Exogenous Sources of Advanced Glycoxidation End Products

AGEs can also be introduced in biological systems from exogenous sources. Methods of food processing (heating in particular) have a significant accelerating effect in the generation of diverse highly reactive a-^-dicarbonyl derivatives of glyco- and lipoxidation reactions that occur in complex mixtures of nutrients (20-23).

About 10% of a single AGE-rich meal is absorbed into the body (24,25). Food-derived AGEs, rich in MG, CML, and other derivatives, are potent inducers of oxidative stress and inflammatory processes. As with endogenous AGEs these processes can be blocked by antioxidants and anti-AGE agents (26), pointing to many similarities (structural and biological) between exogenous and endogenous AGEs.

Animal studies have demonstrated the close relationship between increased dietary AGE intake and development and/or progression of many diabetes-related complications. Nephropathy, postinjury restenosis, accelerated atherosclerosis, and delayed wound healing were significantly inhibited by lowering dietary AGE intake (27-30). Sebekova and associates demonstrated in the remnant-kidney rat model that feeding an AGE-rich diet for 6 weeks increases kidney weight and causes proteinuria, independent of changes in glomerular filtration rate, pointing to the detrimental effect of such diet on the kidney (31). Of particular interest are studies showing that a low-glycotoxin environment can prevent or delay significantly autoimmune diabetes in successive generations of nonobese diabetic (NOD) mice (32) and to improve the insulin-resistant state in db/db (+/+) mice (33). Reduction in exposure to exogenous AGEs of db/db (+/+) mice, lacking in leptin receptor and thus prone to insulin resistance and type 2 diabetes, led to amelioration of the insulin resistance and marked preservation of islet structure and function (33).

Clinical studies have further confirmed the above laboratory data. Studies in diabetic patients with normal renal function and nondiabetic patients with chronic renal insufficiency, another condition with elevated serum AGE levels, demonstrated that lowering dietary AGE intake can significantly decrease circulating AGE levels followed by par-

Fig. 2. Multifactorial influences determining circulating AGE levels.
Fig. 3. Serum AGEs correlate with dietary AGE intake in humans. Association between daily dietary AGE content (assessed by dietary history) and serum AGE levels, measured as CML, in a large cross-section of chronic renal failure patients on dialysis (ref. 35).

allel changes in circulating inflammatory markers such as C-reactive protein (34-37). These preliminary but striking findings added further credence to the hypothesis that exogenous AGEs, in addition to being major determinants of the total AGE pool (Figs. 2 and 3), may be powerful modulators of the inflammatory state that is common in conditions such as chronic renal insufficiency (Fig. 4). This is highly relevant to human aging as it is associated with loss of renal function, often significant (38).

Tobacco smoke is another exogenous source of AGE. Tobacco curing is essentially a Maillard "browning" reaction, as tobacco is processed in the presence of reducing sugars. Combustion of these adducts during smoking gives rise to reactive, toxic AGE formation

Fig. 4. Changes of circulating AGEs and markers of inflammation during dietary AGE modulation. Percent change of serum AGEs (CML, MG, and LDL-CML), C-reactive protein (CRP), tumor necrosis factor (TNF)-a and vascular adhesion molecule (VCAM)-1 in a group of stable diabetic patients fed either AGE-restricted or regular diet for up to 6 weeks (ref. 34).

Fig. 4. Changes of circulating AGEs and markers of inflammation during dietary AGE modulation. Percent change of serum AGEs (CML, MG, and LDL-CML), C-reactive protein (CRP), tumor necrosis factor (TNF)-a and vascular adhesion molecule (VCAM)-1 in a group of stable diabetic patients fed either AGE-restricted or regular diet for up to 6 weeks (ref. 34).

(39). Total serum AGE, or AGE-apolipoprotein (apo)-B levels have been found to be significantly higher in cigarette smokers than in nonsmokers. Smokers and especially diabetic smokers have high AGE levels in their arteries and ocular lenses (40).

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