Development and Progression of Alcohol-Associated Liver Disease: Effect of Aging

酒精相关性肝病（ALD）是全球发病率和死亡率的主要原因。它有一系列 从简单的脂肪肝到更严重形式的肝损伤如脂肪性肝炎的肝脏病理， 肝硬化和肝细胞癌许多肝外因素包括遗传、性别、生活方式（饮食 和运动）和暴露于病毒感染决定了疾病的表型和结果。同样 在ALD发病机制和进展中重要的是其他器官的相关功能障碍。它现在很好- 记录了酒精引起的肠道菌群变化和肠道屏障破坏 完整性，导致细菌衍生的副产物向门-肝转移的增加 循环在ALD进展中起关键的致病作用。在脂肪组织中，慢性乙醇消耗 增强脂解，损害胰岛素活化的葡萄糖摄取，减少保护性脂肪因子的分泌，和 增强促炎介质的释放，所有这些都有助于ALD发病机制。 老龄化是发展为晚期慢性肝病的主要危险因素。新出现的证据 表明高龄与肝脏结构的改变和细胞损伤有关。 功能协调发展的在脂肪组织以及组成中也存在与衰老相关的有害变化。 肠道微生物群稳定性和屏障完整性。老年人中许多与衰老有关的变化类似于 乙醇诱导的肝脏、脂肪和肠道器官系统缺陷。 基于这些考虑，我们假设，衰老相关的结构和功能的变化， 胃肠道，脂肪和肝脏在老年受试者中促进ALD的进展比在老年受试者中更快。 年轻的科目。在这里，我们建议进行深入的研究，以检查老化对ALD的影响 严重性。鉴于老年人和全球人口中大量饮酒的上升趋势，这项研究是有必要的。 老龄化人口的扩大，预计到2050年将翻一番，超过15亿人。 为了验证我们的假设，我们提出以下具体目标： 具体目标1：检查胃肠道中与衰老相关的结构和功能变化， 乙醇喂养啮齿动物的脂肪和肝脏 具体目标2：获得对老年和年轻动物乙醇给药的机制性见解， 相同的持续时间在老年受试者中产生更严重的肝损伤 具体目标3：识别和分析酒精相关性肝病患者的衰老相关变化 与肝脏疾病的严重程度有关

Alcohol-associated liver disease (ALD) is a major cause of morbidity and mortality worldwide. It has an array of liver pathologies that ranges from simple fatty liver to more severe forms of liver injury such as steatohepatitis, cirrhosis, and hepatocellular carcinoma. Many extrahepatic factors including genetics, gender, lifestyle (diet and exercise) and exposures to viral infections determine the disease phenotype and outcome. Equally important in ALD pathogenesis and progression is the associated dysfunction of other organs. It is now well- documented that the alcohol-induced changes in the gut microbiota and disruption of the intestinal barrier integrity resulting in the increased translocation of bacterial-derived byproducts into the portal-hepatic circulation plays a crucial pathogenic role in ALD progression. In adipose tissue, chronic ethanol consumption enhances lipolysis, impairs insulin-activated glucose uptake, reduces secretion of protective adipokines, and enhances release of pro-inflammatory mediators, all of which contribute to ALD pathogenesis. Aging is a predominant risk factor for the development of advanced chronic liver diseases. Emerging evidence indicates that advanced age is associated with alterations to the hepatic structure and impairment of cellular functions. There are also aging-related detrimental changes in adipose tissue as well as in the composition/ stability of gut microbiota and barrier integrity. Many of these aging-related alterations in the elderly resemble ethanol-induced defects in the liver, adipose and gut organ systems. Based on these considerations we hypothesize that aging-related structural and functional changes in the gastrointestinal tract, adipose and liver in older subjects promote a faster progression of ALD than in younger subjects. Here, we propose to conduct an in-depth study to examine the effect of aging on ALD severity. This study is warranted given the upward trend for heavy drinking among the elderly and the global expansion in the aging population which is predicted to double to over 1.5 billion persons by 2050. To test our hypothesis, we propose the following Specific Aims: Specific Aim 1: Examine the aging-related structural and functional changes in the gastrointestinal tract, adipose and liver of ethanol-fed rodents Specific Aim 2: Gain mechanistic insight into how ethanol administration to older and younger animals for the same duration generates more severe liver injury in older subjects Specific Aim 3: Identify and analyze aging-related changes in patients with alcohol-associated liver disease in relation to the severity of liver disease