The epiGenetIcs Leads to aGe-relAted diseases (GILGA-mesh) Network

 描述(申请人提供)：虽然预期寿命持续增长，但健康寿命没有跟上步伐，因为目前的疾病治疗通常会降低死亡率，但不能防止整体健康状况的下降。了解衰老的潜在过程如何影响慢性病和相关疾病的易感性是至关重要的。表观遗传机制可以说已经成为老年学的一个重要前沿。我们和其他人已经表明，表观遗传生物标记物往往比现有的衰老生物标记物与年代年龄有更强的相关性。重要的是，我们最近已经证明，衰老的表观遗传生物标志物是晚年全因死亡的预测，并与老年人身体和认知健康的衡量标准相关。这些数据表明，表观遗传机制可能在调节年龄对疾病易感性的影响中发挥作用。在这份规划拨款中，我们列出了设计一项大规模研究所需的框架，该研究测试了这样一个总体假设：“衰老过程中的表观遗传变化共同构成了衰老作为慢性病和退行性疾病风险因素的基础”。我们将通过利用现有的表观遗传学和表型数据来产生初步结果，这些数据可供我们的合作研究团队和合作者使用。这些资源包括来自ENCODE项目的数据，在多个组织中产生的各种表观遗传学数据，以及丰富的表型队列，如巴尔的摩老龄化纵向研究(BLSA)、INCHIANTI、妇女健康倡议和洛锡安出生队列。我们将评估不同的测量表观遗传年龄、DNA甲基化水平、染色质状态和非编码RNA的平台，根据它们与我们的总体假设、数据质量、覆盖范围和价格的相关性。虽然有大量关于表观遗传学和衰老的文献，但我们的建议在广度和深度方面是新颖的：我们将为一项研究奠定基础，该研究使用多个特征良好的人类队列研究和最先进的统计和生物信息学技术，在多个时间点调查多个表观遗传过程(DNA甲基化、组蛋白修饰、非编码RNA)、多个人类组织、多个慢性病。使用这些研究和其他研究的试点数据，我们将评估尖端表观遗传措施的可靠性和精确度，并估计未来研究所需的资源。我们还将评估可接触的人类组织(例如血液、颊上皮)的表观遗传学特征在多大程度上可以替代受影响的组织和细胞类型。通过在加州大学洛杉矶分校组织两个研讨会，我们将建立一个由老龄化研究、表观遗传学、流行病学、基因组学和系统生物学领域的领先研究人员组成的研究网络。

 DESCRIPTION (provided by applicant): While life expectancy continues to rise, healthspan is not keeping pace because current disease treatments often decrease mortality without preventing the decline in overall health. It is crucial to understand how the underlying processes of aging affect susceptibility to chronic disease and related conditions. Epigenetic mechanisms have arguably become an important frontier in geroscience. We and others have shown that epigenetic biomarkers tend to be more strongly related with chronological age than existing biomarkers of aging. Importantly, we have recently demonstrated that epigenetic biomarkers of aging are prognostic of all-cause mortality in later life and correlate with measures of physical and cognitive fitness in older age. These data suggest that epigenetic mechanisms may play a role in mediating the effect of age on disease susceptibility. In this planning grant we lay out th framework needed to design a large-scale study that tests the overall hypothesis that "epigenetic changes during aging collectively underlie aging as a risk factor for chronic diseases and degenerative conditions". We will generate preliminary results by leveraging existing epigenetic and phenotypic data available to our team of co-investigators and collaborators. These resources include data from the ENCODE project, various epigenetic data generated in multiple tissues, and richly phenotyped cohorts, such as the Baltimore Longitudinal Study of Aging (BLSA), InCHIANTI, the Women's Health Initiative, and the Lothian Birth Cohorts. We will evaluate different platforms for measuring epigenetic age, DNA methylation levels, chromatin states, and non-coding RNAs in terms of their relevance to our overall hypothesis, data quality, coverage, and price. While there exists a large body of literature on epigenetics and aging, our proposal is novel in terms of its breadth and depth: we will lay the groundwork for a study that investigates multiple epigenetic processes (DNA methylation, histone modifications, non-coding RNAs), multiple human tissues, multiple chronic conditions, at multiple time points using multiple well characterized human cohort studies and state-of-the-art statistical and bioinformatics techniques. Using pilot data from these and other studies, we will assess the reliability and precision of cutting-edge epigenetic measures and to estimate the resources needed for a future study. We will also assess to what extent epigenetic features in accessible human tissues (e.g., blood, buccal epithelium) can serve as surrogates for affected tissues and cell types. By organizing two workshops at UCLA, we will establish a research network comprised of leading researchers in the fields of aging research, epigenetics, epidemiology, genomics, and systems biology.