Carnosinase levels in aging brain: redox state induction and cellular stress response

Carnosinase is a dipeptidase found almost exclusively in brain and serum. Its natural substrate carnosine, present at high concentration in the brain, has been proposed as an antioxidant in vivo. We investigated the role of carnosinase in brain aging to establish a possible correlation with age-related changes in cellular stress response and redox status. In addition, a stable HeLa cell line expressing recombinant human serum carnosinase CN1 was established. The enzyme was purified from transfected cells, and specific antibodies were produced against it. Brain expression of CN1, Hsp72, heme oxygenase-1, and thioredoxin reductase increased with age, with a maximal induction in hippocampus and substantia nigra, followed by cerebellum, cortex, septum, and striatum. Hsps induction was associated with significant changes in total SH groups, GSH redox state, carbonyls, and HNE levels. A positive correlation between decrease in GSH and increase in Hsp72 expression was observed in all brain regions examined during aging. Increased carnosinase activity in the brain can lead to decreased carnosine levels and GSH/GSSG ratio. These results, consistent with the current notion that oxidative stress and cellular damage are characteristic hallmarks of the aging process, sustain the critical role of cellular stress-response mechanisms as possible targets for novel antiaging strategies.