Calorie restriction enhances the expression of key metabolic enzymes associated with protein renewal during aging

Our studies show that dietary caloric restriction (CR) alters the expression of key metabolic enzymes in a manner consistent with an increased rate of extrahepatic protein turnover and renewal during aging. Of the key hepatic gluconeogenic enzyme genes affected by CR, glucose 6-phosphatase mRNA increased 1.7- and 2.3-fold in young and old CR mice. Phosphoenolpyruvate carboxykinase mRNA increased 2-fold in young mice, and its mRNA and activity increased 2.5- and 1.7-fold in old mice. These changes indicate that CR enhances the enzymatic capacity for gluconeogenesis. The carbon required for gluconeogenesis appears to be generated from peripheral protein turnover. Muscle glutamine synthetase mRNA increased 1.3- and 2.1-fold in young and old CR mice, suggesting increased disposal of nitrogen and carbon derived from protein catabolism for energy. mRNA for the key liver nitrogen disposal enzymes glutaminase, carbamyl phosphate synthase I, and tyrosine aminotransferase were increased by 2.4-, 1.8-, and 1.8-fold in CR mice. Consistent with increased hepatic nitrogen disposal, hepatic glutamine synthetase mRNA and activity were each decreased about 40% in CR mice. Together, these and our other published data suggest that CR enhances and maintains protein turnover, and thus protein renewal, into old age. These effects are likely to resist the well-documented decline in whole body protein renewal with age. Enhanced renewal may reduce the level of damaged and toxic proteins that accumulate during aging, contributing to the extension of life span by CR.