Impact of Cell Cycle Disruption on Impaired Hepatic Regeneration in Aged Livers with Ischemic Insult

Abstract

The number of elderly patients with hepatobiliary malignancies has increased with the steady growth of elderly population. However, the safety of major hepatectomy for elderly patients remains controversial. This study investigated the effect of aging on the hepatic regenerative response after partial resection of livers subjected to ischemic insult. Two-thirds hepatectomy following 1-h hepatic ischemia was performed in young (12-wk-old) and old (18-mo-old) rats under portosystemic shunt establishment by subcutaneous transposition of the spleen. The survival rate 48 h after hepatectomy of the old rats was significantly lower (20%) than that of the young rats (53%), whereas all animals without hepatic ischemia were alive at 48 h. Hepatic necrosis and hepatocyte apoptosis during the early post-hepatectomy phase were more severe in the aged livers, which also showed delayed Akt activation. Liver mass restoration was significantly retarded in the old rats, despite higher plasma IL-6 levels, rapid and prolonged activation of hepatic STAT3, and increased hepatocyte nuclear cyclin D1 levels. In the young livers, cyclin E, which is essential for G1/S transition, and cyclin A, a marker of S phase, were observed in the nucleus from 24 h, reaching peaks 48 h after hepatectomy. In contrast, the old livers showed greatly delayed and decreased nuclear cyclin E and cyclin A levels. Age-related reductions in the regenerative ability of ischemically damaged livers may be caused by cell cycle disruption at either the late G1 phase or the G1/S transition, despite increased cyclin D1 levels and compensatory IL-6/STAT3 activation.