In vivo and in vitro systems to validate geronic proteins and their mechanisms of action

与衰老相关的迟发性慢性疾病，包括心血管疾病、阿尔茨海默病和 帕金森氏病、糖尿病和组织恶性肿瘤是发病率和死亡率的主要原因 给个人和社会造成最大的情感和经济负担。随着人口老龄 随着疾病的不断扩大，迟发性慢性病将进一步主导生物医学的关注。我们 一直在研究大脑回路和体液因素在健康和衰老中的作用。我们已经确定 下丘脑作为中枢神经系统和外周组织通讯的交叉点，定义血清 在年轻和年老的动物中差异表达的蛋白质，并认为心血管健康是一个主要的 寿命的决定因素。我们和其他人已经确定，下丘脑神经元感觉到变化， 外周环境，并发出信号控制复杂的行为和器官系统和外周 组织功能我们的初步数据和其他人的工作确定了相同的下丘脑回路， 控制老化过程。例如，我们发现控制饥饿的下丘脑神经元 对生存和寿命的重大影响。我们还发现，这些神经元介导的行动， 外周激素与热量限制对延长寿命的影响有关。我们假设， 至少介导了循环老年物质对年龄相关的中枢和外周过程的作用， 部分是由下丘脑控制的。我们将在具体目标1中使用小鼠模型来询问这个问题。我们 将分析控制和实验中的复杂行为，心脏，肌肉，骨骼和免疫功能 动物，包括处于联体共生状态的不同年龄和基因型的动物。从一个翻译 因此，在高等物种中证实老年肽的存在和相关性是至关重要的 例如灵长类动物，包括人类。为了解决这个问题，我们分析了年轻人的血浆， 和年老的灵长类动物蛋白质组学分析确定了灵长类动物中的候选分子， 在老鼠身上被发现。在具体目标2中，我们建议利用我们新建立的高通量体外 系统，以评估在我们的筛选中确定的假定老年靶点的细胞效应， 灵长类成纤维细胞我们将重点关注与衰老细胞相关的细胞内事件。具体目标 3.我们将测试灵长类动物，以评估对CNS和心血管系统的抗衰老和促衰老干预。 我们将分析年轻和老年动物血浆治疗的效果，已知的抗衰老和促衰老作用。 肽和那些新定义的在体内分析的认知脑功能的青年，中年和 古老的灵长类动物总的来说，执行我们的目标将提供有关机制的新见解， 老年物质的作用，新的循环老年分子，并利用强大的测试系统， 他们自己与其他项目和研究人员的合作以及定义生物学的进步， 临床相关应用。

Late onset chronic diseases associated with aging, including cardiovascular disorders, Alzheimer's and Parkinson's disease, diabetes and tissue malignancies, are the leading causes of morbidity and mortality creating the greatest emotional and financial burden on the individual and society. As the aging population continues to expand, late onset chronic diseases will further dominate the attention of biomedicine. We have been pursuing the role of the brain circuits and humoral factors in health and aging. We have identified the hypothalamus as an intersection point between CNS and peripheral tissue communications, defined serum proteins differentially expressed in young and old animals, and recognized cardiovascular health as a principal determinant of lifespan. We and others have established that hypothalamic neurons sense the changing peripheral milieu and also send out signals to control complex behaviors and organ system and peripheral tissue functions. Our preliminary data and the work of others identified the same hypothalamic circuits to control the aging process. For example, we found that neurons of the hypothalamus that control hunger have significant impact on survival and lifespan. We also identified that these neurons mediate the action of peripheral hormones implicated in the lifespan extending impact of calorie restriction. We hypothesize, that action of circulating geronic substances on age related central and peripheral processes are mediated, at least in part, by the hypothalamus. We will interrogate this question using mouse models in Specific Aim 1. We will analyze complex behaviors, cardiac, muscle, bone and immune functions in control and experimental animals, including animals with different age and genotype in a state of parabiosis. From a translational perspective, it is crucial that the presence and relevance of geronic peptides are confirmed in higher species such as primates, including humans. In an effort to address this issue, we have analyzed plasma from young and aged nonhuman primates. Proteomics analysis identified candidate molecules in primates that have not been identified in mice. In Specific Aim 2, we propose to utilize our newly established, high throughput in vitro system to assess the cellular effects of putative geronic targets identified in our screen using nonhuman primate fibroblasts. We will focus on intracellular events that are associated with aging cells. In Specific Aim 3, we will test primates to evaluate anti- and pro-geronic interventions on CNS and cardiovascular systems. We will analyze the effects of young and aged plasma treatment of animals, known anti- and pro-geronic peptides and those newly defined by in vivo analyses on cognitive brain functions of young, middle aged and old nonhuman primates. Overall, execution of our aims will deliver new insights regarding the mechanisms of action of geronic substances, new circulating geronic molecules and exploit robust test systems that will lend themselves for collaborative work with other projects and investigators and the advance of defined biology to clinically relevant application.