains muscle function and prevents premature ageing The study published in Science on the communication between the brain and muscle confirmed that the coordination between the central and peripheral clocks is crucial for maintaining daily muscle function and preventing the premature ageing of this tissue. Restoration of the circadian rhythm reduces the loss of muscle mass and strength, thereby improving deteriorated motor functions in experimental mouse models. The results of the study have also demonstrated that time-restricted feeding (TRF), which involves eating only in the active phase of the day, can partially replace the central clock and enhance the autonomy of the muscle clock. More relevant still is that this restoration of the circadian rhythm through TRF can mitigate muscle loss, the deterioration of metabolic and motor functions, and the loss of muscle strength in aged mice. These findings have significant implications for the development of therapies for muscular ageing and the enhancement of physical performance in older age. Drs. Arun Kumar and Mireia Vaca Dempere, both from the UPF, are the first authors of this study, which has also received contributions from Drs. Eusebio Perdiguero and Antonio Serrano, previously at the UPF and now at Altos Labs. The peripheral clock of the skin integrates and modulates brain signals In the study published in Cell Stem Cell, the team has demonstrated that the skin circadian clock is pivotal in coordinating the daily physiology of this tissue. By integrating brain signals, and sometimes by modifying them, this coordination ensures the correct functioning of the skin. A surprising discovery was that, in the absence of the peripheral clock, the central body clock maintains the circadian rhythm of the skin but it works in the opposite way as usual (that is to say, on an opposite schedule). For example, the researchers observed that DNA replication, if regulated only by the central clock, would occur during the daytime, when skin is exposed to ultraviolet light, which would increase the risk of accumulating mutations. This phenomenon highlights the importance of the peripheral clock, which not only receives signals from the central clock -- which coordinates the rhythms of the entire organism -- but also adapts these signals to the specific needs of the tissue in which they are (in the case of skin stem cells, DNA replication peaks after exposure to ultraviolet light during the day). Dr. Thomas Mortimer, a postdoctoral fellow at IRB Barcelona, and Dr. Patrick-Simon Welz, from the Hospital del Mar Research Institute, have headed this project, together with Drs. Aznar Benitah and Muñoz-Cánoves. The results of the two studies stem from international collaboration with researchers from the University of California and the University of Texas Health in San Antonio (both in the US), the University of Lübeck in Alemania, the Karolinska Institute in Sweden, the Humanitas University in Italy, and Altos Labs San Diego Institute of Science in the US. The project was supported by funding from the European Research Council, the EU H2020 programme, the Ministry of Science, Innovation and Universities, the Government of Catalonia, the Lilliane Bettencourt Foundation, "la Caixa" Foundation, the Marató de TV3 Foundation, the BBVA Foundation and the Novo Nordisk Foundation.

