Life-long telomere dynamics, health and fitness in a long-lived mammal

英国人的预期寿命在上个世纪迅速增长。如果这种情况继续下去，最近的研究预测，自2000年以来出生的大多数婴儿将活到100岁。除非我们能找到办法，减轻生理退化的过程和与老年有关的许多疾病，否则，人口老化会带来严重的经济和医疗问题。简单的生物学测量（或“生物标志物”）能够阐明更广泛的衰老过程和预测老年常见疾病的发生，可以提供重要的新的理解的潜在原因的个体差异的衰老率，以及干预措施，以促进健康的老龄化。端粒长度（TL）是一个令人兴奋的候选衰老生物标志物。端粒覆盖并保护我们的染色体，并随着每次细胞分裂而变短。当端粒变得非常短时，细胞停止正常运作，对更广泛的身体功能产生潜在的负面影响。因此，端粒磨损的过程被认为在我们衰老的方式中起着重要作用。在人类中，端粒通常在白色血细胞中测量，因为血液相对容易获得，并且这些细胞的平均TL随着年龄的增长而下降。令人兴奋的是，成年期的短TL预示着各种与年龄相关的疾病和随后的生存率降低。然而，年龄只能解释个体间TL巨大差异的一小部分，我们目前还不知道为什么成年TL变化如此之大。是因为出生时的遗传或环境影响，还是由于生长速度的差异或早期和成年期的经历影响了端粒缩短的速度？为了回答这个问题，我们需要血液样本和个人一生的信息。这在人类身上是不可能的，因为我们活得太久了。此外，有相当大的差异，在端粒生物学的短命和长寿的哺乳动物，所以实验室小鼠可能是穷人的模型为human.In这个项目中，我们将使用一个非常详细的长期研究的Soay羊在圣基尔达解决的问题，如何和为什么TL在整个生命周期的变化，这意味着什么老化过程。在一个偏远的岛屿上使用野羊来达到这样的目的似乎很奇怪。事实上，绵羊和人类的端粒生物学是相似的，Soay绵羊是世界上任何地方受到最密切监测的哺乳动物种群之一。自1985年以来，每只羊都被单独标记，并在其一生中受到密切关注，因此我们知道它们的生长速度，繁殖时间，生活地点和死亡时间，我们有关于它们的遗传和环境条件的详细信息。重要的是，我们还定期重新捕获这些动物，并从大约3000个个体从出生到死亡反复收集血液样本。我们将从存档的血液样本中测量TL，以测试成年后期TL的差异是否主要是出生时TL差异或此后端粒丢失的结果。我们还将测试基因和环境在发展过程中如何影响TL以及自然选择如何影响TL的变化。我们研究的独特细节，终身性质将提供第一个测试的原因，在端粒磨损率的个体差异在整个寿命的长寿哺乳动物。我们还将扩大对圣基尔达的实地考察，以收集样本进行更广泛的端粒和免疫学分析。实验室研究表明，一些非常短的端粒足以损害细胞功能，在白色血细胞中，这可能会损害我们的免疫系统。使用新收集的现场数据和血液样本，我们将首次在实验室外测试这两种预测，从而揭示TL的变化如何影响我们对抗疾病，保持健康和在成年后期生存的能力。

Life expectancies in the UK have increased rapidly over the last century. If this continues, recent studies have predicted that the majority of babies born since 2000 will live to 100. Our ageing population poses serious economic and medical problems, unless we can find ways of alleviating the process of physiological deterioration and many diseases that are associated with old age. Simple biological measures (or 'biomarkers') capable of illuminating the wider process of ageing and predicting the onset of common diseases of old age could provide important new understanding of the underlying causes of individual variation in ageing rates, as well as interventions to promote healthy ageing.Telomere length (TL) is an exciting candidate biomarker of ageing. Telomeres cap and protect our chromosomes and become shorter with each cell division. When telomeres become very short, cells stop functioning properly, with potentially negative consequences for wider bodily function. Accordingly, the process of telomere attrition is thought to play an important role in the way we age. In humans, telomeres are usually measured in white blood cells, because blood is relatively easy to obtain, and average TL of these cells declines with age. Excitingly, short TL in adulthood predicts various age-related diseases and reduced subsequent survival. However, age only explains a small part of the massive variation in TL among individuals, and we currently do not know why adult TL varies so much. Is it because of genetic or environmental effects on TL at birth, or is it down to differences in growth rates or experiences through early life and adulthood which affect the rate of telomere shortening? To answer this question we need blood samples and information over the entire lifetimes of individuals. This has not been possible in humans because we are so long lived. Furthermore, there are considerable differences in the telomere biology of short-lived and long-lived mammals, so laboratory mice may be poor models for humans.In this project, we will use a remarkably detailed long-term study of Soay sheep on St Kilda to tackle the question of how and why TL varies across the entire lifespan and what this means for the ageing process. It might seem odd to be using wild sheep on a remote island for such a purpose. In fact, the telomere biology of sheep and humans is similar, and the Soay sheep are one of the most closely monitored populations of mammals anywhere in the world. Since 1985, every sheep has been individually marked and followed closely across its lifetime, so we know how quickly they grew, when they bred, where they lived, when they died and we have detailed information on their genetics and the environmental conditions they experience. Importantly, we also regularly re-capture these animals and have collected blood samples repeatedly from around 3000 individuals all the way from birth to death. We will measure TL from archived blood samples to test whether differences in TL in late adulthood are mainly the result of differences in TL at birth or in telomere loss thereafter. We will also test how genes and environment during development influence TL and how natural selection acts on variation in TL. The uniquely detailed, life-long nature of our study will provide the first tests of the causes of individual variation in telomere attrition rates across the entire lifespan of a long-lived mammal. We will also extend the fieldwork on St Kilda to collect samples for more extensive telomere and immunological analyses. Laboratory studies show that a few very short telomeres are enough to compromise cell function, and in white blood cells this could compromise our immune system. Using newly-collected field data and blood samples, we will test both of these predictions outside of the lab for the first time, shedding new light on how changes in TL may influence our ability to fight disease, maintain health and survive in later adulthood.