The environmental drivers of senescence: an experimental test in the wild

年龄预测了我们健康的许多方面，包括我们可能感染哪种感染，我们死于这些感染的风险，或者我们有患哪种慢性疾病的风险。有些人的风险甚至更大，因为他们衰老得非常快，或者“过早变白”。但是为什么呢?对于人类，我们有一些答案：生活方式、繁殖和感染似乎会加速衰老。我们对野生动物衰老和衰老的原因知之甚少，但如果我们能确定导致野生动物快速衰老的因素，我们就能预测哪些个体和种群处于危险之中。最近，一种可用于野生动物的年龄生物标志物被开发出来。这项技术就像树干上的年轮，但它是基于对甲基分子的观察，即随着个体年龄的增长，甲基分子逐渐积聚在DNA上。这些甲基的数量被证明准确地反映了实际年龄。重要的是，快速衰老的个体甲基含量最高。这项研究旨在确定导致一些野生个体在其DNA上积累更多甲基的环境因素。这种现象被称为“表观遗传时钟”，换句话说，我们想要确定为什么有些人的时钟滴答作响得快，而另一些人的时钟滴答作响得慢，因此可能活得更长。为了了解快速衰老的原因，研究一种动物是非常有帮助的，我们可以在这种动物身上做简单而有力的实验。这就是为什么我们建议研究木鼠的甲基化——一种很容易捕获的野生老鼠，我们可以在野外进行控制实验，以修改关键的压力源，并测量它们对衰老速度的影响。我们将在我们的野外地点为一半的老鼠提供高质量的食物或药物治疗（以控制寄生虫），其余的作为未经治疗的对照。为了测量甲基化，我们将使用一种令人兴奋的新技术，即多物种甲基化阵列，这种技术已经在其他哺乳动物身上证明了它的高度有效性。我们的研究结果将使我们更好地了解营养和感染是否以及如何改变甲基化，从而导致个体比预期更快或更慢地衰老。由于营养和感染对几乎任何动物都很重要，我们的工作将引起许多生态学和“健康衰老”研究人员的兴趣。这将是第一次在野生动物身上大规模部署表观遗传时钟，当然也是第一次对压力源及其对衰老速度的连锁反应进行野生实验。

Age predicts many things about our health, including which infections we might have, our risk of dying from these infections, or which chronic diseases we are at risk from. Some individuals present an even greater risk, because they are ageing very fast, or are 'grey before their time'. But why? In humans, we have some answers: lifestyle, reproduction and infections appear to accelerate ageing. We know much less about what drives ageing and senescence in wild animals, but if we could identify the factors that cause rapid ageing in the wild, we could predict which individuals and populations are at risk.Recently, a biomarker of age has been developed that can be used on wild animals. This technology is like rings in tree trunks, but is based on the observation that molecules called methyl groups gradually accumulate on DNA as individuals age. The number of these methyl groups turns out to accurately reflect chronological age. Importantly, individuals who are ageing rapidly have the highest methyl group counts. This study aims to identify environmental factors that cause some wild individuals to accumulate more methyl groups on their DNA. This phenomenon is named an "Epigenetic Clock", so put another way, we want to determine why some individuals have a fast-ticking clock, but others have a slow clicking clock, and so are likely to live longer. To understand the causes of rapid ageing, it is immensely helpful to study an animal on which we can do simple yet powerful experiments. That is why we propose to study methylation in the wood mouse - an easily-captured wild mouse where we can conduct controlled experiments in the field to modify key stressors and measure their impact on the ageing rate. We will provide high quality food or drug treat (to control parasites) to half of the mice in our field locations, leaving the rest as untreated controls. To measure methylation, we will use an exciting new technology known as the multi-species methylation array that has already proven itself highly effective in other mammals. Our results will allow a better understanding of if and how nutrition and infection changes methylation to cause individuals to age faster or slower than expected. Because nutrition and infection are important to almost any animal, our work will be of interest to many researchers in ecology and 'healthy ageing' research. This will be one of the first large-scale deployments of an epigenetic clock to a wild animal, and certainly the first wild-experimental manipulation of stressors and their knock-on effects on the ageing rate.