Age-dependent effects of nongenotoxic hepatocarcinogens on liver apoptosis in vivo.

Aging sensitizes the liver to the hepatocarcinogenic effect of PPARalpha agonists via unknown mechanisms. This study was designed to investigate whether aging enhances the susceptibility of the liver to the anti-apoptotic effect of these chemicals. Since apoptosis serves to purge the liver of transformed cells, exaggerated inhibition of this process in aged livers may facilitate the progress of these cells to cancer. We quantified the effect of the PPARalpha agonists, clofibrate and Wy-14643, on the mRNA levels of various elements of the apoptotic machinery in male Fisher-344 rats ranging in age from immaturity (4-week-old), young adulthood (10-week-old), middle age (50-week-old), to senescence (100-week-old). Clofibrate and Wy-14643 either significantly diminished or exerted no effect on hepatic mRNA levels of several pro-apoptotic factors in immature, middle age and senescent animals. Unexpectedly, however, these PPARalpha agonists caused a remarkable 2- to 45-fold augmentation in the levels of the mRNA of Bax, caspase-2, and Fas mRNA in the young adult 10-week-old rats. A 47-75% decrease in the percent of apoptotic hepatocytes was observed only in 50- and 100-week-old rats treated with Wy-14643. Data suggest that activation of PPARalpha alters the balance between pro- and anti-apoptotic genes most significantly in livers of 50- and 100-week-old rats. Since suppression of apoptosis in the senescent liver is expected to diminish its ability to purge itself of already transformed cells, which may then progress to malignancy, exposure of senescent animals to PPARalpha agonists may be crucial to the ultimate outcome of liver cancer later in their life-span.