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: 7732388
• 负责人: Luigi Ferrucci
• 金额: $ 8.94万
• 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/7732388
• 关键词: Accounting; Address; Affect; Age; Aggressive behavior; Aging; Aging-Related Process; Antioxidants; Autonomic nervous system; Baltimore; Basal metabolic rate; Biological; Biological Markers; Buffers; Cell Respiration; Charge; Chronic; Chronic Disease; Clinic; Clinical; Clinical Research; Cognitive; Collaborations; Complement; Data; Deterioration; Development; Disease susceptibility; Elderly; Elements; Endocrine system; Energy Metabolism; Environment; Epidemiologic Studies; Equilibrium; Evolution; Feedback; Generations; Health; Hemorrhage; Homeostasis; Hormones; Immune system; Impairment; Inflammatory; Inflammatory Response; Institution; Intake; Joints; Left; Longitudinal Studies; Measures; Modeling; Morbidity - disease rate; Motivation; Motor; Muscle; Neurologic; Numbers; Nutrient; Organism; Outcome; Outpatients; Oxidative Stress; Oxygen; Parasympathetic Nervous System; Pathway interactions; Patients; Peripheral Nervous System; Phase; Physical Function; Physical activity; Physiological; Population; Process; Production; Property; Range; Reactive Oxygen Species; Research; Research Personnel; Sardinia; Scientist; Signal Transduction; Sorting - Cell Movement; Stress; Stressful Event; System; Temperature; Testing; Toxic effect; Women' s Health; base; bone; disability; fighting; frailty; free radical oxygen; high throughput screening; macromolecule; mortality; nutrition; programs; sensory system

This project tests the hypothesis that the process that leads to disease susceptibility, disability and frailty in older persons is mostly connected with a progressive dysregulation and reduced researve in the network of biological mechanisms that interact to amintain a stable energetic homeostasis, or to regain some equilibrium when the homestasis is critically challenged by a stressful event. The elements of these network are not completely defined but certainly include: 1. Intake of the essential elements that the body requires to create energy, including both the 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 system. THis is the regulatory system that is in change of rapid adjustments, such as those that occur with rapid changes in temperature, or after bleeding; 4) The endocrine system , which is also in charge of modulating the locoregional distribution of energy flow, but acts more slowly than the ANS; 5. The production of Oxygen Free Radicals (ROS) during the aerobic metabolism has important signaling properties but can also produce large damage to all sort of macromolecules. Therefore, organism have elaborated different mechanism to scavenge ROS and reduce their toxicity. When the flow of energy is reduced or accelerated, the production of ROS tend to increase and if not completely buffered by antioxidant system, can cause severe damage; 6. Ultimately, any type of damage triggers an inflammatory response, which is turn causes the organism to segregate the energy utilization to the function that are supposed to fight the "aggression" to the host. Biomarkers for these 6 systems have been developed over the last few years and some of them use high throughput assays that allow their 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 a number of studies that have some of these information available and that can be used to test one or more partial components of our general hypothesis. By creating a network of collaboration with the research groups that are conducting those studies, we have gained access to data that complement those that we are already collecting 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 the investigators of these studies have been already established. Other studies could be included in this initiative, based on opportiniries and needs of the research group. In the intial period of this project, we will test univariate hypothesis of an indepdent correlation between the different homeostatic domain and their association with geriatric-relevant outcomes, such as morbidity, frailty, disabilitya nd mortality. In thes econd phase of this project, we will attempt to study the effect on outcome 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.

该项目测试了一种假设，即导致老年人疾病易感性、残疾和虚弱的过程主要与渐进性调节失调和生物机制网络中的研究减少有关，这些生物机制相互作用以确保稳定的能量稳态，或在家庭受到应激事件的严重挑战时恢复某种平衡。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)对能量流动的神经控制，主要受交感神经系统和副交感神经系统之间相互作用的影响。这是处于快速调整中的调节系统，例如在温度快速变化时或在出血后发生的那些；4)内分泌系统，它也负责调节能量流的局部区域分布，但作用比ANS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，但也可以对各种大分子产生巨大的损害。因此，生物体阐述了不同的清除ROS和降低其毒性的机制。当能量流动减少或加速时，ROS的产生往往会增加，如果没有完全被抗氧化系统缓冲，就会造成严重的损害；6.最终，任何类型的损害都会触发炎症反应，进而导致生物体将能量利用与本应对抗对宿主的“攻击”的功能分开。 这6个系统的生物标志物是在过去几年中开发的，其中一些使用了高通量分析，使其能够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，我们已经确定了一些研究，这些研究拥有一些可用的信息，可以用来测试我们一般假设的一个或多个部分成分。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。时代的学习。 LSS和这些研究的调查人员之间的合作已经建立。可根据研究小组的意见和需要，将其他研究纳入这一倡议。 在这个项目的初始阶段，我们将测试单变量假说，即不同的动态域之间的独立相关性及其与老年相关结果的关联，如发病率、虚弱、残疾和死亡率。在这个项目的第二阶段，我们将尝试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结果的影响。这个项目的第二部分需要一些计量学和统计学的发展。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。

项目成果

Throwing pots and commitments for 2008.

2008 年的投掷和承诺。

• DOI: 10.1093/gerona/63.2.157
• 发表时间: 2008
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Ferrucci,Luigi

Sex hormone binding globulin levels across the adult lifespan in women--the role of body mass index and fasting insulin.

• DOI: 10.1007/bf03345608
• 发表时间: 2008-07
• 期刊: Journal of endocrinological investigation
• 影响因子: 5.4
• 作者: Maggio M;Lauretani F;Basaria S;Ceda GP;Bandinelli S;Metter EJ;Bos AJ;Ruggiero C;Ceresini G;Paolisso G;Artoni A;Valenti G;Guralnik JM;Ferrucci L
• 通讯作者: Ferrucci L

High-density lipoprotein cholesterol and objective measures of lower extremity performance in older nondisabled persons: the InChianti study.

高密度脂蛋白胆固醇和老年非残疾人下肢性能的客观测量：InChianti 研究。

• DOI: 10.1111/j.1532-5415.2007.01608.x
• 发表时间: 2008
• 期刊: Journal of the American Geriatrics Society
• 影响因子: 6.3
• 作者: Volpato,Stefano;Ble,Alessandro;Metter,EJeffrey;Lauretani,Fulvio;Bandinelli,Stefania;Zuliani,Giovanni;Fellin,Renato;Ferrucci,Luigi;Guralnik,JackM
• 通讯作者: Guralnik,JackM