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

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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.