Long-term impact of caloric restriction on liver health and cell survival in a mouse model

Objective : This study investigated the effects of chronic and intermittent caloric restriction (CR) on apoptotic and anti-apoptotic signaling in the liver of aging male C57BL/6 mice. Methods : A total of 97 mice were assigned to Baseline, Ad Libitum (AL), Chronic Caloric Restriction (CCR; 25% restriction), and Intermittent Caloric Restriction (ICR; alternating 3-week periods of AL feeding and 50% restriction) groups. Liver tissue samples were collected at predefined time points, and BCL-2 and caspase-3 immunoreactivity in hepatocytes and Kupffer cells was evaluated immunohistochemically using a semi-quantitative H-score (0–300). Group differences were analyzed using ANOVA, Kruskal–Wallis, or Mann–Whitney U tests as appropriate. Results : At 49 weeks, hepatocyte caspase-3 expression was significantly higher in CCR and ICR-RF than in AL (Kruskal–Wallis, p=0.0023; adjusted p=0.0096 and p=0.0151, respectively), whereas no significant differences were observed at 85 weeks (p=0.34). At 85 weeks, Kupffer-cell BCL-2 expression was significantly higher in CCR than in AL and ICR-RF (ANOVA, p<0.001), and ICR-RF was also higher than AL. Conclusion : CR modulates hepatic apoptotic and anti-apoptotic signaling in an age- and regimen-dependent manner, with distinct responses in hepatocytes and Kupffer cells. Innovation : This study provides a cell-specific comparison of chronic and intermittent CR across different stages of aging. These findings provide a basis for understanding how different CR regimens may influence hepatic cellular adaptation during aging and support further studies evaluating their relevance to age-related liver health.