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

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

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.

Technical Summary

Telomere attrition is thought to play an important role in the ageing process, and leukocyte telomere length (LTL) measured in adult humans predicts various age-related diseases. We will use an exceptionally detailed longitudinal study of unmanaged Soay sheep on St Kilda, in which around 3,000 individuals have been closely monitored and regularly blood sampled all the way from birth to death. Importantly, sheep have a similar telomere biology to humans and Soay sheep live long, natural lives on St Kilda and show clear signs of ageing in later life. We will use a high-throughput qPCR-based system to measure average LTL from >8000 samples collected from these individuals, and use this data to test how genes, parental and early-life environment effects influence LTL at birth and telomere attrition rates thereafter, and determine how this, in turn, influences adult health and lifespan. We will also continue our annual fieldwork programme over the course of the grant to collect samples suitable for more detailed, high-resolution telomeric and immunological assays. We will develop the high-resolution STELA technique for use in sheep and use it to compare the importance of longitudinal changes in average LTL versus the presence of critically short telomeres in predicting ill-health and mortality in adulthood. We will also use flow cytometry and cell proliferation assays to test how such changes are associated with changes in composition of leukocytes and their proliferative potential, and how these in turn are associated with an individual's ability to resist infection. Taken together, this will provide the most complete study to date of the causes and consequences of life-life variation in LTL in a long-lived mammal.

Planned Impact

Academic community: Our results will add to our current understanding of the links between telomere dynamics at cellular and organismal levels, enhancing the knowledge base across the range of biological disciplines with a focus on telomeres, including immunology, physiology, epidemiology, evolutionary ecology, and biomedical and veterinary science. Our work will also develop the single telomere length analysis (STELA) method, which has so far only been used in humans, for use in sheep. This will provide resources and impetus for the wider application of this extremely high resolution technique by researchers working on non-human study organisms.

Our proposal will support the continuation of the long-term Soay sheep study on St Kilda, which has been running since 1985, for a further 2 years. The Soay sheep project database represents one of the richest sources of longitudinal information on any mammalian system we are aware of, and is freely available to interested researchers (see Data Management Plan). The current team of researchers involved in the project involves more than 20 senior academics and research fellows from institutions across the globe. Thus, the continuation of the long-term study on St Kilda, and the incorporation of new telomere data into the existing project database, will provide an important resource for current and future generations of researchers across a range of biological disciplines.

Animal health: The potential use of leukocyte telomere length as a marker of health or immune state in domestic or wild ruminants has not been seriously explored. Insights gained from our study of life-long telomere dynamics in a free-living sheep population will form an important basis for further studies of the utility of leukocyte telomere length (LTL) as a biomarker of health and target for artificial selection in domestic ruminants and indeed other domestic animals, as well as a tool for monitoring wildlife health.

Public health & policy: Measurement of LTL in humans is currently offered commercially to the general public as an indicator of 'biological age' (e.g. www.lifelength.com), despite our rather limited understanding of the genetic and early-life causes and the health consequences of variation in LTL. Our proposal offers a first window into the life-long processes responsible for LTL variation in adulthood in a relatively long-lived mammal species. As such it could have important implications for the future use and development of LTL as a marker in biomedical and epidemiological contexts.

Students: The Soay sheep project has provided an important training ground for both undergraduate and postgraduate students. We typically bring 8-10 field assistants - usually undergraduates seeking research experience - to the study site each year for between 3-5 weeks, during which time they are trained in key biological field skills. The project database is used by numerous undergraduate and master's students as the basis for projects each year and has been the subject of more than 20 PhD thesis since 1985. Through supporting a continuation and extension of the long-term study, this proposal will provide further important training opportunities for students.

General public: There is a deep-seated public interest in research into the ageing process amongst the general public. The remote St Kilda archipelago and their unique Soay sheep are also the subject of considerable public interest in the UK, reflected by the growing public access to the islands (>3,500 tourists landing for day trips each year). Recent media coverage of stories related to our research on ageing and on the Soay sheep themselves, and interactions between tourists on St Kilda and our fieldworkers, testify to the keen interest and pleasure taken by the general public in learning more about the ageing process and the lives of our study animals.

Publications

10 25 50
 
Description 1. We have developed and validated a high-throughput qPCR method for quantifying telomere length in sheep
2. We have provided the first evidence for a positive association between telomere length and survival in a wild mammal (published Aging Cell 2016)
3. We have provided the first evidence for sex differences in telomere length in a wild mammal (published Molecular Ecology 2017)
4. We have established that the paternal age at conception effect on telomere length, widely observed in humans, is not observed in wild sheep (published Scientific Reports 2017)
5. Established an international, multi-disciplinary network of telomere researchers who meet regularly and have co-edited a special issue of Philosophical Transactions of the Royal Society of London on "Diversity in telomere dynamics" based on the work of this wider group - to which our research group contributed a novel meta-analysis of the associations between telomere length and survival in non-model vertebrates.
6. Generated a large, multi-generational telomere length data set encompassing >4000 samples from wild Soay sheep - analyses of this data set are ongoing.
Exploitation Route Our method and results have already lead to collaborations to measure telomere length in other ruminant species and test for sex differences (wild roe deer, dairy cattle) - indeed we recently began a new collaboration with French colleagues on roe deer telomere length and showed the different deer populations show differing telomere dynamics (Biology Letters, 2017)
Sectors Agriculture, Food and Drink

URL http://nussey.bio.ed.ac.uk
 
Description GCRF-IAA
Amount £15,134 (GBP)
Funding ID BB/GCRF-IAA/17/06 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 12/2017 
End 03/2018
 
Title Telomere length measurement methods in ruminants 
Description We have developed a robust, high-throughput qPCR based methodology (based on those previously developed for samples from humans) to measure relative leukocyte telomere length in sheep and cattle. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact Work currently under way to measure large-scale longitudinal sets of samples from a wild Soay sheep population and a domestic dairy cattle population. We have received requests for collaborations with other researchers with cattle samples, which are in development and have been making our protocols available to anyone who requests them. 
 
Description Collaboration on wild roe deer telomere dynamics 
Organisation University of Lyon
Country France 
Sector Academic/University 
PI Contribution Conducted telomere length assays on samples collected by collaborator from his wild roe deer study systems
Collaborator Contribution Provided samples and we worked together on analyses of data and producing publication
Impact Produced a publication in Biology Letters. Further samples have since been assayed in my lab and are expected to result in further papers.
Start Year 2017