Early-life environmental effects on ageing in an evolutionary context

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

Abstract

There are currently more people aged over 65 than aged under 16 living in the UK. As the elderly compose an increasing proportion of our society, understanding the basic biology of ageing becomes an urgent priority. There is astonishing variation between individuals in both ageing rates and lifespan. Understanding the causes of this variation is central to long-standing hopes of alleviating or postponing the ageing process and meeting the challenges associated with an ageing population. In humans and other long-lived mammals, environmental conditions experienced during early life play an important role in determining health and mortality risk in adulthood. Epidemiological studies in humans show that individuals experiencing poor nutrition or infection during development or infancy have increased risk of ill health (e.g. heart disease, diabetes) and shortened life expectancy. Many researchers have suggested that these early-life environmental effects reflect developmental responses that evolved in our distant ancestors to allow individuals to grow up to 'match' their expected environment. Recently, there have been major advances in our understanding of the proximate physiological mechanisms linking a poor start in life with later health. However, understanding of the ultimate evolutionary mechanisms that have shaped developmental responses to the environment and their consequences for the ageing process in long-lived vertebrates has remained very limited. This is largely because modern humans and domestic and laboratory animals experience benign and protected environments that are not representative of the conditions in which life histories and ageing actually evolved. I will address this crucial gap in our knowledge by testing how natural selection has shaped individual responses to early-life environmental conditions in mammals, using a long-term study of wild Soay sheep on St Kilda. This study population represents a unique system in which to understand the evolution of ageing in nature. Individuals in this population experience a highly variable environment and have been the subject of extremely detailed individual-based monitoring since 1985. Repeated records on individual reproductive performance, body mass and parasite burden have already been collected over the lives of more than 5,000 animals. Blood samples collected at capture as part of the study provide a remarkable, but as yet untapped, resource to assay relevant biochemical and immunological markers associated with ageing. My overarching aim is to test and integrate evolutionary and physiological explanations for how and why early environmental conditions drive variation in ageing rates in the Soay sheep population. I will combine existing longitudinal data on environment and life history with new laboratory work using blood samples to measure immune responses and levels of cellular damage across the lifetimes of thousands of individual sheep I will use this data to address the hypothesis that developmental responses to poor nutrition or infection in early life represent 'predictive adaptive responses' that allow individuals to match their expected adult environment. I will also determine how natural selection acts on the physiological trade-offs between growth, reproduction, immune responses and physiological damage in a complex and variable natural environment. Ultimately, I will quantify how, when and why natural selection favours particular developmental and life history strategies and how this influences ageing rates and lifespan. The completed project will represent one of the most detailed longitudinal studies of the evolutionary and environmental causes of ageing ever undertaken outside of the laboratory. It will provide novel and timely tests of evolutionary predictions that could explain the effects of developmental environment, growth and infection in early life on ageing and health in later adulthood in long-lived mammals.

Technical Summary

Understanding of the evolutionary mechanisms that shape developmental responses to early-life environment and their consequences for ageing in later life in long-lived vertebrates remains limited. I will test and integrate ultimate and proximate explanations for how and why the environment drives variation in ageing rates in a wild population of Soay sheep on St Kilda. This population has been subject to individual-based study since 1985, yielding repeated measures of reproductive performance, morphology and parasite burden, as well as blood samples, from across the lifetimes of thousands of individuals. I will undertake new laboratory work on blood samples to measure key biomarkers of ageing and immune response. I will measure markers of oxidative stress and inflammation in freshly collected and frozen blood samples. In a larger sample, incorporating blood collected previously during the long-term study, I will measure telomere length by QPCR and titres of self-reactive antibodies and antibodies specific to the major nematode parasites infecting the sheep by ELISA. I will use this unique longitudinal data set to test the 'predictive adaptive response' hypothesis against alternative non-adaptive hypotheses explaining early-life environmental effects on health and ageing. I will also how genetic and environmental variation influence trade-offs between growth, reproduction, immunity and somatic maintenance. The new laboratory data will allow me to test how early-life experience of infection influences immune responses and rates of immunosenescence, as well as how early-life investment in growth, reproduction and immunity influences physiological state in later life. Ultimately, I will determine how and why certain developmental and early life history responses to poor nutrition and infection are favoured by natural selection under different environments and what their consequences are for physiological ageing and lifespan in long-lived mammals.

