Biomarkers of Homeostatic 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: 10012633
• 负责人: Luigi Ferrucci
• 金额: $ 9.85万
• 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/10012633
• 关键词: Address; Adult; Affect; Age; Aging; Anatomy; 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; Epidemiology; Equilibrium; Etiology; Evolution; Feedback; Generations; Health; Homeostasis; Hormones; Immune system; Impairment; Inflammatory; Inflammatory Response; Institution; Intake; Joints; Longitudinal Studies; Measures; Methodology; 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; epidemiology study; frailty; free radical oxygen; high throughput screening; improved; macromolecule; mortality; nutrition; programs; repaired; somatosensory

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 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 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 several 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 opportunities and needs of the research group. In the intial period of this project, we continue to test the hypothesis of an independent 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 are studying 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 methodological 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渐进性的失调和储备能力的降低，这些生物机制相互作用以维持稳定的能量稳态和/或当稳态受到应激事件的严重挑战时恢复平衡的能力的缺陷或不足。组成这些网络的元素没有完全定义，但肯定包括：1.身体产生能量所需的基本元素的摄取，包括营养和氧气；2.影响不同形式能量利用的活动，包括静息代谢率、体力活动、认知活动和营养；3.对能量流的神经控制，主要受交感神经系统和副交感神经系统之间的相互作用影响；4.内分泌系统，它也负责调节能量流的局部分布，但比自主神经系统起作用更慢；5.有氧代谢过程中产生的氧自由基(ROS)具有重要的信号特性，但也能对几种大分子产生较大的损伤；6.归根结底，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必需或需要修复的功能上(S)。 这六个系统的能力和/或性能的几个生物标记物是在过去几年中开发的，其中一些使用了高通量分析，以便在流行病学研究中使用。然而，目前还没有一项研究拥有在流行病学背景下解决多干失调假说所需的广泛信息。因此，我们已经确定了几项研究，这些研究包括这些测量的子集，可以用于测试我们一般假设的一个或多个部分组件。通过与进行这些研究的研究小组建立合作网络，我们获得了补充我们已经在BLSA收集的数据的机会。 特别是，在这个项目的背景下，我们打算使用来自以下方面的数据： A.巴尔的摩老龄化纵向研究 B.Inchanti研究 C.撒丁岛研究 D.妇女健康与老龄化研究 E.健康ABC研究 F.ICARE/Dicomano研究 G.意大利ASSI倡议 H.伊尔萨研究 I.Il Sirente研究 L。时代研究 LSS和这些研究的调查人员之间的合作已经建立。根据研究小组的机会和需求，可能会在这一倡议中增加其他研究。 在这个项目的初始阶段，我们继续测试不同的稳态区域之间的独立相关性的假设，以及它们与老年相关结果的关联，如发病率、虚弱、残疾和死亡率。在第二阶段，我们正在研究多个生物标志物和生理措施在特定领域内和不同领域之间对相似结果的影响。这个项目的第二部分需要一些方法和统计方面的发展。这一方法部分被认为是该项目的重要组成部分，将与多个学术机构合作进行。