Enhanced OS and elevation of markers of inflammation often occur with aging (1
). We hypothesized that this age-associated trend is caused by increased levels of AGEs, which are molecules that have been found to cause OS and by this mechanism contribute to diseases such as diabetes, CVD, and renal disease (3
). The current study demonstrates that serum levels of common AGEs, such as CML and MG derivatives, are elevated in older persons. Independent of age, the levels of glycotoxins correlated with the levels of established markers of OS and inflammation. Furthermore, the dietary intake of AGEs is an independent correlate of sCML and sMG derivatives as well as of hsCRP. These findings point to the potential role of dietary and circulating AGEs in age-related diseases, especially of older adults.
We and other groups have used CML and MG derivatives as markers of a complex array of AGEs, or glycotoxins (10
). The highly significant correlation found between circulating levels of CML and of MG derivatives in this group of normal participants is consistent with the previous hypothesis that these derivatives represent markers of the same biological process, namely the nonenzymatic protein and lipid glycoxidation (7
). Our data suggest that immunoassays can be used in the clinical setting, although methods of wider applicability need to be established.
The strong and direct association of serum levels of CML with those of 8-isoprostane, an indicator of endogenously generated lipid peroxidation products and a marker of OS (35
), could be interpreted as evidence that highly reactive carbonyl intermediates such as glyoxal or MG can contribute not only to CML formation but also to lipid peroxidation (3
), which could enhance 8-isoprostane formation. This association has not been previously shown in healthy humans. AGEs, attributed largely to high glycemic levels or impaired renal function (8
), have been known to promote ROS and a wide range of inflammatory responses, via cell surface receptors, under disease conditions (10
). Our study supports the notion that AGE-activated signal pathway(s) may affect OS levels in healthy adults. These findings would be consistent with evidence pointing to serum AGEs as a powerful risk factor for cardiovascular mortality in nondiabetic women (11
). Thus, sCML may be considered as a new indicator of an underlying imbalance of OS and innate immune responses.
Based on several epidemiologic studies, a rise in OS among clinically normal individuals may be important in the pathogenesis of insulin resistance and the metabolic syndrome (28
). The association found between sCML and HOMA levels of normal persons is suggestive of a link between metabolic processes, which may antedate insulin resistance, diabetes mellitus, or vascular dysfunction at any age (11
). A similar relationship between high levels of circulating AGEs and insulin resistance was observed in mice, in connection to high-fat and high-AGE diet–induced diabetes (21
), but not in the low-AGE–fed controls. In view of the significant correlation between sCML and consumption of dietary AGEs found in this study, together with relevant animal and human studies (10
), an elevated sCML level may indicate a need for preventive measures. In this context, the fact that we found dietary AGE consumption to be an independent determinant of serum AGEs, CML and MG, as well as of hsCRP suggests that dietary modification may be the intervention of choice. Dietary AGEs in fact emerged as the best predictors of levels of sCML and hsCRP, even after adjusting for confounders such as age, gender, BMI, and caloric intake. These findings are in agreement with previous evidence in humans suggesting that the usual adult diet contains excessive amounts of AGEs (10
) and that, when ingested in excess, they can be readily reflected in circulation and can cause systemic vascular changes (40
AGEs are excreted by the kidneys, the normal capacity of which may be easily exceeded, especially in the presence of renal disease, diabetes, or high AGE intake. When AGEs accumulate, a large portion of ingested AGEs is retained in tissues (16
), contributing to increased OS and ultimately, to impaired organ function. As renal function slowly diminishes with age, the ability to excrete AGEs could be further impeded (42
), resulting in an expanded total AGE burden, especially in elderly persons. This postulate may explain the mechanism by which serum AGE levels were significantly higher in the older group than in the younger group, even though the intake of dietary AGEs by the older age group was reduced.
The content of AGEs in the food is strongly influenced by the methods of preparation, particularly, the amount and duration of exposure to heat and by the associated amount of water (17
). Thus, methods such as frying or broiling greatly augment the AGE content of common foods, compared to boiling and steaming (17
). Restricting the use of high temperature in food preparation, however modest, could lead to a significant AGE reduction in the same foods. Consuming food with low amount of AGEs may help reduce the levels of systemic glycotoxins, OS, and inflammation. This intervention may be particularly important in patients affected by diseases where OS and inflammation play an important pathophysiologic role, such as diabetes and/or renal diseases. Studies of mice fed a diet with an AGE content 50% lower than usual throughout their life showed a reduction of systemic and tissue OS, metabolic and organ changes, and more importantly, a longer life span (27
). Taken together, these data may suggest that consumption of a diet which contains a moderately low amount of AGEs may be beneficial to healthy aging.
Reevaluation of the dietary calories and AGE intake 6 months after the initial data collection indicated that both remained reasonably constant in this normal population. This finding provides further validation of the instrument used in this study and suggests that this type of assessment is ready for application in larger population studies.
Levels of consumption of dietary AGEs directly influence systemic levels of glycotoxins, and this influence may contribute to a state of elevated OS and inflammation sustained throughout adulthood, with significant adverse health consequences for all adults, and especially for the aging population. This hypothesis should be tested in longitudinal studies and in randomized, controlled trials evaluating the effect of a low AGE dietary intervention and health outcomes.