Effect of aging and dietary restriction on hepatocyte proliferation and death in male F344 rats

The proliferation and death of hepatocytes in rats fed ad libitum and rats on dietary restriction were evaluated in 3 to 24-month-old rats by employing immunocytochemistry for proliferating cell nuclear antigen (PCNA) and terminal dUTP nick end labeling (TUNEL). These techniques were also used to examine hepatic tissue infiltrated with leukemic cells in 24-month-old rats fed ad libitum. PCNA-strongly positive hepatocytes, PCNA-positive hepatocytes, and TUNEL-positive hepatocytes were reported previously to be equivalent to hepatocytes in the S phase, hepatocytes in the cell cycle, and dying hepatocytes, respectively. The proportion of PCNA-strongly positive hepatocytes and PCNA-positive hepatocytes declined with age. Dietary restriction diminished PCNA-strongly positive hepatocytes significantly but not PCNA-positive hepatocytes in young rats, but the proportion of PCNA-strongly positive hepatocytes was significantly higher following dietary restriction than that in rats fed ad libitum in advanced age. Growth stimulation by leukemic cell infiltration resulted in a recovery of the age-related decline of PCNA-strongly positive hepatocytes. Aging was associated with a progressive in crease in the proportion of TUNEL-positive hepatocytes, with a smaller effect following dietary restriction than in rats fed ad libitum after 6 months of age. Our results indicate that age and dietary restriction induce proliferative inhibition. The inhibition depends on PCNA expression; this suggests that suppression of cell proliferation and cell death are enhanced in hepatocytes of senile rats.