Mediterranean Diet Reduces Serum Advanced Glycation End Products and Increases Antioxidant Defenses in Elderly Adults: A Randomized Controlled Trial

To the Editor: A growing body of evidence indicates that oxidative stress and chronic inflammation are primary risk factors underlying the aging process and age-related diseases.1, 2 Addressing these mechanisms could have implications for aging and lead to new therapeutic approaches to these conditions. Advanced glycation end products (AGEs), compounds derived from glycation of proteins and lipids as result of the Maillard reaction, are generated in vivo as a normal consequence of metabolism. Recent studies reveal the contribution of AGEs, particularly methylglyoxal (MG) and N-carboxymethyllysine (CML), the principal forms of AGEs, in the origin and progression of chronic diseases and during the aging process, increasing oxidative stress and inflammation.3-5 Although endogenous AGE formation represents a minor component of the total body pool of AGEs, dietary AGEs (dAGEs) are considered the most important source of AGEs.6 New evidence suggests that an AGE-restricted diet is an effective way to reduce the body's total AGE concentration and decrease oxidative stress and inflammation in different populations.7 Nevertheless, there is still a paucity of data with respect to the influence of dietary fat type on modulation of endogenous AGE levels. The purpose of the current study was to determine whether the quantity and quality of dietary fat could modify serum AGE (sCML and sMG) levels and the expression of genes related to oxidative stress, inflammation, and AGE metabolism in healthy elderly adults. Twenty participants (aged ≥65; 10 male, 10 female) were randomly assigned to receive, in a crossover design, three isocaloric diets for 4-week periods each: Mediterranean diet (38% of energy from fat: 24% monounsaturated fatty acids (MUFA; provided by virgin olive oil), 10% saturated fatty acids (SFA), 4% polyunsaturated fatty acids (PUFA)); Western diet rich in saturated fat (38% of energy as fat: 12% MUFA, 22% SFA, 4% PUFA); low-fat, high-carbohydrate diet enriched in omega-3 PUFA of vegetable origin (omega-3 diet) (28% of energy as fat: 10% SFA, 12% MUFA, 8% PUFA with 2% alpha-linolenic acid). At the end of the dietary intervention period, subjects were given a breakfast with the same fat composition as consumed in each of the diets after a 12-hour fast. Blood samples were collected at the end of each diet period (fasting state) and 4 hours after breakfast (postprandial state). The human investigation review committee of the Reina Sofia University Hospital approved the study protocol according to institutional and Good Clinical Practice guidelines.8 Dietary AGE content;9 CML and MG levels; and AGE receptor-1 (AGER1), receptor for AGEs (RAGE), and glyoxalase I (GloxI) messenger ribonucleic acid levels (mRNA) in peripheral mononuclear cells were determined. PASW Statistics, version a8, SPSS statistical software (SPSS, Inc., Chicago, IL) was used for statistical analysis. Analysis of variance for repeated measures was performed, followed by Bonferroni correction for multiple comparisons. Pearson correlation analyses were performed to examine correlations between dAGE levels and other parameters related to oxidative stress and inflammation. Differences were considered to be significant at P < .05. All data presented are expressed as means and standard errors. During the SFA diet, participants consumed more dAGEs than after the other diets, with the Mediterranean diet providing the lowest amount of food-related AGEs, and the omega-3 diet having an intermediate content (Figure 1A). Fasting and postprandial sMG and sCML were higher after the SFA diet than after the Mediterranean diet, with an intermediate effect for the omega-3 diet (P = .005) (Figure 1B, C). Moreover, sMG levels decreased significantly more during the postprandial phase in Mediterranean diet group (P = .03) (Figure 1B). Fasting and postprandial AGER1 and GloxI mRNA levels, with antioxidant properties, were higher after the Mediterranean diet than after the SFA diet (all P < .005). Furthermore, AGER1 and GloxI mRNA levels were significantly greater during the postprandial state than in the fasting state after the Mediterranean and omega-3 diets (all P < .005) (Figure 1D, E). Fasting and postprandial RAGE mRNA levels, an AGE receptor that induces oxidative stress and inflammation, were lower after the Mediterranean diet than the other diets (all P < .005), with an intermediate effect for the omega-3 diet during the postprandial state (P = .007). RAGE mRNA levels were significantly lower during the postprandial state after the Mediterranean and omega-3 diets than during the fasting state (P = .004) (Figure 1F). A positive correlation was found between sMG and sCML, with genes and markers related to oxidative stress and inflammation such as RAGE, matrix metallopeptidase 9, plasma 8-hydroxydeoxyguanosine, and oxidized low-density lipoprotein levels, and a negative correlation with genes and markers related to antioxidant defenses such as GloxI, glutathione peroxidase, and thioredoxin (data not shown). The present study showed that consumption of a Mediterranean diet reduces oxidant AGEs and increases antioxidant defenses in the fasting and postprandial states, as lower sCML and sMG levels, higher AGER1 and GloxI, and lower RAGE mRNA levels than with the SFA diet manifested, with an intermediate effect of the omega-3 diet. The Mediterranean diet may have protective effects against oxidative stress and inflammation, providing low AGE content and reducing circulating AGEs in elderly people, which may have favorable effects on the aging process and be linked to the benefits of consuming a Mediterranean diet on the prevalence of age-related conditions. Inhibition of AGE formation may limit oxidative and inflammatory damage in tissues, retarding the progression of pathophysiology and improving quality of life during aging. Conflict of Interest: The authors have no conflicts of interest to disclose. Supported in part by research grants from the Ministerio de Ciencia e Innovación (AGL2004–07907, AGL2006–01979, AGL2009–12270), Ministerio de Ciencia y Competitividad (AGL2012–39615) to JL-M; FIS PI10/01041 to P P-M; FIS PI13/00023 to J D-L, Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P06-CTS-01425 and PI0193/09 to JL-M, PI-0252/09 to J D-L, PI-0058/10 to P P-M), Proyecto de Excelencia, Consejería de Economía, Innovación, Ciencia y Empleo (CVI-7450 to J L-M); Merck Serono and Fundacion 2000 (Clinical research in Cardiometabolic to P P-M).The CIBEROBN is an initiative of the Instituto de Salud Carlos III, Madrid, Spain. Author Contributions: Lopez-Miranda, Perez-Jimenez: designed and conducted research. Delgado-Lista, Delgado-Casado, Garcia-Rios, Perez-Martinez, Lopez-Moreno: acquired data and participants. Lopez-Moreno, Camargo, Delgado-Casado, Quintana-Navarro, Yubero-Serrano: data collection. Lopez-Miranda, Yubero-Serrano: data analysis. Lopez-Moreno, Yubero-Serrano: writing the manuscript. Striker, Delgado-Lista, Tinahones, Perez-Martinez: significant advice and support in reviewing the drafting of the paper. Lopez-Miranda, Yubero-Serrano: primary responsibility for final content. All authors read and approved the final manuscript.