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

> **NIH NIH P50** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $241,763

## Abstract

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

## Key facts

- **NIH application ID:** 10797030
- **Project number:** 5P50AA030407-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Kusum K. Kharbanda
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $241,763
- **Award type:** 5
- **Project period:** 2023-02-28 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797030

## Citation

> US National Institutes of Health, RePORTER application 10797030, Development and Progression of Alcohol-Associated Liver Disease: Effect of Aging (5P50AA030407-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10797030. Licensed CC0.

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