Telomeres and time: Effects of circadian rhythm disruption on telomere dynamics

端粒和时间：昼夜节律破坏对端粒动态的影响

• 批准号: BB/P009174/1
• 负责人: Pat Monaghan
• 金额: $ 72.75万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP009174%2F1
• 关键词: Telomeres; time; Effects; circadian; rhythm

Biological rhythms are found throughout the tree of life, and new tools used to study them have demonstrated the pervasiveness of circadian regulation across processes in the body. The circadian system had evolved to interact with reliable alternation of 24 h day-night rhythmicity, but human lifestyles have become increasingly disconnected from geophysical time. The availability of light at night, an increasing demand for shift-work and travel across time zones all disrupt the circadian system in modern life. Such disruption has major impacts on health including reduced longevity and accelerated ageing. Captive animals such as nocturnal laboratory rodents can also experience severe circadian disruption, often being kept in inappropriate light regimes, and fed and disturbed during the hours of daylight. A clear understanding of how the adverse effects of circadian disruption come about is therefore needed.The circadian clocks within the body ensure that different physiological processes take place at the most appropriate time of day. Temporal partitioning through circadian regulation ensures that processes such as DNA replication and cell division take place at a time when the risk of DNA damage from the Reactive Oxygen Species (ROS) produced during metabolism is minimised. One largely unstudied route whereby circadian disruption could affect long term health and the incidence of age related disease is through effects on telomere loss. Telomeres are protective caps at the end of linear chromosomes and enable cells to identify chromosome ends. They consist of tandem repeats of a non-coding sequence of bases. Some DNA is lost from the chromosome ends during cell division, and the amount lost can be increased by oxidative damage to the telomere. Telomeres in most body cells therefore shorten with each round of cell division. They eventually reach a critical length at which the cells stop dividing and often die. The rate of telomere loss differs among individuals and is accelerated by environmental influences. If the circadian orchestration of cell division, generation of ROS and antioxidant protection is disrupted, increased telomere shortening could give rise to premature aging. In this project we will investigate whether circadian disruption accelerates telomere loss by disrupting the light cues that animals use to set their circadian rhythms. We will measure the consequences of this for the temporal patterning of key physiological and molecular process, patterns of cell division and telomere loss. We will use continuous light, which supresses the circadian rhythm, and using a simulated shift-work protocol. We will do this with three age classes of animal, since young animals, where telomere loss is generally higher, may be at more risk. We will use the zebra finch, a well-studied vertebrate that has daytime activity and telomere dynamics similar to humans, and whose telomere length is predictive of longevity. We will address the following questions:1) Does circadian disruption increase telomere loss? We will compare telomere loss under control conditions to that of birds exposed to circadian disruption. We predict that telomeres will shorten more quickly under circadian disruption. 2) Are the effects on telomere loss associated with reduced temporal coordination in the body? We will continuously monitor activity patterns and the temporal pattern of key physiological parameters and the pattern of cell division. We will relate this to telomere loss and DNA damage. 3) Do the effects differ among age classes? We will apply the treatments to young, mid-age, and old birds.4) Do the effects vary with the nature of the circadian disruption? We expect the effects of the clock suppression under constant light to be more severe than those of the shift-work protocol.

生物节律在生命之树中随处可见，用于研究它们的新工具已经证明了昼夜节律调节在身体各个过程中的普遍存在。昼夜节律系统已经进化到与24小时昼夜节律的可靠交替相互作用，但人类的生活方式已经越来越脱离地球物理时间。在现代生活中，夜间光线的充足、轮班工作需求的增加以及跨时区旅行都扰乱了昼夜节律系统。这种破坏对健康产生重大影响，包括缩短寿命和加速衰老。圈养动物，如夜间活动的实验室啮齿动物，也可能经历严重的昼夜节律紊乱，它们经常被关在不适当的光照环境中，在白天进食和打扰。因此，需要清楚地了解昼夜节律中断的不利影响是如何产生的。体内的生物钟确保不同的生理过程在一天中最合适的时间发生。通过昼夜节律调节的时间分配确保DNA复制和细胞分裂等过程发生在代谢过程中产生的活性氧（ROS）造成DNA损伤的风险最小化的时候。昼夜节律紊乱可能影响长期健康和年龄相关疾病发病率的一个基本未经研究的途径是通过对端粒损失的影响。端粒是线状染色体末端的保护帽，使细胞能够识别染色体末端。它们由非编码碱基序列的串联重复组成。在细胞分裂过程中，染色体末端的一些DNA会丢失，端粒的氧化损伤会增加丢失的数量。因此，大多数体细胞的端粒会随着细胞的每一轮分裂而缩短。它们最终会达到细胞停止分裂并死亡的临界长度。端粒丢失的速度因个体而异，并受环境影响而加速。如果细胞分裂的昼夜节律、ROS的产生和抗氧化保护被破坏，端粒缩短的增加可能会导致过早衰老。在这个项目中，我们将研究昼夜节律中断是否会通过破坏动物用来设定昼夜节律的光线索来加速端粒的损失。我们将测量这对关键生理和分子过程，细胞分裂和端粒丢失模式的时间模式的影响。我们将使用连续的光线，这抑制了昼夜节律，并使用模拟轮班工作协议。我们将用三种年龄的动物来做这个实验，因为年轻的动物端粒损失通常更高，可能面临更大的风险。我们将使用斑胸草雀，一种经过充分研究的脊椎动物，其白天活动和端粒动力学与人类相似，其端粒长度可以预测寿命。我们将解决以下问题：1)昼夜节律中断是否会增加端粒损失？我们将比较控制条件下的端粒损失与暴露于昼夜节律中断的鸟类的端粒损失。我们预测，在昼夜节律中断的情况下，端粒会缩短得更快。2)对端粒损失的影响是否与身体时间协调能力下降有关？我们将持续监测关键生理参数的活动模式和时间模式以及细胞分裂模式。我们将把这与端粒丢失和DNA损伤联系起来。3)不同年龄层的效果不同吗？我们将对幼鸟、中年鸟和老鸟进行治疗。”4)影响是否随昼夜节律中断的性质而变化？我们预计在恒定光下时钟抑制的影响比轮班工作协议的影响更严重。

项目成果

Tissue-specific reductions in mitochondrial efficiency and increased ROS release rates during ageing in zebra finches, Taeniopygia guttata.

• DOI: 10.1007/s11357-022-00624-1
• 发表时间: 2023-02
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Salmon, Pablo;Millet, Caroline;Selman, Colin;Monaghan, Pat;Dawson, Neal J.
• 通讯作者: Dawson, Neal J.

Repeated exposure to challenging environmental conditions influences telomere dynamics across adult life as predicted by changes in mortality risk

正如死亡风险变化所预测的那样，反复暴露于具有挑战性的环境条件会影响整个成年生活中的端粒动态

• DOI: 10.1096/fj.202100556r
• 发表时间: 2021
• 期刊: The FASEB Journal
• 作者: Marasco, Valeria;Boner, Winnie;Griffiths, Kate;Heidinger, Britt;Monaghan, Pat
• 通讯作者: Monaghan, Pat