Biomarkers of Homestatic Dysregulation in Aging and Chronic Disease

衰老和慢性病中稳态失调的生物标志物

• 批准号: 8336000
• 负责人: Luigi Ferrucci
• 金额: $ 11.61万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8336000
• 关键词: Accounting; Address; Adult; Affect; Age; Aging; Aging-Related Process; Antioxidants; Autonomic nervous system; Baltimore; Basal metabolic rate; Biological; Biological Markers; Cell Respiration; Charge; Chronic; Chronic Disease; Clinical; Clinical Research; Cognitive; Collaborations; Complement; Data; Defect; Deterioration; Development; Disease susceptibility; Elderly; Elements; Endocrine system; Energy Metabolism; Environment; Epidemiologic Studies; Epidemiology; Equilibrium; Etiology; Evolution; Feedback; Generations; Health; Homeostasis; Hormones; Immune system; Impairment; Inflammatory; Inflammatory Response; Institution; Intake; Joints; Longitudinal Studies; Measures; Modeling; Morbidity - disease rate; Motivation; Motor; Muscle; Neuraxis; Neurologic; Nutrient; Outcome; Oxidative Stress; Oxygen; Parasympathetic Nervous System; Pathway interactions; Performance; Peripheral Nervous System; Phase; Physical activity; Physiological; Process; Production; Property; Reactive Oxygen Species; Research; Research Personnel; Sardinia; Scientist; Signal Transduction; Stress; Stressful Event; System; Testing; Women' s Health; base; bone; disability; frailty; free radical oxygen; high throughput screening; improved; macromolecule; mortality; nutrition; programs; repaired; sensory system

This project tests the hypothesis that the process that leads to disease susceptibility, disability and frailty in older persons largely constitutes a progressive dysregulation and reduced reserve capacity in the network of biological mechanisms that interact to maintain a stable energetic homeostasis and/or a defect or deficiency in the capacity to regain equilibrium when homeostasis is critically challenged by a stressful event. Elements comprising these networks are not completely defined but certainly include: 1. Intake of essential elements the body requires to create energy, including both nutrients and oxygen; 2. Activities that affect the different forms of energy utilization, including resting metabolic rate, physical activity, cognitive activity and nutrition; 3) Neurological control of the energy flow, mostly affected by the interplay between the sympathetic and the parasympathetic nervous systems; 4) The endocrine system, which is also in charge of modulating the locoregional distribution of energy flow, but acts more slowly than the autonomic nervous system; 5. The production of Oxygen Free Radicals (ROS) during the aerobic metabolism has important signaling properties but can also produce large damage to several macromolecules; 6. Ultimately, any type of damage triggers an inflammatory response, which in turn diverts energy utilization to the function(s) necessary for or in need of repair. Several biomarkers of the capacity and/or performance of these six systems have been developed over the last few years and some use high throughput assays that allow utilization in epidemiological studies. However, no current study has the broad range of information required to address the multysistem dysregulation hypothesis in an epidemiological setting. Therefore, we have identified several studies that include a subset of these measures that can be used to test one or more partial components of our general hypothesis. By creating a network of collaborations with the research groups conducting these studies, we have gained access to data that complement those that we already collect in the BLSA. In particular, in the context of this project, we intend to use data from: a. The Baltimore Longitudinal Study of Aging b. The InChianti Study c. The SardiNIA study d. The Women's Health and Aging Study e. The Health ABC Study f. The ICare/Dicomano Study g. The ASSI Italian Initiative h. The ILSA Study i. The Il Sirente Study l. The AGES study Collaborations between the LSS and investigators of these studies have been established. Other studies may be added to this initiative, based on opportiniries and needs of the research group. In the intial period of this project, we will test the hypothesis of an indepdent correlation between the different homeostatic domains and their association with geriatric-relevant outcomes, such as morbidity, frailty, disability and mortality. In the second phase, we aim to study the effects on similar outcomes of multiple biomarkers and physiological measures, within a specific domain and across different domains. The second part of this project requires some metodological and statistical development. This methodological component is considered an essential component of the project and will be conducted in collaboration with multiple academic institutions.

该项目测试了这样一种假设，即导致老年人疾病易感性、残疾和虚弱的过程在很大程度上构成了生物机制网络中的渐进式失调和储备能力下降，这些机制相互作用以维持稳定的能量稳态和/或在稳态受到压力事件严重挑战时恢复平衡的能力存在缺陷或不足。构成这些网络的元素没有完全定义，但肯定包括：摄入身体产生能量所需的基本元素，包括营养物质和氧气；2. 影响不同形式能量利用的活动，包括静息代谢率、身体活动、认知活动和营养；3)能量流的神经控制，主要受交感神经系统和副交感神经系统的相互作用影响；4)内分泌系统，它也负责调节能量流的局部区域分布，但比自主神经系统慢；5. 氧自由基（ROS）在有氧代谢过程中的产生具有重要的信号特性，但也会对一些大分子产生较大的损伤；6. 最终，任何类型的损伤都会引发炎症反应，进而将能量利用转移到修复所需或需要修复的功能上。