Ecological and environmental determinants of epigenetic aging

由于其几乎普遍发生，了解衰老的原因和后果是广泛的生物学，生态学和进化问题的核心。最近的进展表明，表观基因组在介导生物衰老中的核心作用，因为它提供了整合内在和外在力量的分子背景。该项目的目的是发现环境引导表观遗传衰老轨迹最终影响生物体功能的基本机制。该项目将利用易于处理和生态相关的鱼类，日本青鳉作为模型系统，因为它们的大部分基因组和生理学在动物王国中广泛保存。该研究将支持一名博士后研究员，两名研究生和一名本科生研究员的培训和指导，并针对科学领域代表性不足的群体进行招聘。该项目将开发一本入门书，介绍生活史生态学和进化的基本概念，并将突出在动物王国中观察到的可变生活史。初级读本和项目调查结果将作为既定推广计划的一部分提交给地区学校的学生。总之，这项工作将促进目前对生物体及其环境之间的相互作用如何影响生物衰老的理解，并将为下一代科学家提供培训机会。这项工作将集中在最近开发的表观遗传衰老时钟，以推进基于个体遗传和内分泌的理解，了解生态和环境挑战如何塑造生物衰老以及伴随的生活历史事件（例如，成熟时的年龄）。表观遗传衰老时钟基于年龄依赖性DNA甲基化模式，并总结了来自基因组中选择的基因座的年龄相关的高甲基化和低甲基化的读数，这些基因座共同能够以高准确度预测实际年龄。尽管表观遗传时钟具有前所未有的准确性，但它所显示的年龄可能与个体的实际年龄不同。这被称为表观遗传与实足年龄的不一致性，这种不一致性的大小和方向与生理功能和生活史特征有关。表观遗传与实足年龄不一致的起源尚未解决，本项目旨在调查生态和环境动态在驱动这种不一致中的作用。该项目还将测试特定内分泌信号通路在介导环境对表观遗传衰老的影响中的作用。生物体与其环境之间的相互作用可能会导致不同的结果，这取决于它们在生命中何时发生。在生命的早期，依赖于环境的表观遗传模式似乎特别动态，实验将测试环境-生物体相互作用是否在特定的生命阶段产生不成比例的影响。总的来说，项目的发现将提供一个新的视角，关于环境因素转化为衰老轨迹，影响生物体功能和产生可变的生命史的近端机制。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

Because of its near universal occurrence, understanding the causes and consequences of aging is central to broad biological, ecological, and evolutionary questions. Recent advances demonstrate a central role of the epigenome in mediating biological aging as it provides a molecular context for integrating both intrinsic and extrinsic forces. The purpose of this project is to discover fundamental mechanisms by which the environment directs epigenetic aging trajectories to ultimately impact organismal function. The project will utilize the tractable and ecologically relevant fish, Japanese medaka as a model system as much of their genome and physiology are broadly conserved across the animal kingdom. The study will support the training and mentoring of a postdoctoral researcher, two graduate students, and an undergraduate researcher, with recruiting efforts aimed at under-represented groups in the sciences. The project will develop a primer that introduces fundamental concepts in life history ecology and evolution, and will highlight variable life histories observed across the animal kingdom. The primer and project findings will be presented to students at area schools as part of an established outreach program. Together, this work will advance current understanding of how interactions between organisms and their environment affect biological aging and will provide training opportunities for the next generation of scientists. The work will focus on recently developed epigenetic aging clocks to advance an ontogenetic- and endocrine-based understanding of how ecological and environmental challenges shape biological aging and attendant variation in the timing of live history events (e.g., age at maturity). Epigenetic aging clocks are based on age-dependent DNA methylation patterning and summarize the readout of age-associated hyper- and hypo-methylation from a selection of loci across the genome which are collectively capable of predicting chronological age with high accuracy. Despite their unprecedented accuracy, the age indicated by epigenetic clocks can differ from an individual’s actual age. This is referred to as epigenetic-to-chronological age discordance, and the magnitude and directionality of this discordance are associated with physiological function and life history traits. The origins of epigenetic-to-chronological age discordance are not resolved, and this project aims to investigate the role of ecological and environmental dynamics in driving this discordance. The project will also test the role of specific endocrine signaling pathways in mediating the influence of the environment on epigenetic aging. Interactions between organisms and their environments can result in different outcomes depending on when during life they occur. Age-dependent epigenetic patterning appears especially dynamic during early life and experiments will test if environment-organism interactions exert disproportionate influences during specific life stages. Collectively, project findings will provide a novel perspective regarding the proximal mechanisms by which environmental factors are translated into aging trajectories to affect organismal function and produce variable life histories.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.