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

长寿哺乳动物的终生端粒动态、健康和适应性

基本信息

批准号：
BB/L020769/1
负责人：
Daniel Nussey
金额：
$ 69.34万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL020769%2F1
关键词：
Life long telomere dynamics health

项目摘要

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.

在过去的一个世纪里，英国人的预期寿命迅速增加。最近的研究预测，如果这种情况持续下去，2000年以后出生的大多数婴儿将活到100岁。我们的人口老龄化造成了严重的经济和医疗问题，除非我们能找到办法缓解生理恶化的过程和许多与老年有关的疾病。简单的生物学测量(或生物标记物)能够照亮更广泛的衰老过程并预测老年常见疾病的发生，这可能为人们对老龄化速度个体差异的根本原因提供重要的新理解，以及促进健康老龄化的干预措施。端粒长度(TL)是一种令人兴奋的衰老候选生物标记物。端粒覆盖和保护我们的染色体，并随着细胞的每次分裂而变得更短。当端粒变得非常短时，细胞就会停止正常运作，这可能会对更广泛的身体功能产生负面影响。因此，端粒磨损的过程被认为在我们衰老的方式中扮演着重要的角色。在人类中，端粒通常是用白细胞来测量的，因为血液相对容易获得，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，并降低了随后的存活率。然而，年龄只解释了个体间TL巨大差异的一小部分，我们目前不知道为什么成人TL差异如此之大。是因为基因或环境对出生时TL的影响，还是由于早期生命和成年期的生长速度或经历的差异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，因为我们活得太长了。此外，短寿和长寿哺乳动物的端粒生物学有相当大的差异，因此实验室小鼠可能是人类的糟糕模型。在这个项目中，我们将使用圣基尔达Soay绵羊非常详细的长期研究来解决TL如何以及为什么在整个寿命中变化以及这对衰老过程意味着什么的问题。将偏远岛屿上的野生绵羊用于这样的目的可能看起来很奇怪。事实上，绵羊和人类的端粒生物学是相似的，Soay绵羊是世界上最受关注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密切跟踪，所以我们知道它们成长的速度有多快，它们何时繁殖，它们在哪里生活，它们何时死亡，我们有关于它们的遗传学和它们经历的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，并从出生到死亡的过程中反复采集了大约3000个个体的血液样本。我们将从存档的血液样本中测量TL，以测试成年后期TL的差异是否主要是由于出生时TL的差异或此后端粒丢失的结果。我们还将测试发育过程中的基因和环境如何影响TL，以及自然选择如何影响TL的变异。我们的研究具有独特的详细、终生的性质，将首次测试长寿哺乳动物整个生命周期中端粒磨损率的个体差异的原因。我们还将扩大在圣基尔达的实地工作，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，几个非常短的端粒足以损害细胞功能，在白细胞中，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的变化可能如何影响我们抗击疾病、维持健康和成年后生存的能力。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Asynchrony of senescence among phenotypic traits in a wild mammal population.

DOI：
10.1016/j.exger.2015.08.003
发表时间：
2015-11
期刊：
Experimental gerontology
影响因子：
3.9
作者：
Hayward AD;Moorad J;Regan CE;Berenos C;Pilkington JG;Pemberton JM;Nussey DH
通讯作者：
Nussey DH

Consequences of measurement error in qPCR telomere data: A simulation study

DOI：
10.1371/journal.pone.0216118
发表时间：
2019-05-01
期刊：
PLOS ONE
影响因子：
3.7
作者：
Nettle, Daniel;Seeker, Luise;Bateson, Melissa
通讯作者：
Bateson, Melissa

No evidence for parental age effects on offspring leukocyte telomere length in free-living Soay sheep.

没有证据表明父母的年龄对自由生活的绵羊中后代白细胞端粒长度的影响。

DOI：
10.1038/s41598-017-09861-3
发表时间：
2017-08-30
期刊：
Scientific reports
影响因子：
4.6
作者：
Froy H;Bird EJ;Wilbourn RV;Fairlie J;Underwood SL;Salvo-Chirnside E;Pilkington JG;Bérénos C;Pemberton JM;Nussey DH
通讯作者：
Nussey DH

Lifelong leukocyte telomere dynamics and survival in a free-living mammal.

终生的白细胞端粒动力学和自由哺乳动物中的生存。