Suppression of FOXO1 attenuates inflamm‐aging and improves liver function during aging

The liver is a key metabolic organ that maintains whole‐body nutrient homeostasis. Aging‐induced liver function alterations contribute to systemic susceptibility to aging‐related diseases. However, the molecular mechanisms of liver aging remain insufficiently understood. In this study, we performed bulk RNA‐Seq and single‐cell RNA‐Seq analyses to investigate the underlying mechanisms of the aging‐induced liver function changes. We found that liver inflammation, glucose intolerance, and liver fat deposition were aggravated in old mice. Aging significantly increased pro‐inflammation in hepatic macrophages. Furthermore, we found that Kupffer cells (KCs) were the major driver to induce pro‐inflammation in hepatic macrophages during aging. In KCs, aging significantly increased pro‐inflammatory levels; in monocyte‐derived macrophages (MDMs), aging had a limited effect on pro‐inflammation but led to a functional quiescence in antigen presentation and phagosome process. In addition, we identified an aging‐responsive KC‐specific (ARKC) gene set that potentially mediates aging‐induced pro‐inflammation in KCs. Interestingly, FOXO1 activity was significantly increased in the liver of old mice. FOXO1 inhibition by AS1842856 significantly alleviated glucose intolerance, hepatic steatosis, and systemic inflammation in old mice. FOXO1 inhibition significantly attenuated aging‐induced pro‐inflammation in KCs partially through downregulation of ARKC genes. However, FOXO1 inhibition had a limited effect on aging‐induced functional quiescence in MDMs. These results indicate that aging induces pro‐inflammation in liver mainly through targeting KCs and FOXO1 is a key player in aging‐induced pro‐inflammation in KCs. Thus, FOXO1 could be a potential therapeutic target for the treatment of age‐associated chronic diseases.