Planned Impact

Field researchers: The work proposed in this fellowship will pioneer the use of laboratory techniques to study immunology, oxidative stress and telomere length in wild ungulate populations. Data will be incorporated in the existing Soay sheep project database and made available to the expanding community of researchers involved in this project. I will also aim to stimulate and support the application of these techniques to address new evolutionary, physiological and immunological questions in other long-term field studies of vertebrate populations. Local research community: There is considerable research interest in the evolutionary biology of ageing within Scottish universities. I recently organised the first meeting of the Scottish Evolutionary Ageing Research Group (SEARG) in Edinburgh (June 2009). The meeting provided an excellent opportunity for discussion across disciplines and backgrounds. I hope to continue my involvement in SEARG by setting up a website and assisting with organization of further meetings with the aim of developing an integrated, cross-disciplinary local community of scientists working on the evolution of ageing (see Impact Plan). Evolutionary Biologists: My work will present rare tests of the predictions and assumptions of evolutionary theories of ageing in natural populations and also new insights into the physiological and immunological mechanisms responsible for phenotypic variation in nature. I will communicate my findings through publications in high impact international journals and by presentations at international conferences. Wider academic community: My work will also be of interest to a wider range of disciplines within biological sciences, including immunology, physiology, molecular biology, psychology and biomedical and veterinary science. Increasingly, researchers in these fields are turning to evolutionary biology for a unifying framework from which to derive predictions and interpret results. I will disseminate findings to this wider academic audience through publications in journals from relevant disciplines and by producing review / synthesis papers for different academic audiences in collaboration with my inter-disciplinary project partners. Junior Researchers: Over the course of the proposed fellowship, I would expect to provide several undergraduate and masters students with laboratory projects each year and develop and supervise several PhD projects. This will provide important opportunities for young researchers to learn new laboratory, field and statistical techniques and develop their careers. General Public: There is a deep-seated public interest in research into the ageing process. My recent work on ageing in wild ungulates has been covered in BBC news (on-line, radio and television), The Scotsman, The Daily Herald, The Daily Telegraph, The Metro and New Scientist. I am committed to communicating science to the public. I have worked closely with Edinburgh University's Press Office over the last two years to produce press releases to coincide with publication of my work and I will continue to do so (see Impact Plan). Medicine & Policy: My work will represent the first study to explore the links between cellular damage, immunosenescence and organismal ageing in a long-lived mammal. I will also explore the factors influencing ageing in an important but largely unstudied context: natural conditions. The longitudinal nature of the study will also provide a rare opportunity to link early life conditions and experiences to cellular damage and immune function and, in turn, to later survival, reproduction and physiology within the same individual. This study is timely, as it may identify processes or patterns which also occur in humans but have not so far been detected, and could contribute to research directed at alleviating ageing medically or advising social policy and public advice.

Publications

10 25 50
 
Description 1. Development and validation of new methods to measure immune variation in a wild mammal, and application of these methods to demonstrate age-related variation different aspects of the immune response and strong associations between immunity and fitness under natural conditions.
2. Demonstration that different markers of oxidative stress are not associated with one another, or consistently associated with environmental conditions or fitness in a wild mammal.
3. Development and validation of methods to measure telomere length in sheep, and application of these methods in wild Soay sheep to provide the first evidence for positive associations between telomere length and survival in a wild mammal
4. New insights into the patterns and causes of variation in ageing in the wild, particularly how and why different traits age at different rates.
Exploitation Route Immunological and telomere length measurement methods are being applied by other researchers, in collaboration with my group, to address related questions in different ruminant species
Sectors Agriculture, Food and Drink

URL http://nussey.bio.ed.ac.uk
 
Description Immune ageing in a wild mammal
Amount £75,000 (GBP)
Funding ID 1276232 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2012 
End 08/2016
 
Description International Workshop Grant
Amount £98,000 (GBP)
Organisation The Leverhulme Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2013 
End 10/2016
 
Description Life-long telomere dynamics, health and fitness in a long-lived mammal
Amount £544,176 (GBP)
Funding ID BB/L020769/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 12/2017
 
Description Measurements of telomere length at different life stages as predictive biomarkers of health, reproduction and longevity in dairy cattle
Amount £249,707 (GBP)
Funding ID BB/L007312/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2014 
End 03/2017
 
Description The Ecology of Ageing in Albatrosses
Amount £75,000 (GBP)
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 09/2011 
End 03/2014
 
Title Faecal antibody measurements in sheep 
Description We have developed and validated a non-invasive method for measuring antibodies from faecal samples in sheep. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2016 
Provided To Others? Yes  
Impact We have provided our protocols for measuring faecal antibody measurements to colleagues in the UK (Edinburgh and Stirling) working on wild mice and sheep, and abroad (South Africa, buffalo). We will continue to support interest in the application of this method as fully as possible. 
 
