Prolonged oxidative stress and delayed tissue repair exacerbate acetaminophen-induced liver injury in aged mice

The liver gradually loses its regenerative capabilities with aging. However, it remains unknown whether aging affects drug-induced liver injury. Here, we used acetaminophen induced acute liver injury model to compare tissue injury and regeneration of aged mice (>80 weeks old) with young ones (8–10 weeks old). The mortality of aged mice after acetaminophen injury was higher than that of young mice. Transient increase of serum GOT and decrease of reduced glutathione (GSH) were not returned to original levels in aged mice even at 48 hours. In addition, Foxm1b and its targets Ccnd1 and Cdk1 were upregulated in young but not in aged mice after 48 hours. Moreover, an apoptosis-related gene, Cidea, was upregulated specifically in aged livers, which was consistent with increased number of TUNEL(+) hepatocytes. Unexpectedly, damaged hepatocytes were retained in aged liver tissue, which may be caused by impaired recruitment of macrophages to the damaged area, without increases in Ccl2 after acetaminophen injury. Collectively, prolonged oxidative stress due to delayed recovery of GSH and the retention of damaged hepatocytes may suppress tissue repair and hepatocyte proliferation, resulting in exacerbation of acetaminophen injury in aged mice. Thus, aging is a risk factor conferring susceptibility against drug-induced liver injury.