218 POSTER Phase I/II study of CNTO 95, a fully human monoclonal antibody (mAb) to alpha-v integrins, in patients with metastatic melanoma

Protein synthesis is universally affected by aging in all organisms. There is no clear consensus about the mechanism underlying the decline of translation with aging. Previous reports from our laboratory have shown that the elongation step is especially affected with aging as a consequence of alterations in elongation factor-2 (eEF-2), the monomeric protein that catalyzes the movement of the ribosome along the mRNA during protein synthesis. eEF-2 seems to be specifically affected by lipid peroxidant compounds, which concomitantly produce several reactive, toxic aldehydes, such as MDA and HNE. These aldehydes are able to form adducts with proteins that lead to their inactivation. In this paper we studied the formation of adducts between MDA or HNE and eEF-2. The study was performed both in vitro, using liver homogenates treated with cumene hydroperoxide, and in vivo using young control rats, treated with the same oxidant, and 12-and 24-month-old rats. In all cases we found a decrease in the levels of eEF-2, an increase in the amount of lipid peroxidation, and a concomitant formation of adducts between eEF-2 and MDA or HNE. The results suggest that one possible mechanism responsible for the decline of protein synthesis during aging could be the alteration in eEF-2 levels, secondary to lipid peroxidation and adduct formation with these aldehydes.