Senescence and Growth Differentiation Factors as Modifiers of Aging

衰老和生长分化因子作为衰老调节剂

• 批准号: 9755279
• 负责人: Nathan K LeBrasseur
• 金额: $ 59.51万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755279
• 关键词: Address; Affect; Aging; Amino Acid Sequence; Antibodies; Arteries; Basic Science; Biological; Biological Aging; Biological Assay; Biological Markers; Blood Pressure; Blood specimen; Body Composition; CCL11 gene; Cardiopulmonary; Cardiovascular system; Cell Adhesion Molecules; Cell Aging; Cells; Chronic; Chronic Disease; Clinical; Code; Cognitive; Cohort Studies; Collaborations; Data; Differentiation and Growth; Disease; Drug Targeting; Elderly; Eotaxin; Event; Excision; Forced expiratory volume function; GDF11 gene; GDF8 gene; Gait speed; Geroscience; Health; Health Status; Health education; Heart failure; Human; ICD-9; Impairment; Incidence; Inflammation; Innovative Therapy; Intervention; Liquid Chromatography; Longevity; Low Prevalence; Measures; Mediating; Mediator of activation protein; Memory; Methods; Mus; Muscle; Myocardial Infarction; Outcome; Participant; Partner in relationship; Phenotype; Physical Function; Physical Performance; Physical activity; Plasma; Plasminogen Activator Inhibitor 2; Pre-Clinical Model; Prevalence; Proteins; Rejuvenation; Research; Risk Factors; Sampling; Sensitivity and Specificity; Stroke; Structure; Testing; Therapeutic Intervention; Time Study; Tissues; Translations; Vascular remodeling; Walking; Work; activin A; adjudicate; age related; analytical method; base; cognitive function; disability; evidence base; exercise intervention; falls; healthspan; innovation; lifestyle intervention; multidisciplinary; multiple chronic conditions; neurogenesis; novel; older men; older women; prevent; processing speed; programs; randomized trial; regenerative; senescence; tandem mass spectrometry; tissue regeneration

PROJECT SUMMARY/ABSTRACT Aging is the primary risk factor for the majority of chronic diseases. Studies in mice have implicated specific growth and differentiation factors (GDFs) and proteins secreted by senescent cells as potential modifiers of aging. The objective of this proposal is to establish the rationale and provide robust clinical evidence for GDF8, GDF11, and senescence-related proteins eotaxin (CCL11), intracellular adhesion molecule 1 (ICAM1), activin A (AA), and plasminogen activator inhibitor 2 (PAI2), as indicators of biological age and age-related conditions in humans. The central hypothesis is that circulating concentrations of GDFs and senescence-related proteins are associated with, and predictive of, clinically important health outcomes and can be altered by physical activity. Samples from the Lifestyle Interventions and Independence for Elders (LIFE) Study; the largest and longest randomized trial of a physical activity intervention in older adults, will be used to test this hypothesis, and samples from the Health, Aging, and Body Composition (HABC) Study will be used to validate study findings. A novel multiplexed liquid chromatography-tandem mass spectrometry assay will be leveraged to accurately quantify GDFs, and an advanced multiplexing platform will be used to measure senescence-related proteins in LIFE and HABC biospecimens. In Specific Aim 1, a multidisciplinary team will first determine the extent to which baseline concentrations of GDF8, GDF11, CCL11, ICAM1, AA and PAI2 are associated with baseline measures of physical (i.e., gait speed, Short Physical Performance Battery (SPPB) score), cardiopulmonary (i.e., blood pressure, forced expiratory volume), and cognitive (i.e., processing speed, memory) function, inflammation, and prevalence of multimorbidity (based on the ICD-9 codes for 20 chronic conditions). In Specific Aim 2, the degree to which baseline concentrations of GDFs and senescence-related proteins predict longitudinal changes in a) gait speed and SPPB score, b) major mobility disability (i.e., the inability to walk 400m), c) combined cardiovascular events (e.g., myocardial infarction, heart failure, stroke); d) adjudicated falls and injurious falls, e) cognitive function (as Aim 1), and f) the number of chronic conditions (as in Aim 1), at 1 and 2 years in LIFE and at 2 and 4 years in HABC will be determined. Finally, Specific Aim 3 will address whether a structured physical activity intervention impacts longitudinal changes in GDF8, GDF11, CCL11, ICAM1, AA, and PAI2, compared to a health education control intervention, and the degree to which change in the concentrations of these proteins parallel change in the health outcomes described in Aim 2. The successful completion of the proposed research will fill an important translational gap in our understanding of how GDFs and senescence-related proteins predict and, therefore, potentially mediate aging related disability and disease in older women and men. Ultimately, these proteins may be viable targets for innovative therapies to extend human healthspan.

项目摘要/摘要 衰老是大多数慢性疾病的主要危险因素。在小鼠中的研究暗示了特定的 生长和分化因子（GDF）和由衰老细胞分泌的蛋白质作为潜在的修饰剂 老化。该提案的目的是建立理由并为GDF8提供强大的临床证据， GDF11和衰老相关蛋白Eotaxin（CCL11），细胞内粘附分子1（ICAM1），激活素 A（AA）和纤溶酶原激活剂抑制剂2（PAI2）作为生物年龄和与年龄有关的指标 在人类中。中心假设是GDF和衰老相关蛋白的循环浓度 与临床上重要的健康结果相关联和预测，可以通过身体改变 活动。生活方式干预措施的样本和长老研究的独立性；最大和 在老年人中进行身体活动干预的最长随机试验将用于检验这一假设， 健康，衰老和身体成分（HABC）研究的样本将用于验证研究 发现。一种新型的多重液相色谱串联质谱法测定法将被利用为 准确量化GDF，并将使用高级多路复用平台来测量与衰老相关的 生命中的蛋白质和HABC生物测量。在特定目标1中，多学科团队将首先确定 GDF8，GDF11，CCL11，ICAM1，AA和PAI2的基线浓度与哪种基线浓度与 物理的基线度量（即步态速度，短体性能电池（SPPB）得分）， 心肺（即血压，强迫呼气量）和认知（即处理速度， 记忆）功能，炎症和多种病的患病率（基于20个慢性的ICD-9代码 状况）。在特定目标2中，GDF和与衰老有关的基线浓度的程度 蛋白质预测a）步态速度和SPPB评分的纵向变化，b）主要的迁移率残疾（即， 无法步行400m），c）结合心血管事件（例如，心肌梗塞，心力衰竭，中风）； d） 裁定的跌倒和有害的跌倒，e）认知功能（AIM 1）和f）慢性病的数量（如 在AIM 1）中，将确定生命中的1和2年，在HABC中的2年和4年。最后，特定的目标3将 解决结构化的体育活动干预是否会影响GDF8，GDF11的纵向变化， 与健康教育控制干预措施相比，CCL11，ICAM1，AA和PAI2以及 这些蛋白质浓度的变化在AIM 2中所描述的健康结果中平行变化。 拟议研究的成功完成将填补我们对 GDF和与衰老相关的蛋白如何预测，因此有可能介导与衰老相关的残疾 和老年男女的疾病。最终，这些蛋白质可能是创新疗法的可行靶标 扩展人类健康范围。