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

项目总结 虽然美国人的预期寿命在过去几十年里戏剧性地增长，但 没有重大疾病和残疾的年份(健康跨度)相对保持不变。这是一个 主要的公共卫生问题。同龄个体之间的健康差异反映了 与年龄相关的恶化和衰退(生物老化)，不能通过固定的指标来衡量，如 按时间顺序排列的年龄。时序年龄是疾病和死亡率相对较强但非常有限的预测指标。 风险，因为与生物年龄不同，它不能解释环境驱动的老龄化速度的变化。 最近在人类和小鼠身上开发的表观遗传学时钟模型预测的实际年龄非常高 准确，并能够识别谁偏离了预期的老龄化速度。这种能力可以 量化生物年龄并确定在哪些情况下生物年龄超过实际年龄(年龄 加速)可以帮助解构衰老过程的复杂、多方面的性质。然而，它仍然 很难确定特定的环境因素是如何影响人类衰老进程的 天生缺乏对高度多变的环境的控制。加上中的受控环境 哪些猕猴研究群体得以维持，它们与人类的密切进化关系使 猕猴是一种理想的生物医学模型，可以解决我们对生物衰老的理解上的差距。研究项目： 无论是模型生物还是非模型生物都表明代谢过程的失调是 老化的过程。因此，我们在这里提出了恒河猴肝脏特异的表观遗传学时钟的发展。 这将使我们能够研究环境因素(例如，饮食)、 生物老化和与年龄相关的疾病。这项拟议的研究将开发一种肝脏特有的表观遗传学时钟 恒河猴模型(次级目标1A)及其与年龄相关的差异甲基化和基因特征 在肝脏中的表达(亚目的1B)。此外，我们还将利用这些数据和我们 从大脑(海马体)和血液中收集，为恒河猴产生一个多组织时钟。 因为营养是长寿期间影响健康的最有力的环境决定因素之一 典型的人类和其他灵长类物种，我们将通过长期的研究来测试我们时钟的可塑性 卡路里限制和西式(肥胖)饮食来确定这种饮食调整 在生物衰老的速度上产生可检测到的变化(子目标2A)。为了补充这一方法，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受到这些干预措施的干扰(次级目标2B)。长的- 这项研究的术语目标是提供一种生物医学研究工具，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有效性。

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.