Reversal of Protein Chemical Aging by Enzymatic Deglycation

The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, Nε-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive precursors, the stable CML adduct has historically been considered irreversible. The authors report the development of CMLase - an enzyme engineered through the directed evolution of over 500 million variants to specifically oxidize CML and restore the native lysine residue. In vitro studies demonstrate that CMLase effectively reverses CML modifications in model proteins, while in human tissue samples from elderly donors, it restores native lysine residues previously modified by CML. These findings provide proof-of-concept that protein damage previously deemed irreversible is amenable to enzymatic repair. The approach establishes a platform for developing enzymes to reverse age-related molecular damage and ultimately repair tissue proteins compromised by aging and disease.