Biomarkers of Homestatic Dysregulation in Aging and Chronic Disease

该项目检验了一个假设，即导致老年人疾病易感性、残疾和虚弱的过程主要与生物机制网络的进行性失调和减少研究有关，这些生物机制相互作用，以维持稳定的能量稳态，或在稳态受到压力事件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。摄入身体需要的基本元素来创造能量，包括营养素和氧气; 2.影响不同形式的能量利用的活动，包括静息代谢率、体力活动、认知活动和营养; 3）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。这是调节系统，是在变化的快速调整，如那些发生在温度的快速变化，或出血后; 4）内分泌系统，这也是负责调节局部分布的能量流，但行动更慢比ANS; 5.有氧代谢过程中产生的氧自由基（ROS）具有重要的信号传导功能，但也会对各种大分子产生较大的损伤。因此，生物体阐述了不同的机制来抑制ROS并降低其毒性。当能量流动减少或加速时，ROS的产生往往会增加，如果没有被抗氧化系统完全缓冲，可能会造成严重的损害;最终，任何类型的损伤都会引发炎症反应，这反过来会导致生物体将能量利用与应该对抗宿主的“侵略”的功能分离。 在过去的几年中，已经开发了这6种系统的生物标志物，其中一些使用高通量测定，使其能够用于流行病学研究。然而，目前还没有一项研究具有广泛的信息来解决流行病学背景下的多系统失调假说。因此，我们已经确定了一些研究，其中一些信息可用，可以用来测试我们的一般假设的一个或多个部分组成部分。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中收集的数据的数据。 特别是，在本项目中，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. InChianti研究 C. Sardinia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. ASSI意大利倡议 H. ILSA研究 I. Sirente研究 L.年龄研究。 LSS和这些研究的调查人员之间已经建立了合作关系。根据研究小组的机会和需要，可将其他研究纳入这一举措。 在本项目的初期，我们将检验不同稳态域之间独立相关的单变量假设及其与老年相关结果（如发病率、虚弱、残疾和死亡率）的关系。在该项目的第二阶段，我们将尝试研究在特定领域内和跨不同领域的多种生物标志物和生理指标对结果的影响。该项目的第二部分需要在方法学和统计学方面有所发展。这一方法构成部分被认为是该项目的一个重要组成部分，将与多个学术机构合作进行。

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.