心血管疾病（CVD）是全球头号死因，每年约有794万例心血管疾病相关死亡，而不健康的饮食则是心血管疾病的主要危险因素。快节奏的现代生活和与日俱增的对于健康、身材的追求，网上各种很火的轻断食、禁食方法层出不穷，确实许多研究证实，少吃可以改善代谢、延长寿命。但不正确的禁食方法会引发不健康的营养行为，如太晚吃晚饭和不吃早餐。每日进食/禁食周期是外周器官（肝脏、心脏、肾脏和胰腺等）昼夜节律的主要同步器，并会对心脏代谢功能（包括血压调节）产生较大影响。因此，来自巴塞罗那全球健康研究所、庞培法布拉大学（UPF）的研究人员，探索了一天中最合适的第一餐和最后一餐的时间，以及进食次数和夜间禁食时间与CVD风险的关系。文章题为“Dietary circadian rhythms and cardiovasculardisease risk in theprospective NutriNet-Santé cohort”，发表于Nature communications。 DOI: 10.1038/s41467-023-43444-3队列研究以及进餐、禁食时间与心血管疾病风险的关系本研究共纳入103,389名参与者（79%为女性），平均基线年龄为42.6岁。总体而言，年轻参与者、学生或失业者、单身者、无心血管疾病家族史者、目前经常吸烟者、体力活动水平较高者、教育水平较高者和月收入较低者倾向于较晚的第一餐和最后一餐时间。此外，与较早进餐的参与者相比，较晚进餐的参与者饮酒量更高，酗酒次数更多，报告的就寝时间更晚，并且在一周内进餐时间的变化性更大（定义为进食时差）。 表1：2009-2021年NutriNet-Santé 队列纳入受试者的基线特征，N=103,389在699,547人/年和7.2年的中位随访时间内，研究队列共确定了2036例CVD事件，其中，脑血管病988例（脑卒中253例、短暂性脑缺血发作765例），冠心病1071例（心肌梗死162例、急性冠脉综合征89例、心绞痛428例等）。研究人员观察到每天第一餐时间每延迟一小时与总体CVD风险增加相关（HR= 1.06，95% CI 1.01-1.12，P=0.02）。最后一餐时间每延迟1小时，脑血管疾病风险增加8%（HR= 1.08，95% CI 1.01-1.15，P=0.02）。更具体地说，与晚上8点前吃当天最后一餐相比，晚上9点后再进食，脑血管疾病风险增高28%（HR= 1.28，95% CI 1.05-1.55，P<0.01）。来自随机对照试验的证据表明，晚吃晚餐，即当褪黑激素水平高时，摄入食物会导致葡萄糖耐受不良、胰岛素抵抗、胆固醇和甘油三酯水平升高等。此外，结果显示，夜间禁食时间与脑血管疾病风险呈负相关。夜间禁食时间每增加一小时，脑血管疾病风险降低7%（HR=0.93，95% CI，0.87-0.99，P=0.02）。在这项研究中，研究人员没有发现进餐次数与冠心病风险之间存在关联性。进食时间晚对女性伤害更大研究结果表明，女性进食时间与心血管疾病风险的关联性比男性更强。具体来说，女性的第一餐和最后一餐时间较晚与总体CVD和脑血管疾病的风险较高显著相关，但男性则不然。与结果一致，相关研究也显示深夜进食与女性的动脉硬化和代谢综合征有关，但与男性无关[2,3]。此外，晚上摄入较高的卡路里也与C-反应蛋白水平增加有关，并与女性BMI、腰围和血压的增加更有关联。 表2：2009-2021年NutriNet-santécohort中按性别划分的进餐时间、次数和夜间禁食时间与心血管疾病风险的相关性，N= 103,389总结在本项研究中，晚吃第一餐（早于8 AM /晚于9 AM）和最后一餐（早于8 PM / 晚于9 PM ）与心血管疾病的风险升高相关联，且尤其对于女性，较晚的进食时间会引起诸如肥胖、糖尿病等健康问题。研究结果表明，健康的进食/禁食模式，应是：1. 采用更早的进食时间模式，即早吃早饭和晚饭；2. 更长的夜间禁食期；3. 禁食不可不吃早餐。在生活中，有许多小伙伴或是因为太忙，或是选择不吃早饭来制造一天的卡路里缺口，或者是热衷于白天少吃点，晚点吃夜宵，但研究表明，这样过晚的饮食时间实则不利于健康。看来追求健康并不简单，不仅要会吃，还要吃对时间~参考文献：[1] Palomar-Cros A, Andreeva VA, Fezeu LK, et al. Dietary circadian rhythms and cardiovascular disease risk in the prospective NutriNet-Santé cohort. Nat Commun. 2023;14(1):7899. Published 2023 Dec 14. doi:10.1038/s41467-023-43444-3[2] Zhang X, Wu Y, Na M, et al. Habitual Night Eating Was Positively Associated With Progress of Arterial Stiffness in Chinese Adults. J Am Heart Assoc. 2020;9(19):e016455. doi:10.1161/JAHA.120.016455[3] Yoshida J, Eguchi E, Nagaoka K, Ito T, Ogino K. Association of night eating habits with metabolic syndrome and its components: a longitudinal study. BMC Public Health. 2018;18(1):1366. Published 2018 Dec 11. doi:10.1186/s12889-018-6262-3撰文 | lcc编辑 | lcc部分文字来源于网络，本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！精彩推荐：1、「司美格鲁肽升级版」，Nat Metab 新研究：每月一针AMG 133，仅3针便可减重约26斤，且疗效可持续5个月以上2、新冠强效药迎来曙光！西湖大学最新研究：开发增强的广谱肽可有效抑制多种SARS-CoV-2变体3、国内首例太空器官芯片研究完成、使用器官芯片数据的三款新药获批进入临床试验｜回顾+类器官&器官芯片开启生物医药新篇章4、各位deadline战士，拖延=无效焦虑｜两大研究结果表明：越拖压力越大，且对健康不利5、努力运动能获得“快乐水”自由？超10万人长达30年的研究表明：含糖或甜味剂饮料，增加心血管疾病风险，即使运动也无济于事！