Systemic rejuvenating factors and human aging phenotypes.

全身年轻化因子和人类衰老表型。

• 批准号: 10421273
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421273
• 关键词: Address; Adult; Affect; Age; Aging; Anemia; Animal Model; Animals; Attention; Baltimore; Binding; Biological; Biological Assay; Blood; Bone Density; C-terminal; 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; antagonist; aptamer; disability; inhibitor; 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。这些候选人的“复兴因素”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丙肽， Follistatin，Follistatin相关蛋白3，WFIKKN1和WFIKKN2。另外两个重要的候选者是氧加毒素 虽然这些循环恢复的因素与动物的衰老表型有关 模型，一个主要的未解决的问题是这些循环蛋白或多肽是否与 人老化表型。这些多肽或蛋白质很难在血液中使用 常规免疫测定，因为某些宠物或蛋白质存在于多种同工型中，因此经历了 翻译修饰（例如切割或终端降解），或与每个降解具有高序列身份 其他。另外，循环拮抗剂可以抑制GDF8和GDF11的生物学活性。为了 克服这些障碍，我们使用液体开发了一种新型的多路复用反应监测测定法 色谱串联质谱法，测量13个血浆蛋白或多肽 在修订研究中代表八种重要蛋白质。我们将测试血浆的假设 这些候选者恢复活力因素的浓度独立相关并预测特定 老年人的老化表型。我们的目的是对流通的全面评估 恢复活力的因素及其与人类特定衰老表型的关系。为了解决这个目标，我们 将在巴尔的摩纵向研究（BLSA）和 长者（生活）研究的生活方式干预和独立性。衰老表型将包括普遍 和事故肌肉减少症，下肢身体表现，移动性残疾，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者的恢复因素与人类衰老的表型的关联。 验证人类衰老表型中恢复活力因素的作用应提高风险分层和 针对预防或处理广告衰老结果的特定途径。

项目成果

Relationships of GDF8 and 11 and Their Antagonists With Decline of Grip Strength Among Older Adults in the Baltimore Longitudinal Study of Aging.

巴尔的摩老龄纵向研究中 GDF8 和 11 及其拮抗剂与老年人握力下降的关系。

• DOI: 10.1093/gerona/glad135
• 发表时间: 2023
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Yamaguchi,Yuko;Zhu,Min;Moaddel,Ruin;Palchamy,Elango;Ferrucci,Luigi;Semba,RichardD
• 通讯作者: Semba,RichardD

Proteomics in aging research: A roadmap to clinical, translational research.

• DOI: 10.1111/acel.13325
• 发表时间: 2021-04
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Moaddel R;Ubaida-Mohien C;Tanaka T;Lyashkov A;Basisty N;Schilling B;Semba RD;Franceschi C;Gorospe M;Ferrucci L
• 通讯作者: Ferrucci L

The Plasma Proteome Fingerprint Associated with Circulating Carotenoids and Retinol in Older Adults

与老年人循环类胡萝卜素和视黄醇相关的血浆蛋白质组指纹

• DOI: 10.1093/jn/nxab340
• 发表时间: 2022
• 期刊: Journal of Nutrition
• 影响因子: 4.2
• 作者: Yuko Yamaguchi;Marta Zampino;Toshiko Tanaka;Stefania Bandinelli;Ruin Moaddel;Giovanna Fantoni;Julian Candia;Luigi Ferrucci;Richard D Semba
• 通讯作者: Richard D Semba