Development and comparison of multi-tissue and liver-specific epigenetic clock models to measure variation in biological aging in the rhesus macaque.

项目摘要 虽然美国人的预期寿命在过去几十年里急剧上升， 无重大疾病和残疾的年数（健康跨度）保持相对不变。这是一 重大公共卫生问题。同龄人之间的健康差异反映了年龄增长速度的变化。 与年龄相关的恶化和衰退（生物老化），无法通过固定指标（如 实际年龄实足年龄是疾病和死亡率的一个相对强但非常有限的预测因素 风险，因为与生物年龄不同，它不能解释环境驱动的衰老速度变化。 最近开发的人类和小鼠的表观遗传时钟模型预测实际年龄， 准确性，并能够识别偏离预期衰老速度的个体。的这种能力 量化生物年龄并确定在何种条件下生物年龄超过实足年龄（年龄 加速）可以帮助解构衰老过程的复杂性，多面性。但委员会仍 很难确定特定的环境因素如何影响人类的衰老进程， 对高度多变的环境缺乏控制。再加上控制环境， 猕猴研究群体的维持，它们与人类的密切进化关系， 猕猴是一个理想的生物医学模型，可以弥补我们对生物衰老的理解。研究 模型和非模型生物都表明代谢过程的失调是 衰老的过程因此，在这里，我们提出了一个表观遗传时钟的发展，具体为肝脏在恒河猴 猕猴，这将使我们能够调查环境因素之间的关系（例如，饮食）， 生物老化和与年龄有关的疾病。这项拟议中的研究将开发一种肝脏特异性表观遗传时钟 恒河猴模型（子目标1A），并表征年龄相关的差异甲基化和基因 在肝脏中的表达（子目标1B）。此外，我们将利用这些数据和可比数据集， 从大脑（海马体）和血液中收集，以产生恒河猴的多组织时钟。 因为营养是在人的一生中影响健康的最重要的环境因素之一 典型的人类和其他灵长类物种，我们将测试我们的时钟的可塑性，使用长期的研究， 热量限制和西式（肥胖）饮食，以确定这种饮食调整是否 在生物衰老的速度上产生可检测的变化（子目标2A）。为了补充这种方法，我们 还将使用两种极端饮食之间的差异甲基化和基因表达模式， 控制，以确定哪些代谢途径被这些干预措施破坏（子目标2B）。很长的- 这项研究的长期目标是提供一个生物医学研究工具，使更严格的评估， 旨在减缓甚至逆转衰老过程的治疗干预的功效。

PROJECT SUMMARY While life expectancy in the United States has risen dramatically over the past several decades, the number of years spent free of major disease and disability (healthspan) has remained relatively unchanged. This is a major public health concern. Health disparities among same-aged individuals reflect variation in the pace of age-related deterioration and decline (biological aging) that is not captured by a fixed metric like chronological age. Chronological age is a relatively strong but highly limited predictor of disease and mortality risk because, unlike biological age, it cannot account for environmentally-driven variation in the pace of aging. Recently developed epigenetic clock models in humans and mice predict chronological age with very high accuracy and are able to identify individuals who deviate from the expected pace of aging. This ability to quantify biological age and determine under which conditions biological age exceeds chronological age (age acceleration) can help deconstruct the complex, multifaceted nature of the aging process. However, it remains difficult to determine how specific environmental factors impact the progression of aging in humans due to inherent lack of control over the highly variable environment. Coupled with the controlled environments in which macaque research colonies are maintained, their close evolutionary relationship to humans makes macaques an ideal biomedical model for addressing gaps in our understanding of biological aging. Studies in both model and non-model organisms suggest that dysregulation of metabolic processes is a central theme in the aging process. Hence, here we propose the development of an epigenetic clock specific for liver in rhesus macaques that will enable us to investigate the relationship between environmental factors (e.g., diet), biological aging, and age-related diseases. The proposed research will develop a liver-specific epigenetic clock model for rhesus macaques (Sub-Aim 1A) and characterize age-related differential methylation and gene expression in the liver (Sub-Aim 1B). In addition, we will leverage these data and comparable datasets that we have collected from brain (hippocampus) and blood to generate a multi-tissue clock for rhesus macaques. Because nutrition is one of the most powerful environmental determinants of health over the long lifespan typical of humans and other primate species, we will test the plasticity of our clocks using studies of long-term calorie restriction and Western-style (obesogenic) diet to determine whether such dietary modifications engender a detectable change in the pace of biological aging (Sub-Aim 2A).To complement this approach, we will also use patterns of differential methylation and gene expression between the two extreme diets and controls to identify which metabolic pathways are disrupted by these interventions (Sub-Aim 2B). The long- term goal of this research is to provide a biomedical research tool that enables more rigorous assessment of the efficacy of therapeutic interventions that aim to slow, or even reverse, the aging process.