Ecological and environmental determinants of epigenetic aging

表观遗传衰老的生态和环境决定因素

• 批准号: 2026210
• 负责人: Benjamin Parrott
• 金额: $ 85.33万
• 依托单位: University of Georgia Research Foundation Inc
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2026210&HistoricalAwards=false
• 关键词: Ecological; environmental; determinants; epigenetic; aging

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.

由于它几乎普遍发生，了解衰老的原因和后果对广泛的生物学、生态学和进化问题至关重要。最近的研究进展表明，表观基因组在调节生物衰老方面发挥了核心作用，因为它为整合内在和外在力量提供了分子背景。该项目的目的是发现环境指导表观遗传衰老轨迹最终影响机体功能的基本机制。该项目将利用易驯化和生态相关的鱼，日本medaka作为模型系统，因为它们的大部分基因组和生理在动物王国中广泛保存。该研究将支持培训和指导一名博士后研究员、两名研究生和一名本科生研究员，并针对科学领域代表性不足的群体进行招募工作。该项目将开发一本入门书，介绍生命史生态学和进化的基本概念，并将重点介绍在动物王国中观察到的各种生命史。作为已建立的外展计划的一部分，入门和项目结果将呈现给地区学校的学生。总之，这项工作将促进目前对生物与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上，以推进基于个体发生和内分泌的理解，了解生态和环境挑战如何影响生物衰老和伴随的生活历史事件（例如，成熟年龄）的时间变化。表观遗传衰老时钟基于年龄依赖的DNA甲基化模式，并从基因组中选择的位点中总结出与年龄相关的高甲基化和低甲基化的读数，这些位点能够高精度地预测实际年龄。尽管具有前所未有的准确性，表观遗传时钟显示的年龄可能与个人的实际年龄不同。这被称为表观遗传-实足年龄不一致，这种不一致的幅度和方向性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，本项目旨在研究生态和环境动力学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导致不同的结果，这取决于它们在生命中发生的时间。年龄依赖的表观遗传模式在生命早期显得尤其动态，实验将测试环境-生物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，项目发现将为环境因素转化为影响机体功能和产生可变生活史的衰老轨迹的近端机制提供一个新的视角。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。