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

酒精相关性肝病(ALD)是世界范围内发病率和死亡率的主要原因。它有一组 从单纯性脂肪肝到脂肪性肝炎等更严重的肝损伤的肝脏病理， 肝硬变和肝细胞癌。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 其他器官的相关功能障碍在ALD的发生和发展中起重要作用。现在是很好的- 研究证明，酒精导致肠道微生物区系的变化和肠道屏障的破坏 完整性导致细菌衍生的副产物更多地转移到门静脉-肝脏 循环在ALD的进展中起着重要的致病作用。在脂肪组织中，慢性酒精消费 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 促进促炎介质的释放，所有这些都参与了ALD的发病。 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 提示高龄与肝脏结构改变和细胞损伤有关。 功能。也有与衰老有关的脂肪组织和成分的有害变化。 肠道微生物区系的稳定性和屏障的完整性。老年人中的许多与衰老相关的变化类似于 酒精引起的肝脏、脂肪和肠道器官系统的缺陷。 基于这些考虑，我们假设与衰老相关的结构和功能变化 老年人的胃肠道、脂肪和肝脏促进ALD的进展快于老年人 年轻的受试者。在这里，我们建议进行一项深入的研究，以检验衰老对ALD的影响 严肃性。鉴于老年人和全球酗酒者酗酒的上升趋势，这项研究是有必要的 老龄化人口的扩张，预计到2050年将翻一番，超过15亿人。 为了验证我们的假设，我们提出了以下具体目标： 具体目标1：检查与衰老有关的胃肠道的结构和功能变化， 酒精喂养啮齿类动物的脂肪和肝脏 具体目标2：获得对年长的和年轻的动物如何使用乙醇的机械性见解 同样的持续时间在老年人中会产生更严重的肝脏损伤 具体目标3：识别和分析酒精相关性肝病患者的增龄相关变化 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