Perspective: The Paradox in Dietary Advanced Glycation End Products Research—The Source of the Serum and Urinary Advanced Glycation End Products Is the Intestines, Not the Food

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AbstractInconsistent research results have impeded our understanding of the degree to which dietary advanced glycation end products (dAGEs) contribute to chronic disease. Early research suggested that Western-style fast foods, including grilled and broiled meats and French fries, contain high levels of proinflammatory advanced glycation end products (AGEs). However, recent studies with state-of-the-art ultraperformance LC-tandem mass spectrometry (UPLC-MS) found that there is no evidence that these foods have elevated levels of dAGEs relative to other foods. Paradoxically, observational research found that the intake of fruits (mainly apples), fruit juices (apple juice), vegetables, nuts, seeds, soy, and nonfat milk, which are foods synonymous with healthy eating, as well as the intake of cold breakfast cereals, whole grains (breads), and sweets, which are sources of high-fructose corn syrup (HFCS), were associated with elevated serum and urinary N-ε-carboxymethyl-lysine (CML). Ironically, these are the same foods found to have lower CML levels, as measured by UPLC-MS. One possible explanation for this paradox is that the source of the elevated CML is the intestines, not the food. When considered collectively, dAGE research results are consistent with the “fructositis” hypothesis, which states that intake of foods and beverages with high fructose-to-glucose ratios (HFCS-sweetened foods and beverages, agave syrup, crystalline fructose, apple juice, and apple juice blends) promotes the intestinal in situ formation of readily absorbed, proinflammatory extracellular, newly identified, fructose-associated AGE, an overlooked source of immunogenic AGEs.