Aging and the liver: functional aspects.

The drastic decline in the function of the hepatic microsomal cytochrome monooxygenase system, initially reported in male rat livers, was shown to be due to a feminization of male rat livers with aging. In female rat livers as well as in mouse livers, this system was found to stay unchanged with age. Phase II reactions which showed some decline with aging in male rat livers again stayed fairly stable with age in female rat and mouse livers. Glutathione S-transferase (GST) enzyme activities, which are very stable with age in female rat and mouse livers, demonstrated highly age-dependent changes when dietary conditions were manipulated, suggesting a potential age difference in the homeostatic regulation of this enzyme system. Using the fluorescence recovery after photobleaching (FRAP) technique, unique studies revealed an age-dependent decline in the lateral mobility of proteins in hepatocyte surface membranes. The protease inhibitor model of aging, initially proposed by Ivy for brain cells, has been validated in hepatocytes, demonstrating an accumulation of lipofuscin-like granules in young animals treated with i.p. infusion of leupeptin for only 2 weeks. Antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase (CAT) in the liver were clearly demonstrated no to be reduced in general terms with aging. Rather, a clear increase in CAT enzyme activities with age was demonstrated in female rat livers, thus challenging the concept that intracellular enzyme activities generally decline with aging. In this paper, studies performed in Japan on aging and the liver over the past 30 years, with a focus on its functional aspects, are critically reviewed in terms of the clinical implications of these studies as well as on theories of aging in general.