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

酒精相关性肝病（ALD）是全世界发病和死亡的主要原因。它有一个数组 肝脏病变范围从简单的脂肪肝到更严重的肝损伤，例如脂肪性肝炎， 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）和接触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。现在已经好了—— 记录了酒精引起的肠道微生物群变化和肠道屏障破坏 完整性导致细菌衍生的副产物增加进入门肝 循环在 ALD 进展中起着至关重要的致病作用。在脂肪组织中，慢性乙醇消耗 增强脂肪分解，损害胰岛素激活的葡萄糖摄取，减少保护性脂肪因子的分泌，以及 增强促炎介质的释放，所有这些都有助于 ALD 发病机制。 衰老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。脂肪组织及其成分/也存在与衰老相关的有害变化。 肠道微生物群的稳定性和屏障完整性。老年人中许多与衰老相关的变化类似于 乙醇引起的肝脏、脂肪和肠道器官系统缺陷。 基于这些考虑，我们假设与衰老相关的结构和功能变化 老年受试者的胃肠道、脂肪和肝脏比老年人更快地促进 ALD 进展 较年轻的科目。在这里，我们建议进行深入研究来检验衰老对 ALD 的影响 严重程度。鉴于老年人和全球酗酒现象呈上升趋势，这项研究是有必要的。 老龄化人口规模扩大，预计到 2050 年将翻一番，达到 15 亿以上。 为了检验我们的假设，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， 乙醇喂养的啮齿动物的脂肪和肝脏 具体目标 2：深入了解如何向年老和年幼的动物施用乙醇 相同的持续时间会对老年受试者造成更严重的肝损伤 具体目标 3：识别并分析酒精相关性肝病患者的衰老相关变化 与肝病的严重程度有关

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