Research Review on Aging-Exacerbated Metabolic Dysfunction-Related Lipid Liver Diseases

Academic Background

As the aging population increases, metabolic diseases induced by aging are becoming a severe public health challenge. The liver, being the primary metabolic organ, requires special attention to its functional disorders during aging. Studies have shown that aging can aggravate liver lesions by inducing ferroptosis stress, but the specific molecular mechanisms remain unclear. Therefore, an in-depth exploration of how aging affects liver lesions at the molecular level is crucial for disease prevention and intervention.

Paper Information

This paper was jointly completed by Kuo Du, Liuyang Wang, Ji Hye Jun, Rajesh K. Dutta, Raquel Maeso-Díaz, Seh Hoon Oh, Dennis C. Ko, and Anna Mae Diehl from the Duke University School of Medicine, Department of Molecular Genetics and Microbiology. The research results were published in July 2024 in “Nature Aging” (Volume 4, Pages 949-968), doi: https://doi.org/10.1038/s43587-024-00652-w.

Research Details

Research Process

This research includes the following key steps: 1. Transcriptome analysis of aging liver cells. 2. Defining Aging Hepatocyte Gene Signatures (AHGS). 3. Applying AHGS to analyze human and mouse metabolic function disorder-related liver disease (MASLD) samples. 4. Functional studies: Experimental verification in mouse models.

Subjects and Samples

1. The study used healthy young and elderly male mice.
2. Collected and analyzed liver RNA-seq data from MASLD patients and control groups.

Experimental Methods

1. Liver cells were isolated from young and old mice livers for RNA sequencing.
2. Constructed the Aging Hepatocyte Gene Signatures.
3. Used AHGS to analyze MASLD transcriptome datasets of humans and mice.
4. Verified high-fat diet-induced MASLD in mouse models.

Data Analysis Algorithms

1. DESeq2 was used to identify differentially expressed genes.
2. Gene Set Enrichment Analysis (GSEA) was used to analyze gene expression patterns.

Research Results

Main Findings

The study revealed that with aging, gene expressions promoting degeneration increased in mouse liver cells, while expressions of longevity-related genes decreased.

Conclusion and Significance

The study found that under metabolic stress diets, the degree of ferroptosis and liver degradation in elderly mice exceeded that in young mice. By inhibiting ferroptosis, the transcriptome of elderly mice livers could be shifted towards the state of young mice livers, reversing the aging-exacerbated liver damage. Ferroptosis was identified as a controllable shared mechanism of aging-related tissue degeneration.

Highlights

1. Defined the Aging Hepatocyte Gene Signatures (AHGS) and demonstrated their enrichment in diseased livers, linking to multi-organ degeneration.
2. Verified that ferroptosis is a key driver of aging-related tissue degeneration.
3. Found that inhibiting ferroptosis can reverse liver damage in elderly mice and improve liver function.

Additional Information

The analysis in this study is not limited to the liver; AHGS was also found to be enriched in aging heart, kidney, and islet cells, suggesting that the metabolic stress mechanism carried by aging may be shared across multiple organs.

Summary

This study provides new perspectives and potential strategies for understanding and treating MASLD and other aging-related diseases, particularly showing that therapies inhibiting ferroptosis could extend the healthy lifespan of elderly livers and possibly overall systemic health.