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在人体各个过程中的普遍性。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，但人类的生活方式已经越来越与地球物理时间脱节。夜间光线的可获得性，对倒班工作和跨时区旅行的日益增长的需求，都扰乱了现代生活中的生物钟系统。这种干扰对健康有重大影响，包括寿命缩短和加速衰老。被圈养的动物，如夜间活动的实验室啮齿动物，也会经历严重的昼夜节律紊乱，经常被关在不适当的光照条件下，并在白天进食和受到干扰。因此，需要清楚地了解生理节律紊乱的不利影响是如何发生的。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。通过昼夜节律的时间分割确保了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物种(ROS)对DNA损伤的风险最低的时候。一个很大程度上没有研究过的途径是通过影响端粒丢失来影响长期的健康和与年龄相关的疾病的发病率。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。它们由碱基的非编码序列的串联重复组成。在细胞分裂过程中，一些DNA会从染色体末端丢失，而端粒的氧化损伤会增加丢失的DNA数量。因此，大多数体细胞的端粒在每一轮细胞分裂时都会变短。它们最终达到一个临界长度，在这个长度上细胞停止分裂并经常死亡。端粒丢失的速度因个体不同而不同，并受环境影响加速。如果细胞分裂、ROS生成和抗氧化保护的昼夜节律被打乱，端粒缩短的增加可能会导致过早衰老。在这个项目中，我们将调查昼夜节律的干扰是否会通过扰乱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。我们将使用抑制昼夜节律的连续光，并使用模拟的轮班工作方案。我们将对三个年龄段的动物进行这一研究，因为端粒丢失通常较高的幼年动物可能面临更大的风险。我们将使用斑马雀，这是一种经过充分研究的脊椎动物，具有与人类相似的白天活动和端粒动力学，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丢失？我们将比较在控制条件下的端粒丢失和暴露在昼夜节律干扰下的鸟类的端粒丢失。我们预测，在昼夜节律中断的情况下，端粒将缩短得更快。2)对端粒丢失的影响是否与体内时间协调性降低有关？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。我们会将其与端粒丢失和DNA损伤联系起来。3)不同年龄段的影响是否有所不同？我们将对年轻、中年和老年的鸟类进行治疗。4)这些影响是否会因昼夜节律紊乱的性质而有所不同？我们预计恒定光照下的时钟抑制的影响将比轮班工作协议的影响更严重。

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.