Systemic rejuvenating factors and human aging phenotypes.

全身年轻化因子和人类衰老表型。

• 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
• 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

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.

最近的动物研究已经确定了几种可以逆转或加速衰老的多肽或蛋白质 表型。这些候选的“年轻化因子”包括生长/分化因子11(GDF11)， 生长分化因子8(GDF8)，以及GDF11和GDF8的抑制剂：GDF11和GDF8前肽， 卵泡抑素、卵泡抑素相关蛋白3、WFIKKN1和WFIKKN2。另外两种重要的候选药物是催产素 和嗜酸性粒细胞趋化因子。尽管这些循环再生因子与动物的衰老表型有关 模型中，一个尚未回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。这些多肽或蛋白质很难在血液中进行研究 由于一些多肽或蛋白质以多种异构体存在，传统的免疫分析方法要经过 翻译修饰，如切割或末端降解，或与每个具有高度序列同源性 其他的。此外，循环拮抗剂还可抑制GDF8和GDF11的生物活性。为了 克服这些障碍，我们建立了一种新型的液体多重选择反应监测方法。 测定13种血浆蛋白质或多肽的色谱-串联质谱法 代表了返老还童研究中的八种重要蛋白质。我们将检验一种假设，即血浆 这些候选年轻因子的浓度独立地与特定的 老年人的衰老表型。我们的目标是对流通领域进行全面评估 返老剂及其与人类特定衰老表型的关系。为了达到这一目标，我们 将在巴尔的摩老龄化纵向研究(BLSA)的参与者中测量这些循环因素 生活方式干预与老年人独立性(LIFE)研究。老龄化表型将包括流行的 以及偶发性骨质疏松症、下肢体能、活动障碍、认知、记忆、心脏 肥大、骨质疏松症、胰岛素抵抗和贫血。到项目结束时，我们应该能够 验证或驳斥这些候选的返老剂与人类衰老表型之间的关联。 对返老还童因素在人类衰老表型中的作用的验证应促进风险分层和 针对特定途径预防或治疗不利的衰老结果。