Immune and metabolic dysfunction during aging in human cohorts

人类衰老过程中的免疫和代谢功能障碍

• 批准号: 10707456
• 负责人: BLANCA I RESTREPO
• 金额: $ 58.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707456
• 关键词: Acceleration; Adult; Affect; Age; Aging; Anti-Inflammatory Agents; Autoimmune Diseases; Biological; Biological Markers; Blood; Brain; Cells; Clinical; Communities; Complement; Containment; Cross-Sectional Studies; Defect; Diabetes Mellitus; Diagnosis; Elderly; Enrollment; Event; Exposure to; Failure; Foundations; Functional disorder; Future; Genetic; Goals; Growth; HIV; Health; Health system; High Prevalence; Hispanic; Homeostasis; Human; Immune; Immune System Diseases; Immunologics; Impairment; Individual; Infection; Inflammation; Intervention; Joints; Lead; Longitudinal Studies; Lung; Lung infections; Measures; Metabolic; Metabolic dysfunction; Metabolism; Mexico; Mitochondria; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Non-Insulin-Dependent Diabetes Mellitus; Organ failure; Outcome; Oxidative Stress; Oxidative Stress Induction; Oxidative Stress Pathway; Participant; Pathway interactions; Patients; Persons; Phenotype; Plasma; Premature aging syndrome; Process; Proteins; Pulmonary Tuberculosis; Research Personnel; Role; Sampling; Site; Skeletal Muscle; Specimen; Testing; Texas; Time; Tuberculosis; Waste Management; age effect; age group; body system; chemokine; cohort; cytokine; functional decline; healthspan; high risk; human old age (65+); immune function; in vivo; monocyte; mortality; novel; older patient; oxidation; pathogen; prevent; research clinical testing; resilience; response; restoration; synergism; therapy development; tuberculosis treatment

Old age is associated with a high prevalence of metabolic alterations like type 2 diabetes mellitus (DM) and preOM 0ointly 'dysglycemia'), and with an immunologic decline associated with higher risk of developing and dying from lung infections like pulmonary tuberculosis (PTB). These immune-metabolic alterations are accompanied by failure in other organ systems (lung, brain, skeletal muscle), leading to increased morbidity and mortality. Understanding these interactions and detecting them early is critical for delaying, preventing or restoring an individual's organ system health. The underlying mechanisms for immunometabolic alterations are unknown, but our joint studies in humans and mice with and without Mycobacterium tuberculosis (M.tb) infection provide support for the role of oxidative stress and associated inflammation as a driver. Accordingly, in our Hispanic human cohort, we find that systemic oxidative stress is higher in TB or DM patients, and exacerbates age effects. We hypothesize that aging-related immunometabolic changes that drive organ failure are largely originated from impaired mitochondria-driven oxidative stress pathways. We will test these hypotheses, conducting snap-shot and longitudinal studies in humans. We will identify the age at which these changes initiate and the most affected pathway, focusing on monocytes attained from relatively non-invasive specimens. i.e., blood. These studies will take advantage of a well-defined Hispanic clinical cohort at the Texas-Mexico border and our established team of field investigators. In Aim 1, we will determine: i) when altered measures of mitochondria-induced oxidative stress and immune dysfunction are first detected in blood and monocytes during the process of aging, to identify the most effective age for interventions. In Aim 2, we will determine the impact of host biological perturbations (dysglycemia and PTB) on these outcomes. We will further evaluate if PTB may serve as a new model of accelerated aging, given its association with inflammation and oxidative stress. Overall, results will provide the foundation for future clinical testing selected interventions in-vivo and monitoring individualized responsiveness with simple biomarker testing, to promote extended cellular health and organ system healthspan.

老年与代谢改变的高流行有关，例如2型糖尿病（DM）和preom 0ointly'dysglycemia'），并且免疫学下降与发展和垂死的风险更高有关 从肺结核（PTB）等肺部感染中。这些免疫代谢的改变伴随 通过其他器官系统（肺，大脑，骨骼肌）的失败，导致发病率和死亡率增加。 了解这些互动并尽早检测它们对于延迟，防止或恢复至关重要 个体的器官系统健康。免疫代谢改变的基本机制尚不清楚，但 我们在人类和小鼠有和没有结核分枝杆菌（M.TB）感染的联合研究提供 支持氧化应激和相关炎症作为驱动器的作用。因此，在我们的西班牙裔 人类队列，我们​​发现TB或DM患者的全身氧化应激较高，并加剧年龄的影响。 我们假设与衰老相关的免疫代谢变化驱动器官衰竭主要起源于 线粒体驱动的氧化应激途径受损。我们将测试这些假设，进行快照 和人类的纵向研究。我们将确定这些变化启动和受影响最大的年龄 途径，重点是从相对非侵入性标本获得的单核细胞。即血液。这些研究会 利用德克萨斯州 - 墨西哥边境和我们既定的团队的明确定义的西班牙裔临床队列 现场调查人员。在AIM 1中，我们将确定：i）当改变线粒体诱导的氧化措施时 在衰老过程中，首先在血液和单核细胞中检测到压力和免疫功能障碍，以鉴定 干预措施的最有效年龄。在AIM 2中，我们将确定宿主生物扰动的影响 （血糖和PTB）关于这些结果。我们将进一步评估PTB是否可以作为新模型 鉴于它与炎症和氧化应激的关联，加速衰老。总体而言，结果将提供 未来临床测试的基础，体内和监测个性化响应能力 通过简单的生物标志物测试，以促进扩展的细胞健康和器官系统健康范围。