Comprehensive Evaluation of Aging-Related Clinical Outcomes and Geroproteins

衰老相关临床结果和Gero蛋白的综合评价

• 批准号: 9519838
• 负责人: STEVEN RON CUMMINGS
• 金额: $ 63.5万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519838
• 关键词: ART protein; Adult; Adverse effects; Age; Aging; Anemia; Atherosclerosis; Baltimore; Biological Assay; Biology; Biometry; Blood Vessels; Body Composition; Brain; CCL11 gene; Cardiology; Cardiovascular Diseases; Cause of Death; Cessation of life; Clinical; Cognition; Cognitive; Colon Carcinoma; Communities; Coronary heart disease; Data; Dementia; Diagnosis; EFRAC; Elderly; Enzyme-Linked Immunosorbent Assay; Epidemiologic Methods; Erythropoiesis; Evaluation; Exhibits; FSTL3 gene; Family; Follistatin; GDF11 gene; GDF8 gene; General Population; Geriatrics; Goals; Growth and Development function; Health; Heart Hypertrophy; Heart failure; Homologous Gene; Hormones; Hospitalization; Human; Immunoassay; Impaired cognition; Inflammatory Response; Injury; Investigation; Laboratories; Left Ventricular Mass; Longevity; Longitudinal Studies; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Memory; Mus; Muscle; Myocardium; Natural regeneration; Neurology; Outcome; Oxytocin; Parabiosis; Pathway interactions; Pattern; Peptides; Phenotype; Physiological; Play; Proteins; Proteomics; Protocols documentation; Race; Reporting; Research Personnel; Risk; Role; Science; Skeletal Muscle; Smell Perception; Specific qualifier value; Specificity; Specimen; Testing; Tissues; Transforming Growth Factor beta; Translating; Variant; adverse outcome; age related; aptamer; base; beta-2 Microglobulin; biracial; cardiovascular disorder risk; cardiovascular health; clinical phenotype; cognitive function; cohort; disability; effective therapy; experimental study; follow-up; hemodynamics; improved; innovation; liquid chromatography mass spectrometry; member; mortality; muscle strength; neurogenesis; new therapeutic target; population based; psychologic; public health relevance; reproductive; sex; young adult

 DESCRIPTION (provided by applicant): We propose to test whether mouse experiments showing that circulating proteins can rejuvenate or accelerate aging in the brain, heart, and skeletal muscle translate into corresponding associations with important clinical outcomes in older adults. Using an assay for GDF11 that has since been determined also to measure its close structural homologue, GDF8, we demonstrated in preliminary studies that these geronic proteins are associated with incident heart failure (HF) and atherosclerotic cardiovascular disease (ASCVD) in cohorts with prevalent coronary disease. By contrast, follistatin-like 3, an antagonist of GDF11 and GDF8, exhibited the opposite associations. These findings highlight the need to identify more specific assays, and they also call for broader investigation of relevant pathways in general population-based cohorts. We will therefore undertake systematic comparisons of state-of-the-art LC mass spectroscopy, aptamer-based proteomics, and immunoassays to select the best assay for each protein. We will then harness the comprehensive clinical phenotyping and exceptional statistical power of two large, biracial cohorts, the Cardiovascular Health Study and the Health Aging, and Body Composition Study to efficiently test the following hypotheses. First, that higher levels of CCL11 and of ß2 microglobulin, which decrease neurogenesis in mice, are associated with impaired cognitive function and increased risk of dementia. Second, that as in mice, higher levels of GDF11 are associated with lower left ventricular (LV) mass and reduced risk of heart failure, particularly with preserved ejection fraction (HFpEF), ASCVD, and risk of dementia. Third, that higher levels of GDF11 and oxytocin are associated with improved skeletal muscle strength and reduced risk of mobility disability. Beyond these endpoints, we will also examine various adverse outcomes. Moreover, we will describe how levels of these proteins vary across the lifespan, from age 20 to 96, using data and specimens from the Baltimore Longitudinal Study of Aging. These data will enable us to analyze how levels of these proteins influence cognition, LV mass, and muscle strength across the life span. The proposed study will be led by a coordinated team of PIs and investigators who are leaders in their fields of laboratory science, geriatrics, cardiology, neurology, muscle and mobility, and biostatistics. An exceptional Scientific Advisory board of leaders in parabiosis and the basic biology of these proteins has and will continue to inform our choices of peptides and phenotypes, and guide analyses of our data. Hence, the proposed study will provide a comprehensive analysis of these exciting proteins in human cohorts with the aim of identifying novel therapeutic targets for major causes of disability and mortality for which few effective treatments are currently available.