Early-life environmental effects on ageing in an evolutionary context

目前，英国65岁以上的人比16岁以下的人多。随着老年人在我们社会中的比例越来越大，了解老龄化的基本生物学成为当务之急。在老龄化速度和寿命方面，个体之间存在着惊人的差异。了解这种差异的原因对于缓解或推迟老龄化进程和应对与人口老龄化相关的挑战的长期希望至关重要。在人类和其他长寿哺乳动物中，早期经历的环境条件在决定成年后的健康和死亡风险方面发挥着重要作用。在人类中的流行病学研究表明，在发育或婴儿期营养不良或受到感染的人会增加健康不佳(如心脏病、糖尿病)的风险，并缩短预期寿命。许多研究人员认为，这些早期环境效应反映了我们遥远的祖先进化出的发育反应，使个体长大后能够与预期的环境“匹配”。最近，我们在理解将不良的生活开端与后来的健康联系起来的最接近的生理机制方面取得了重大进展。然而，对形成对环境的发育反应及其对长寿脊椎动物衰老过程的影响的最终进化机制的了解仍然非常有限。这在很大程度上是因为现代人以及家畜和实验室动物经历了良性和受保护的环境，而这些环境并不能代表生活史和老龄化实际演变的条件。我将通过对圣基尔达野生大豆羊的长期研究，测试自然选择如何塑造哺乳动物对早期环境条件的个体反应，从而解决我们知识中的这一关键差距。这一研究人口代表了一个独特的系统，在这个系统中理解自然老龄化的演变。这一人群中的个人经历了高度多变的环境，自1985年以来一直是极其详细的以个人为基础的监测对象。在5000多只动物的生活中，已经收集了关于个体繁殖表现、身体质量和寄生虫负担的反复记录。作为研究的一部分，捕获时采集的血液样本提供了一种非凡的、但尚未开发的资源，用于分析与衰老有关的相关生化和免疫标记物。我的首要目标是测试和整合进化论和生理学的解释，解释早期环境条件如何以及为什么会导致Soay绵羊种群老龄化速度的差异。我将把现有的关于环境和生活史的纵向数据与新的实验室工作结合起来，使用血液样本来测量数千只绵羊一生中的免疫反应和细胞损伤水平。我将利用这些数据来解决这样一种假设，即早期生命中对营养不良或感染的发育反应代表着‘预测性适应反应’，使个体能够与预期的成年环境相匹配。我还将确定在复杂多变的自然环境中，自然选择如何作用于生长、繁殖、免疫反应和生理损伤之间的生理权衡。最终，我将量化自然选择如何、何时以及为什么有利于特定的发展和生活史战略，以及这如何影响老龄化速度和寿命。完成的项目将是实验室外对衰老的进化和环境原因进行的最详细的纵向研究之一。它将为进化预测提供新颖和及时的测试，这些预测可以解释早期生命的发育环境、生长和感染对长寿哺乳动物成年后衰老和健康的影响。

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.