Abstract
Aging is a critical factor influencing susceptibility to hepatic injury. In this study, the spontaneous development of liver injury with advancing age and potential sex-related differences in these processes are examined. This study focuses on key mechanisms such as fatty acid metabolism, immune response, and cellular stress in male and female C57BL/6 mice. Aged male and female mice (20 to 22 months old) exhibited higher body weight and an altered metabolic profile and fatty acid metabolism compared to their younger counterparts (8 to 10 weeks old). In addition, increased oxidative stress, cellular senescence, expression of inflammatory markers, and cytokines/chemokines levels were also observed in aged male and female mice compared to younger mice. Furthermore, the aged mice exhibited increased indices of hepatic fibrosis, evident from the upregulation of smooth muscle actin-α, collagen, and transforming growth factor-β. In conclusion, aging promotes spontaneous liver injury by increasing indices of oxidative stress, steatosis, inflammation, and fibrosis. These results highlight the impact of chronological age on the liver that can increase its susceptibility to secondary hepatic stressors such as alcohol, high-calorie diet, or hepatotropic infections. Understanding how metabolic and inflammatory pathways change with aging in males and females is essential for elucidating the mechanisms that drive chronic liver disease progression. These insights are particularly important for developing targeted, sex-specific prevention and therapeutic strategies for the aging population.