Xingjun Fan

　　Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA

　　In recent years, a novel form of protein damage has been recognized and postulated to originate from almost any reactive carbonyl compound that is generated during the Maillard reaction. This reaction is commonly observed during cooking or baking of foods, and may involve sugars, oxoaldehydes such as methyglyoxal, oxidized lipids, or ascorbic acid itself. Many of these products are yellow and crosslinked. Because of the high reactivity of ascorbic acid reaction products with proteins and its presence in high concentrations in the certain human tissues, i.e. lens and brain, we and others have postulated an important role for Vitamin C in mediating progressive damage to the aging human tissues. To prove the concept, we engineered a mouse that selectively overexpresses the human vitamin C transporter SVCT2 in the lens, and displays vitamin C levels identical with those of the human lens (PNAS, 2006). At 12 months of age all advanced glycation end products (AGEs) attributable to vitamin C (pentosidine, CML, K2P, vesperlysine A and total fluorescence) were highly significantly increased, and the lenses were yellow like those from a 70 years old human lens.

　　Among AGEs, the arginine-derived modification by methylglyoxal-derived hydroimidazolones (MG-H1) is believed to be the most prevalent cellular AGE in animal tissues. It has been suggested that at least one MG-H1 adduct is present in 3-13% of protein, corresponding to about 1–2% of total arginine residues of proteins found in mammalian tissue, plasma and extracellular matrix. Such levels are significant as they may affect protein confirmation and chaperone function. In addition, MG-H1 is a ligand for the RAGE receptor whose engagement triggers a proinflammatory cascade. MG-H1 could also come from food products since modern diets are mostly heat processed and thus resulted in high levels of AGEs including MG-H1. Animal tests via consumption of high AGE diet are found associated with atherosclerosis, kidney disease, metabolic syndrome, and elevated inflammatory responses.

　　We have here tested the hypothesis that oxidation of vitamin C can contribute to this damage when the homeostatic redox balance is disrupted, especially in tissues rich in vitamin C such as lens and brain. MG-H1 quantitated by LC/MS is found several folds increased in lens and brain from transgenic mice expressing the human vitamin C transporter 2 (hSVCT2). MG-H1 levels in Alzheimer Disease (AD) hippocampus extract are two-four-fold increased and significantly higher levels are found in sarkosyl-insoluble tissue fractions. Immunostaining with antibodies against methylglyoxal hydroimidazolone is similarly increased in substantia nigra neurons from human Parkinson’s disease (PD) subjects. Modeling studies and intraventricular injection of ¹³C-labeled vitamin C reveal that vitamin C backbone carbons 4-6 are incorporated into MG-H1 in vitro and in vivo, likely via a glyceraldehyde precursor. Drugs that prevent oxoaldehyde stress or excessive vitamin C oxidation may offer protection against age-related cataract and neurodegenerative diseases.