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

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体内过程中的普遍性。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，但人类的生活方式越来越与地球物理时间脱节。夜晚的光线，对轮班工作和跨时区旅行的需求不断增加，都扰乱了现代生活中的昼夜节律系统。这种破坏对健康产生重大影响，包括寿命缩短和加速老化。圈养动物，如夜间实验室啮齿动物，也可能经历严重的昼夜节律紊乱，通常被关在不适当的光照条件下，在白天进食和打扰。因此，我们需要清楚地了解昼夜节律紊乱的不良影响是如何产生的。人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划分确保了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的发生率的一个基本上未研究的途径是通过对端粒损失的影响。端粒是线性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序列组成。在细胞分裂期间，一些DNA从染色体末端丢失，并且丢失的量可以通过对端粒的氧化损伤而增加。因此，大多数体细胞中的端粒随着每一轮细胞分裂而缩短。它们最终达到一个临界长度，细胞停止分裂并经常死亡。端粒丢失的速率在个体之间不同，并且受到环境影响的加速。如果细胞分裂、ROS产生和抗氧化保护的昼夜节律被破坏，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的破坏是否会通过破坏动物用来设定昼夜节律的光信号来加速端粒的丢失。我们将测量这对关键生理和分子过程的时间模式、细胞分裂模式和端粒丢失的影响。我们将使用持续的光，这抑制了昼夜节律，并使用模拟轮班工作协议。我们将对三个年龄段的动物进行这项研究，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，这是一种被充分研究的脊椎动物，它的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）昼夜节律中断增加端粒丢失？我们将比较控制条件下的端粒损失与暴露于昼夜节律破坏的鸟类的端粒损失。我们预测，在昼夜节律紊乱的情况下，端粒会缩短得更快。2)对端粒丢失的影响是否与身体时间协调性的降低有关？我们将持续监测活动模式和关键生理参数的时间模式以及细胞分裂模式。我们将把它与端粒丢失和DNA损伤联系起来。3)各年龄段的影响是否不同？我们将对年轻、中年和老年的鸟类进行治疗。4）影响是否因昼夜节律紊乱的性质而异？我们预计，在恒定的光下的时钟抑制的影响将比轮班工作协议更严重。

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.