Systemic rejuvenating factors and human aging phenotypes.

全身年轻化因子和人类衰老表型。

基本信息

批准号：
10152484
负责人：
RICHARD D SEMBA
金额：
$ 35.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152484
关键词：
Address Adult Affect Age Aging Anemia Animal Model Animals Attention Baltimore Binding Biological Biological Assay Blood Bone Density C-terminal Cleaved cell Clinical Cognition Complex Conflict (Psychology)Cross-Sectional Studies Elderly Eotaxin Epitopes Follistatin Follistatin-Like Protein 3 GDF11 gene GDF8 gene Growth Inhibitors Heart Hypertrophy Human Immunoassay Insulin Resistance Intervention Knee Liquid Chromatography Longitudinal Studies Lower Extremity Measures Memory Modeling Molecular Conformation Monitor Osteoporosis Outcome Oxytocin Participant Pathway interactions Peptides Pharmacology Phenotype Physical Performance Plasma Plasma Proteins Post-Translational Protein Processing Prevention Protein Isoforms Proteins Public Health Reaction Reagent Rejuvenation Reporting Research Research Design Role Skeletal Muscle Testing Woman age related aptamer disability inhibitor/antagonist lifestyle intervention men muscle strength novel polypeptide risk stratification sarcopenia secondary outcome sex skeletal muscle growth tandem mass spectrometry therapeutic target

项目摘要

Recent animal studies have identified several polypeptides or proteins that can reverse or accelerate aging phenotypes. These candidate “rejuvenating factors” include growth/differentiation factor 11 (GDF11), growth/differentiation factor 8 (GDF8), and inhibitors of GDF11 and GDF8: GDF11 and GDF8 propeptides, follistatin, follistatin-related protein 3, WFIKKN1, and WFIKKN2. Two other important candidates are oxytocin and eotaxin. Although these circulating rejuvenating factors are associated with aging phenotypes in animal models, a major unanswered question is whether these circulating proteins or polypeptides are relevant to human aging phenotypes. These polypeptides or proteins have been difficult to study in the blood using conventional immunoassays, since some of the peptides or proteins exist in multiple isoforms, undergo post- translational modifications such as cleavage or terminal degradation, or have high sequence identity with each other. In addition, circulating antagonists can inhibit the biological activity of GDF8 and GDF11. In order to overcome these obstacles, we developed a novel multiplexed selected reaction monitoring assay using liquid chromatography-tandem mass spectrometry that measures thirteen plasma proteins or polypeptides representing eight important proteins in rejuvenation research. We will test the hypothesis that plasma concentrations of these candidate rejuvenating factors are independently associated with and predict specific aging phenotypes in older adults. Our aim is to conduct a comprehensive assessment of circulating rejuvenating factors and their relationships to specific aging phenotypes in humans. To address this aim, we will measure these circulating factors in participants of the Baltimore Longitudinal Study of Aging (BLSA) and the Lifestyle Interventions and Independence for Elders (LIFE) Study. Aging phenotypes will include prevalent and incident sarcopenia, lower extremity physical performance, mobility disability, cognition, memory, cardiac hypertrophy, osteoporosis, insulin resistance, and anemia. By the end of the project, we should be able to verify or refute the association of these candidate rejuvenating factors with phenotypes of human aging. Verification of a role for rejuvenating factors in human aging phenotypes should advance risk stratification and targeting of specific pathways in the prevention or treatment of adverse aging outcomes.

最近的动物研究发现了几种可以逆转或加速衰老的多肽或蛋白质这些候选“恢复活力因子”包括生长/分化因子 11 (GDF11)、生长/分化因子 8 (GDF8)，以及 GDF11 和 GDF8 抑制剂：GDF11 和 GDF8 前肽，卵泡抑素、卵泡抑素相关蛋白 3、WFIKKN1 和 WFIKKN2 是另外两个重要的候选药物。尽管这些循环恢复活力因子与动物的衰老表型有关。模型中，一个未解答的主要问题是这些循环蛋白或多肽是否与人类衰老表型很难在血液中进行研究。传统的免疫测定法，由于一些肽或蛋白质以多种亚型存在，因此需要经过后处理翻译修饰，例如切割或末端降解，或与每个具有高序列同一性另外，循环拮抗剂可以抑制GDF8和GDF11的生物活性。克服这些障碍，我们开发了一种使用液体的新型多重选择反应监测测定法色谱-串联质谱法可测量 13 种血浆蛋白或多肽代表了复兴研究中的八种重要蛋白质，我们将检验血浆的假设。这些候选恢复活力因子的浓度独立相关并预测特定的我们的目标是对老年人的衰老表型进行全面评估。恢复活力因素及其与人类特定衰老表型的关系为了实现这一目标，我们。将测量巴尔的摩老龄化纵向研究 (BLSA) 参与者的这些循环因素，生活方式干预和老年人独立性（LIFE）研究将包括普遍的老龄化表型。和事件性肌肉减少症、下肢身体机能、活动障碍、认知、记忆、心脏到项目结束时，我们应该能够解决肥厚、骨质疏松、胰岛素抵抗和贫血等问题。验证或反驳这些候选恢复活力因子与人类衰老表型的关联。验证恢复活力因子在人类衰老表型中的作用应能促进风险分层和针对预防或治疗不良衰老结果的特定途径。