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

开发和比较多组织和肝脏特异性表观遗传时钟模型，以测量恒河猴生物衰老的变化。

• 批准号: 10353243
• 负责人: Kirstin Sterner
• 金额: $ 23.83万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353243
• 关键词: Acceleration; Address; Adolescent; Affect; Age; Aging; Biological; Biological Aging; Biomedical Research; Blood; Brain; Caloric Restriction; Chronic Disease; Chronology; Complement; Complex; Control Groups; Controlled Environment; Coupled; DNA Methylation; DNA Sequence; Data; Data Set; Deterioration; Development; Diet; Diet Modification; Dietary Intervention; Disease; Elderly; Energy Metabolism; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Goals; Health; Hippocampus (Brain); Human; Individual; Intervention; Life Expectancy; Liver; Longevity; Longitudinal Studies; Macaca; Macaca mulatta; Measures; Metabolic Pathway; Metabolism; Methylation; Modeling; Molecular; Mus; Nature; Organ; Pattern; Persons; Physiological; Population; Primates; Process; Psychosocial Stress; Public Health; Research; Rhesus; Sampling; Shapes; Site; Testing; Therapeutic Intervention; Tissue-Specific Gene Expression; Tissues; United States; Variant; age group; age related; aged; base; cell type; dietary control; dietary restriction; disability; disease phenotype; disorder risk; efficacy evaluation; epigenome; experimental group; health disparity; healthspan; histone modification; insight; methylation pattern; middle age; mortality; mortality risk; nutrition; obesogenic; performance tests; predictive modeling; therapeutic development; tool; transcriptome; young adult

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.

项目概要 尽管美国的预期寿命在过去几十年中急剧上升，但 无重大疾病和残疾的年数（健康寿命）相对保持不变。这是一个 主要公共卫生问题。同龄人之间的健康差异反映了健康速度的差异 与年龄相关的恶化和衰退（生物衰老），无法通过固定指标来捕获，例如 实际年龄。实际年龄是疾病和死亡率相对较强但非常有限的预测因素 风险，因为与生物年龄不同，它无法解释环境驱动的衰老速度变化。 最近开发的人类和小鼠表观遗传时钟模型可以非常高地预测实际年龄 准确性并能够识别偏离预期衰老速度的个体。这种能力能够 量化生物年龄并确定在什么条件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性、多方面性。然而，它仍然 很难确定特定的环境因素如何影响人类衰老的进程，因为 固有地缺乏对高度变化的环境的控制。再加上受控环境 维持哪些猕猴研究群体，它们与人类密切的进化关系使得 猕猴是解决我们对生物衰老理解空白的理想生物医学模型。研究于 模型和非模型生物都表明代谢过程失调是 老化过程。因此，我们在这里建议开发针对恒河猴肝脏的表观遗传时钟 猕猴将使我们能够研究环境因素（例如饮食）之间的关系， 生物衰老和与年龄相关的疾病。拟议的研究将开发肝脏特异性表观遗传时钟 恒河猴模型（Sub-Aim 1A）并表征与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我们所收集的可比数据集 从大脑（海马体）和血液中收集了恒河猴的多组织时钟。 因为营养是影响长寿的最强大的环境决定因素之一 作为人类和其他灵长类动物的典型特征，我们将通过长期研究来测试我们的时钟的可塑性 热量限制和西式（致肥胖）饮食以确定是否进行此类饮食调整 导致生物衰老速度发生可检测的变化（子目标 2A）。为了补充这种方法，我们 还将利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）。长- 这项研究的长期目标是提供一种生物医学研究工具，能够更严格地评估 旨在减缓甚至逆转衰老过程的治疗干预措施的功效。