Translational Studies of Age-Associated Arterial Dysfunction, Western Diet and Aerobic Exercise: Role of the Gut Microbiome

项目摘要 年龄相关性动脉功能障碍是心血管疾病(CVD)的主要危险因素。最近，我们有 在小鼠身上进行了短期和终生研究，以确定西式饮食(WD；高脂肪和高糖， 低纤维和低营养密度)和有氧运动(EX)这两种常见的生活方式因素与衰老相互作用 影响大弹性动脉内皮功能障碍和硬化。我们发现WD加速，并且 EX通过氧化应激和炎症的变化来预防动脉老化的这些关键特征。 肠道微生物群是宿主新陈代谢健康和炎症的强大调节器，受 年龄、饮食和性别，但在这些或其他环境下，没有关于它对动脉功能影响的信息。 我们的综合假设是肠道微生物群的失调(肠道生物失调)与初级衰老有关 和WD的消耗，再加上肠道通透性的增加，使肠道衍生的颗粒泄漏 进入循环，可能通过改变不利的肠源性代谢物来损害动脉功能，如 动脉粥样硬化相关的三甲胺-N-氧化物(TMAO)和刺激Toll样受体4诱导的前 炎症信号，而慢性有氧运动可以保护身体免受这些影响。 这项应用的目的是确定肠道微生物群在影响中的潜在因果作用。 衰老、WD和EX对动脉功能的影响，并深入了解潜在的代谢和炎症 机械装置。我们将采用3种高度创新、互为补充的翻译方法： 1.使我们能够辨别因果关系的小鼠研究：a)通过评估动脉功能与年龄±WD 在肠道微生物组和相关信号存在与不存在的情况下；以及b)通过确定血管 与衰老、WD和EX相关的表型可以通过肠道微生物群转移。我们还将探索 使用药物抑制和/或敲除可疑途径的可能机制。 2.评估饮食(WD与非WD)诱导的时间进程(时间关联)的人体研究 运动和非运动健康青年和老年人肠道微生物群与动脉功能的变化 成人，采用随机、单盲、受控喂养的交叉研究设计。 3.结合老鼠和人类的研究，使用“人性化”的老鼠来确定这些特征是否 随着年龄、WD和EX出现在人类肠道微生物群中，可以预见地影响动脉功能。 这些研究不仅将确定肠道微生物的存在和相对丰度随着年龄的变化， WD和EX，以及这些变化的功能影响，使我们能够对角色有新的见解 肠道微生物群在调节血管功能与衰老和这些常见生活方式中的作用 影响。预期的结果有可能建立肠道微生物群作为关键机制和 年龄相关性动脉功能障碍的治疗目标，并确定生活方式或药物策略 这可能会保护微生物健康，增强动脉功能，降低与年龄相关的心血管疾病的风险。

Project Summary Age-related arterial dysfunction is the main risk factor for cardiovascular diseases (CVD). Recently, we have used short-term and lifelong studies in mice to determine how a Western-style diet (WD; high fat and sugar, low fiber and nutrient density) and aerobic exercise (EX), common lifestyle factors, interact with aging to influence endothelial dysfunction and stiffening of the large elastic arteries. We found that WD accelerates, and EX prevents, these key features of arterial aging via changes in oxidative stress and inflammation. The gut microbiome is a strong modulator of host metabolic health and inflammation that is influenced by age, diet and EX, but there is no information about its effects on arterial function in these or other settings. Our integrative hypothesis is that dysregulation of the gut microbiome (gut dysbiosis) with primary aging and WD consumption, coupled with increased intestinal permeability that allows gut-derived particles to leak into circulation, may act to impair arterial function via changes to adverse gut-derived metabolites such as atherosclerosis-linked trimethylamine-N-oxide (TMAO), and stimulation of toll-like receptor 4-induced pro- inflammatory signaling, whereas chronic aerobic exercise protects against these effects. The purpose of this application is to determine the potential causal role of the gut microbiome in the effects of aging, WD and EX on arterial function, and gain insight into the underlying metabolomic and inflammatory mechanisms. We will employ 3 highly innovative, complementary translational approaches: 1. Mouse studies that allow us to discern cause-and-effect: a) by assessing arterial function with aging ± WD in the presence vs. absence of the gut microbiome and associated signaling; and b) by determining if vascular phenotypes associated with aging, WD and EX can be transferred via the gut microbiome. We also will explore possible mechanisms using pharmacological inhibition and/or knock-out of suspected pathways. 2. Human studies assessing the time course (temporal associations) of diet (WD vs. non-WD)-induced changes in the gut microbiome vs. arterial function in young and older exercising and non-exercising healthy adults, using a randomized, single-blind, controlled feeding crossover study design. 3. Combined mouse/human studies employing “humanized” mice to determine if the characteristics present in the human gut microbiome with age, WD and EX predictably influence arterial function. These studies will determine not only changes to gut microbe presence and relative abundance with aging, WD and EX, but also the functional effects of those changes, allowing us to gain novel insight into the role of the gut microbiome in modulating vascular function with aging and these common lifestyle influences. The expected results have the potential to establish the gut microbiome as a key mechanism and therapeutic target for age-related arterial dysfunction, and to identify lifestyle or pharmacological strategies that may preserve microbial health, enhance arterial function and reduce the risk of age-related CVD.