ConProject-001

基本信息

批准号：
10006259
负责人：
Daniel Spencer Evans
金额：
$ 59.91万
依托单位：
TRANSLATIONAL GENOMICS RESEARCH INST
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10006259
关键词：
African American Aging American Biological Biological Assay Blood Cells Communities Data Data Aggregation Data Analyses Development Disease Drug Targeting Elements Epigenetic Process European Exhibits Factor Analysis Fatty acid glycerol esters Feasibility Studies Fibrinogen Follow-Up Studies Genome Genotype-Tissue Expression Project Health Human Individual Intervention Lead Longevity Measures Methods Modeling Molecular Morbidity - disease rate Mus Muscle Pathogenesis Pathway interactions Pharmaceutical Preparations Phase Population Study Process Proteins Proteomics Public Domains Research Research Design Resources Risk Sampling Skin Source Specimen System Tissue Sample Tissues Validation Work age related analytical method anti aging base biological heterogeneity cohort comparative data management database of Genotypes and Phenotypes design drug discovery genome wide association study healthy aging improved insight longitudinal human study metabolomics novel programs protective factors therapeutic development

项目摘要

A number of drugs and interventions have been identified that curb morbidities associated with individual age-related diseases, and a few compounds have been identified that increase longevity in mice and other nonhuman species. However, few, if any, have been definitively shown to work by slowing the aging process and thereby simultaneously delaying the onset of multiple diseases and ultimately extending human longevity. Thus, current searches for drug and intervention targets that can lead to the development of longevity-enhancing ‘geroprotectors,’ i.e., interventions which stave off multiple age-related diseases and increase longevity by slowing or disrupting aspects of the aging process, need to be improved. Only very integrated approaches are likely to lead to successful searches given the need to reconcile complexities surrounding the pathogenesis of age-related diseases with processes contributing to the synchronized decay of multiple systems that defines aging. We believe that such integration can be achieved practically by: 1. pursuing multiple human longitudinal studies focusing on the discovery of metabolites and proteins associated with a biologically-compelling definition of slow and healthy human aging in different tissues; 2. exploiting novel cross-species longevity studies involving multiple tissues to obtain insights into conserved pathways impacting longevity whose elements may be consistent with factors discovered in human studies and hence validate them as truly related to longevity and not just disease; and 3. aggregating data arising from items 1-2 along with relevant available public domain data to generate/validate hypotheses, in addition to pursuing a GWAS to identify protective factors for disease and using novel statistical and inferential methods. Our proposed studies are some of the first to champion the notion that the ‘triangulation’ of disparate scientific studies and discoveries, i.e., the attempt to unify results from different study designs based on their biological coherence, is the optimal way to advance identification of human targets for longevity-enhancing geroprotective drugs and interventions. Importantly, although we believe that each of the individual studies we are proposing is itself powerful enough to identify potential geroprotector targets, their collective and integrated use with novel analytic methods will have unprecedented power and provide a paradigm for anti-aging drug discovery research within the academic community. For example, we are proposing the first human longitudinal study to search for druggable factors associated with the epigenetic clock and other validated measures of the aging rate/healthy aging in thousands of individuals; the largest metabolomics and proteomic cross-species multi-tissue study (N=60 species) of factors associated with lifespan; the largest human longitudinal comparative tissue study of aging exploring blood, muscle, fat and skin samples; and the largest study of aggregated data from public domain sources for association analyses including standard GWAS and a unique polygenic risk score-based healthy genome GWAS.

已经确定了许多药物和干预措施可以抑制与个人年龄相关的发病率疾病，并且已经鉴定出一些化合物可以延长小鼠和其他非人类的寿命然而，很少有物种（如果有的话）被明确证明可以减缓衰老过程并发挥作用。从而同时延缓多种疾病的发生并最终延长人类的寿命。因此，目前正在寻找可以促进长寿的药物和干预靶点的开发 “老年保护剂”，即预防多种与年龄相关的疾病并增加患病率的干预措施长寿需要通过减缓或破坏衰老过程的各个方面来提高。鉴于需要协调周围的复杂性，这些方法可能会导致成功的搜索与年龄相关的疾病的发病机制，其过程导致多种疾病同步衰退我们相信，这种整合可以通过以下方式实际实现： 1. 追求多项人类纵向研究，重点是发现与a相关的代谢物和蛋白质 2. 探索新的跨物种；涉及多个组织的长寿研究，以深入了解影响的保守途径长寿的因素可能与人类研究中发现的因素一致并因此得到验证它们确实与长寿有关，而不仅仅是与疾病有关；以及 3. 汇总第 1-2 项中产生的数据；除了追求 GWAS 之外，还利用相关的可用公共领域数据来生成/验证假设确定疾病的保护因素并使用新的统计和推理方法。是最先倡导不同科学研究的“三角测量”这一概念的人之一发现，即尝试根据不同研究设计的生物学一致性来统一结果，推进确定人类长寿药物靶标的最佳方法以及重要的是，尽管我们相信我们提出的每项单独研究都是其本身。强大到足以识别潜在的老年保护剂目标，以及它们与新颖的集体和综合使用分析方法将具有前所未有的力量，并为抗衰老药物的发现提供范例例如，我们正在提出第一个人类纵向研究。寻找与表观遗传时钟和其他经过验证的衰老指标相关的药物因子数千人的速率/健康衰老；最大的代谢组学和蛋白质组学跨物种多组织与寿命相关的因素研究（N=60）；最大的人类纵向比较；探索老化血液、肌肉、脂肪和皮肤样本的组织研究以及最大的汇总数据研究；来自公共领域来源的关联分析，包括标准 GWAS 和独特的多基因风险基于评分的健康基因组 GWAS。