Unveiling the Role of Age in MASLD Progression and Biological Process Activation: Implications for Translational Research

Middle-aged males developed insulin resistance and more severe hepatic injury than young males after HFD. NAFLD Activity Score confirmed more advanced disease in middle-aged mice, with extensive lipid accumulation, hepatocellular hypertrophy, inflammation and fibrosis. Females showed milder hepatic damage.

Diet was the main determinant of transcriptomic changes in males, with young HFD mice activating tissue remodeling pathways and middle-aged mice showing inflammatory activation and reduced energy metabolism. In females, transcriptomic responses were attenuated, with metabolic and stress-related changes restricted largely to young HFD animals. MHPS ranked the middle-aged male model highest in translational similarity to human MASLD.These findings highlight that age is a primary 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.