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

表观遗传学导致老年相关疾病 (GILGA-mesh) 网络

• 批准号: 9291402
• 负责人: Steve Horvath
• 金额: $ 30.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291402
• 关键词: Academia; Address; Affect; Age; Aging; Aging-Related Process; Baltimore; Bioinformatics; Biological; Biological Assay; Biological Markers; Birth; Blood; Chromatin; Chronic; Chronic Disease; Chronology; Cognitive; Cohort Studies; Communities; Computer software; Consent Forms; DNA Methylation; Data; Data Quality; Degenerative Disorder; Disease; Disease susceptibility; Educational workshop; Elderly; Epidemiology; Epigenetic Process; Epithelium; Feasibility Studies; Funding; Future; Genomics; Geroscience; Goals; Grant; Health; Human; Industry; Interdisciplinary Study; Life Cycle Stages; Life Expectancy; Literature; Logistics; Longitudinal Studies; Measurement; Measures; Mediating; Mediator of activation protein; Phenotype; Pilot Projects; Play; Population; Predisposition; Price; Recommendation; Reporting; Reproducibility; Research; Research Infrastructure; Research Personnel; Resources; Risk Factors; Role; Sampling; Selection Criteria; Systems Biology; Techniques; Technology; Teleconferences; Testing; Time; TimeLine; Tissue Sample; Tissues; Untranslated RNA; Women' s Health; age effect; age related; analytical method; base; cell type; cohort; cost; design; disability; disease phenotype; epigenetic marker; fitness; frontier; histone modification; human study; human tissue; insight; meetings; mortality; multiple chronic conditions; novel; phenotypic data; prevent; prognostic; public health relevance; symposium; tool

 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.

 描述（由申请人提供）：虽然预期寿命持续增长，但健康寿命却未能跟上，因为当前的疾病治疗通常会降低死亡率，但无法阻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的易感性至关重要。我们和其他人已经证明，表观遗传机制可能比现有的衰老生物标志物与实际年龄的关系更为密切。衰老的表观遗传生物标志物可以预测晚年的全因死亡率，并与老年人的身体和认知健康指标相关。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。我们制定了设计一项大规模研究所需的框架，以测试“衰老过程中的表观遗传变化共同构成衰老作为慢性疾病和退行性疾病的危险因素”的总体假设。我们的共同研究人员和合作者团队可以获得的表型数据这些资源包括来自 ENCODE 项目的数据、在多个组织中生成的各种表观遗传数据以及丰富的表型队列，例如巴尔的摩纵向衰老研究 (BLSA)、InCHIANTI、妇女健康倡议和洛锡安出生队列我们将评估用于测量表观遗传年龄、DNA 甲基化水平、染色质状态和非编码的不同平台。 RNA 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存在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都是新颖的：我们将为以下方面奠定基础。这项研究利用多个特征明确的人类队列研究以及最先进的统计和生物信息学，在多个时间点调查多种表观遗传过程（DNA 甲基化、组蛋白修饰、非编码 RNA）、多种人体组织、多种慢性疾病技术。利用这些和其他研究的试点数据，我们将评估尖端表观遗传学测量的可靠性和精确度，并估计未来研究所需的资源。我们还将评估可触及的人体组织（例如血液）中表观遗传学特征的程度。通过在加州大学洛杉矶分校组织两次研讨会，我们将建立一个由衰老研究、表观遗传学、流行病学、基因组学和系统领域的领先研究人员组成的研究网络。生物学。

项目成果

Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies.

• DOI: 10.1093/hmg/ddv456
• 发表时间: 2016-01-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Simpkin AJ;Hemani G;Suderman M;Gaunt TR;Lyttleton O;Mcardle WL;Ring SM;Sharp GC;Tilling K;Horvath S;Kunze S;Peters A;Waldenberger M;Ward-Caviness C;Nohr EA;Sørensen TI;Relton CL;Smith GD
• 通讯作者: Smith GD

Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression.

• DOI: 10.18632/aging.101588
• 发表时间: 2018-10-17
• 期刊: Aging
• 作者: Kabacik S;Horvath S;Cohen H;Raj K
• 通讯作者: Raj K

The epigenetic clock and physical development during childhood and adolescence: longitudinal analysis from a UK birth cohort.

• DOI: 10.1093/ije/dyw307
• 发表时间: 2017-04-01
• 期刊: International journal of epidemiology
• 影响因子: 7.7
• 作者: Simpkin AJ;Howe LD;Tilling K;Gaunt TR;Lyttleton O;McArdle WL;Ring SM;Horvath S;Smith GD;Relton CL
• 通讯作者: Relton CL

Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring.

• DOI: 10.18632/aging.100861
• 发表时间: 2015-12
• 期刊: Aging
• 作者: Horvath S;Pirazzini C;Bacalini MG;Gentilini D;Di Blasio AM;Delledonne M;Mari D;Arosio B;Monti D;Passarino G;De Rango F;D'Aquila P;Giuliani C;Marasco E;Collino S;Descombes P;Garagnani P;Franceschi C
• 通讯作者: Franceschi C

DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility.

• DOI: 10.1016/j.ejca.2017.01.014
• 发表时间: 2017-04
• 期刊: European journal of cancer (Oxford, England : 1990)
• 作者: Ambatipudi S;Horvath S;Perrier F;Cuenin C;Hernandez-Vargas H;Le Calvez-Kelm F;Durand G;Byrnes G;Ferrari P;Bouaoun L;Sklias A;Chajes V;Overvad K;Severi G;Baglietto L;Clavel-Chapelon F;Kaaks R;Barrdahl M;Boeing H;Trichopoulou A;Lagiou P;Naska A;Masala G;Agnoli C;Polidoro S;Tumino R;Panico S;Dollé M;Peeters PHM;Onland-Moret NC;Sandanger TM;Nøst TH;Weiderpass E;Quirós JR;Agudo A;Rodriguez-Barranco M;Huerta Castaño JM;Barricarte A;Fernández AM;Travis RC;Vineis P;Muller DC;Riboli E;Gunter M;Romieu I;Herceg Z
• 通讯作者: Herceg Z