Epigenetics of Successful Aging

项目摘要 许多研究已经证明了遗传基因变异在常见慢性病中的作用，他们的 风险因素和总体寿命。然而，这些相同情况的分布和发生率 在现代(1946-2014)发生了戏剧性的变化；这种转变在太短的时间内太戏剧性 受进化压力的影响，导致等位基因频率的变化。相反，这种转变最有可能是 原因是医疗保健和生活方式的变化，这反过来又导致了寿命的延长和 开启了成功衰老的大门。生活方式的改变和衰老本身会导致行为的改变 通过对DNA进行表观遗传修饰来获得相关基因。这项拟议的研究将检验这些假设 中年成年人血液中检测到的DNA甲基化特征与 晚年成功的衰老模式(目标1)；这些特征在老年中持续存在(目标2)；以及 这些特征与随后相关基因表达水平的差异有关 (目标3)。已经确定了复制机会，并将其作为工作范围的组成部分。我们将专注于 关于成功衰老的整体结构(即身体、认知和功能幸福感)，而不是任何 具有科学性(即多效性)和实用性(对生活质量的影响)的一种疾病实体或风险因素 理由。我们将使用McLaughlin等人提出并验证的成功老化的第二级定义 健康与退休研究。社区动脉粥样硬化风险(ARIC)研究，一项双指标研究 关于动脉粥样硬化发展及其危险因素的纵向队列研究，已收集和储存 在之前的五次检查中每一次都进行了生物样本，并测量了血液生物标记物和DNA序列 疾病风险预测因子的成功搜索中的差异。这项拟议的辅助研究将支持 测量与成功衰老相关的表观遗传模式。以下是具体目标 追求：1)识别在中年成年人血液中测量到的DNA甲基化特征 与晚年的成功衰老状态相关；2)确定DNA甲基化签名是否 来自目标1的1800名ARIC参与者在中年成功衰老，并在21年后继续存在 当他们到老年时；3)检查在中年发现的基因的DNA甲基化状态 年龄(目标1)与老年时的基因表达相关。拟议项目的长期目标是通过 增加我们对成功衰老的生物决定因素和轨迹的理解，这项研究可能 帮助将重点放在可改变的风险因素上的公共卫生干预措施和新的 治疗剂将使成功衰老成为更多人的可实现目标 人口。

Project Abstract Numerous studies have documented a role for inherited genetic variation in common chronic diseases, their risk factors and overall longevity. However, the distributions and incidence rates of these same conditions have changed dramatically during modern times (1946-2014); a shift too dramatic in too short of a period to be affected by evolutionary pressures leading to changes in allele frequencies. Rather, this shift is most likely accounted for by changes in health care and lifestyle, which, in turn, have led to increased longevity and opening the door to successful aging. Lifestyle changes and aging itself can lead to alterations in the action of relevant genes via epigenetic modification of the DNA. This proposed research will test the hypotheses that signatures of DNA methylation measured in the blood of middle-aged adults are associated with successful aging patterns later in life (Aim 1); that these signatures persist in old age (Aim 2); and these signatures are associated with subsequent differences in the expression level of relevant genes (Aim 3). Replication opportunities have been identified and are an integral part of the workscope. We will focus on the overall construct of successful aging (i.e., physical, cognitive and functional well-being) instead of any one disease entity or risk factor for both scientific (i.e., pleiotropy) and practical (impact on quality of life) reasons. We will use the Level II definition of successful aging proposed and validated by McLaughlin et al in the Health and Retirement Study. The Atherosclerosis Risk in Communities (ARIC) Study, a biracial longitudinal cohort study of the development of atherosclerosis and its risk factors, has collected and stored biosamples at each of its previous five examinations, and measured blood biomarkers and DNA sequence variation in successful searches for predictors of disease risk. This proposed ancillary study will support measurement of epigenetic patterns associated with successful aging. The following specific aims will be pursued: 1) To identify signatures of DNA methylation measured in the blood of middle-aged adults that are associated with successful aging status later in life; 2) To determine whether DNA methylation signatures of successful aging established in middle age among 1,800 ARIC participants from Aim 1 persist ~21 years later when they reach old age; 3) To examine whether the DNA methylation status of the genes identified in middle age (Aim 1) is correlated with gene expression in old age. The long-term goal of the proposed project is that by increasing our understanding of the biological determinants and trajectory of successful aging, this study may help to inform public health interventions focused on modifiable risk factors and the development of new therapeutic agents that will make successful aging an attainable goal for a greater number of individuals in the population.