Title Anti-nematode parasite antibody data set from long-term Soay sheep 
Description We have assayed a variety of antibody types against prevalent nematode parasite species from the archive of blood samples collected over 30 years as part of the long-term study of Soay sheep on St Kilda. We recently completed assays of all samples collected during summer (>6,000 samples) on St Kilda. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Over the next year or so, we hope to use this data set to tackle a number of important questions about immunity and epidemiology in the wild, and will also integrate this data with our existing database from the Soay sheep project. This data will be made available at request by the project's co-ordinators to interested researchers. 
 
Title Data from: The genetic architecture of helminth-specific immune responses in a wild population of Soay sheep (Ovis aries) 
Description Much of our knowledge of the drivers of immune variation, and how these responses vary over time, comes from humans, domesticated livestock or laboratory organisms. While the genetic basis of variation in immune responses have been investigated in these systems, there is a poor understanding of how genetic variation influences immunity in natural, untreated populations living in complex environments. Here, we examine the genetic architecture of variation in immune traits in the Soay sheep of St Kilda, an unmanaged population of sheep infected with strongyle gastrointestinal nematodes. We assayed IgA, IgE and IgG antibodies against the prevalent nematode Teladorsagia circumcincta in the blood plasma of > 3,000 sheep collected over 26 years. Antibody levels were significantly heritable (h2 = 0.21 to 0.57) and highly stable over an individual's lifespan. IgA levels were strongly associated with a region on chromosome 24 explaining 21.1% and 24.5% of heritable variation in lambs and adults, respectively. This region was adjacent to two candidate loci, Class II Major Histocompatibility Complex Transactivator (CIITA) and C-Type Lectin Domain Containing 16A (CLEC16A). Lamb IgA levels were also associated with the immunoglobulin heavy constant loci (IGH) complex, and adult IgE levels and lamb IgA and IgG levels were associated with the major histocompatibility complex (MHC). This study provides evidence of high heritability of a complex immunological trait under natural conditions and provides the first evidence from a genome-wide study that large effect genes located outside the MHC region exist for immune traits in the wild. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
 
Description Dairy cattle telomere study with SRUC 
Organisation Scotland's Rural College
Country United Kingdom 
Sector Academic/University 
PI Contribution Methods for measuring telomere length in sheep developed as part of my BBSRC fellowship lead to collaboration with SRUC to study telomere dynamics in the Crichton dairy cattle herd. My team has developed similar methods for use with dairy cattle samples, and are proceeding to measure telomeres in the available blood sample bank from Cricton. This collaboration has led to a successful BBSRC responsive mode grant application and SRUC-funded PhD studentship which are both ongoing.
Collaborator Contribution SRUC has provided access to samples and information cattle they came from, and we have regular team meetings to discuss and plan progress. SRUC will conduct analyses once telomere measurement work in my lab is complete to determine how useful the measures are as a biomarker of health and functional longevity.
Impact Protocol for measurement on cattle leukocyte telomere length by QPCR established and fully validated.
Start Year 2012
 
Description Soay sheep immunology project with Moredun 
Organisation Moredun Research Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Collection of samples from field site Soay sheep on St Kilda for use in a variety of immune assays (FACS, ex vivo proliferation, heamatological counts, ELISA, Western blots) conducted following training and discussion with collaborators at Moredun (principally Tom McNeilly). My team conduct the assays back in my lab in Edinburgh with guidance from collaborators.
Collaborator Contribution Training and collaborative guidance with methodological and veterinary aspects of the project, as well as involvement in analyses and collaborative writing of papers.
Impact BBSRC responsive mode grant (BB/L020779/1) utilises methodologies developed through this collaboration.
Start Year 2009
 
Description Soay sheep project 30th anniversary event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact A day of talks and discussion to celebrate 30 years of the St Kilda Soay sheep research project was organised at the Royal Society of Edinburgh. Over 100 people attended, from a wide variety of audiences including researchers, students, members of the general public and the media. The event was also covered on the BBC news website.
Year(s) Of Engagement Activity 2015
URL http://sbsweb2.bio.ed.ac.uk/soay/