Early-life environmental effects on ageing in an evolutionary context

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.

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.

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.