Increased ischemic injury in old mouse liver: an ATP-dependent mechanism

Although livers exhibit only minimal morphologic changes with age, how older livers tolerate pathologic conditions such as normothermic ischemia is unknown. Young 6-week-old mice and old 60-week-old mice underwent 60 minutes of hepatic ischemia and various periods of reperfusion. Markers of hepatocyte injury, hepatic energy content, and mitochondrial function were determined. Ischemic preconditioning and glucose injection were evaluated as protective strategies against reperfusion injury in old mice. Reperfusion injury was far worse in old mice compared with mice in the young control group. Ischemic preconditioning was highly protective against reperfusion injury in young but not in old mice. Older livers had dramatically reduced adenosine triphosphate (ATP) levels and glycogen contents. The low intrahepatic energy level in old mice was associated with a reduced mitochondrial ATP production. Preoperative injection of glucose restored the intrahepatic ATP content and protected against reperfusion injury. Furthermore, glucose injection restored the protective effect of ischemic preconditioning, resulting in additive protection when both strategies were combined. Aging of the liver is associated with mitochondrial dysfunction and decreased intrahepatic energy content, resulting in poorer tolerance against ischemic injury. Improving intrahepatic ATP levels in old livers by glucose injection protects the old liver against ischemic injury and restores the protective effects of ischemic preconditioning.