The effect of age on the synthesis of specific proteins by hepatocytes was studied in Fischer F344 rats using two-dimensional polyacrylamide gel electrophoresis. Almost all proteins synthesized by hepatocytes from young rats were synthesized by hepatocytes isolated from old rats. Of over 500 proteins visually compared by two-dimensional polyacrylamide gel electrophoresis, only 11 proteins were observed to disappear and/or appear consistently with increasing age. The rates of synthesis of 36 randomly chosen proteins were quantified. Interestingly, the synthesis of 35 of the 36 proteins decreased between 5 and 30 months of age. The decrease in protein synthesis varied (15% to 70%) from one protein to another; i.e., a heterogeneity was observed in the age-related decrease in the synthesis of proteins. The age-related decrease in protein synthesis was statistically significant for 53% of the proteins studied. The total decrease in the rate of synthesis of all 36 proteins studied was 40% between 5 and 30 months of age, which is essentially the same as the decrease in total protein synthesis by suspension of hepatocytes isolated from 5- and 30-month-old rats. The results of this study demonstrate that the mechanism underlaying aging is different from development, which is characterized by a major change in the species of proteins synthesized by a cell.