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Unveiling the role of age in MASLD development and biological process activation: Implications for translational
Lucía Lameroli Mauriz1,2, Andrea Scelza-Figueredo3,4, Miranda Sol Orellano4
1Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET - Universidad Austral, Pilar, Argentina.
Abstract:
Age is a risk factor for severity and progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), yet its specific contributions to liver injury and molecular alterations remain unclear. Current animal models often overlook this variable. This study investigates how aging influences MASLD progression in a murine model, focusing on histological, biochemical, and transcriptomic differences. Young (2-month-old) and middle-aged (10-month-old) C57BL/6N male and female mice were fed chow (CD) or high-fat diet (HFD) for 20 weeks. Metabolic and biochemical parameters were assessed, and liver tissue analyzed by histology and RNA sequencing. Differentially expressed genes were identified with Limma, followed by gene ontolgy enrichment. Translational relevance was evaluated using the MASLD Human Proximity Score (MHPS). Middle-aged males developed insulin resistance and more severe hepatic injury than young males after HFD. Histological and biochemical assessments confirmed advanced disease in middle-aged mice, with extensive lipid accumulation, hepatocellular hypertrophy, inflammation and fibrosis. Females showed milder damage. Diet was the main determinant of transcriptomic changes in males: young HFD mice activated tissue remodeling pathways, whereas middle-aged mice showed inflammatory activation and reduced energy metabolism. In females, transcriptomic responses were attenuated, with metabolic and stress-related changes restricted mostly to young HFD animals. MHPS ranked the middle-aged male model highest in similarity to human MASLD. Age is a critical determinant of hepatic responses to dietary stress, with sex-specific modulation. The middle-aged male model closely mirrors human MASLD, providing a more relevant preclinical platform to improve patient stratification and therapeutic discovery.
Insights
Aging significantly worsens Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in male mice, increasing liver injury and inflammation. Middle-aged male models best represent human MASLD, aiding therapeutic discovery.
Area of Science:
- Hepatology
- Aging Research
- Translational Medicine
Background:
- Age is a known risk factor for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) severity.
- The specific impact of aging on MASLD progression and molecular changes is not well understood.
- Existing animal models often do not account for age-related differences.
Purpose of the Study:
- To investigate the influence of aging on MASLD progression in a murine model.
- To analyze histological, biochemical, and transcriptomic differences between young and middle-aged mice with MASLD.
- To assess the translational relevance of aged models for human MASLD.
Main Methods:
- Comparison of young (2-month) and middle-aged (10-month) male and female C57BL/6N mice fed chow or high-fat diet (HFD) for 20 weeks.
- Assessment of metabolic and biochemical parameters, liver histology, and RNA sequencing.
- Differential gene expression analysis (Limma) and gene ontology enrichment.
- Evaluation of translational relevance using the MASLD Human Proximity Score (MHPS).
Main Results:
- Middle-aged male mice on HFD exhibited insulin resistance and more severe hepatic injury, including lipid accumulation, hypertrophy, inflammation, and fibrosis, compared to young males.
- Transcriptomic analysis in males revealed diet-driven changes: young mice showed tissue remodeling, while middle-aged mice displayed inflammation and reduced energy metabolism.
- Female mice showed milder MASLD progression and attenuated transcriptomic responses.
- The middle-aged male model demonstrated the highest MHPS, indicating strong similarity to human MASLD.
Conclusions:
- Age is a critical factor influencing hepatic responses to dietary challenges, with sex-specific effects.
- The middle-aged male mouse model provides a more accurate preclinical platform for studying human MASLD.
- This aged model can enhance patient stratification and accelerate the discovery of novel therapeutics for MASLD.
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