Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 3 • March 2013


AGEless: Deleting AGEs to Prevent Metabolic Syndrome

High AGE Diet May Be “Missing Link” Between Adipose Tissue Accumulation, Inflammation, and Insulin Resistance



Advanced Glycation Endproducts (AGEs) have become a hot research subject because of the coming together of mechanisms where accumulation of AGEs appear to be causative factors that go beyond overnutrition in the “epidemic” of age-associated metabolic diseases including obesity and diabetes. A newly published paper1 and an accompanying commentary2 report some of the new discoveries whereby AGEs have become the centerpiece of the causes and potential prevention of these disorders.

As the title of the paper1 makes clear, the bottom line of the new research is that AGEs promote insulin resistance and diabetes by depleting antioxidant defenses that protect against AGE-induced inflammation, including the AGE receptor-1 (AGER-1), a key anti-AGE defense, and SIRT1, which suppresses inflammatory signals and, importantly, enhances levels of the anti-inflammatory adipokine adiponectin to improve insulin sensitivity and fat mobilization. The researchers found that AGER1 and SIRT1 were independently suppressed by chronic oxidative stress as is found in conditions such as diabetes, obesity, aging, or high AGEs containing diets.

The researchers fed a powerful alpha-dicarbonyl glycating agent, methylglyoxal (MG), found in patients with diabetes and in those consuming high AGE diets, to mice. As we have written in an earlier Durk & Sandy newsletter, one way to reduce dietary AGEs is to cook food at a relatively low temperature, as the AGEs are formed by high temperature heating of foods containing protein and sugars. This process, called the Maillard reaction, creates tasty food that is crispy and has a brown color—hard to resist except when you consider the result of eating too much of it.

The mice on a high MG diet gained weight, with increased adiposity, and metabolic changes as compared to mice on a regular diet. In addition, the MG-fed animals had increased markers of oxidative stress and inflammation, including increased plasma 8-isoprostanes and vascular cell adhesion protein-1 and lower plasma adiponectin levels. Moreover, insulin action was impaired in the MG+ mice. “… levels of AGER1 and SIRT1 were suppressed in primary adipocytes isolated from MG+ WAT [white adipose tissue from MG+ mice], and NF-kappaB acetylp65 and RAGE levels were increased, compared with adipocytes from MG-mice, suggesting the presence of a proinflammatory state in MG+ WAT adipocytes.”1

The researchers comment: “It is notable that this combination of features is virtually absent in genetically identical mice born and raised in an environment differing only with respect to the lower amount of ingested MG-AGEs.”

“Chronic MG+ intake was also associated with elevated fasting plasma insulin and leptin and suppressed adiponectin levels in MG+ mice. These findings are consistent with an insulin-resistant state, as seen previously in Reg mice, but not in MG– mice.”

According to Leonid Poretsky, the author of the commentary article,2 “[n]ew tests measuring AGEs in circulating, including those absorbed from the diet, have been developed and are poised to enter clinical practice.” This is wonderful news and we certainly hope that “poised to enter clinical practice” means pretty soon, not being delayed for years by bureaucratic process at the FDA. As the author2 also comments, “[c]irculating AGE levels can be reduced without altering the caloric content of meals simply by changing the way the food is prepared, that is, by using less heat and more water (e.g., stewing instead of frying).” He adds that “[m]edications that can reduce AGE absorption from food need to be developed, and initial steps in this direction have already been taken.”

Nutrients that block the development of AGEs or reduce the damage caused by AGEs include: benfotiamine (a lipid soluble form of thiamine), vitamin B6, alpha lipoic acid, carnosine, histidine, and rutin. We take a formulation containing all these ingredients 3 or 4 times a day. See our interview on reducing AGEs (with included references) “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue of Life Enhancement.

References

  1. Cai et al. Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. Proc Nat Acad Sci USA. 109(39):15888-93 (2012).
  2. Poretsky. Looking beyond overnutrition for causes of epidemic metabolic disease. Proc Nat Acad Sci USA. 109(39):15537-8 (2012).

Setting a Trap for AGEs

Curcumin Acts as Methylglyoxal Trap in Cell-Free Systems and in Human Umbilical Vein Endothelial Cells

But that isn’t the end of the story of ways available to your body for either blocking the formation of AGEs or increasing their disposal. Methylglyoxal is a major precursor of AGEs, the levels of which are elevated in, among other conditions, diabetes, dialysis, and chronic kidney disease. As a 2012 paper1 reports, “several dietary flavonoids have been shown to inhibit AGE formation through blocking the carbonyl or dicarbonyl groups and thus may prevent diabetes and its complications.”

Curcumin has now been reported1 to directly trap methylglyoxal, inhiting its conversion to AGEs and, as a result, possibly preventing methylglyoxal-induced endothelial dysfunction. The new paper1 reveals the chemical mechanism that may be responsible for the methylglyoxal trapping by curcumin. The paper also mentions other trapping agents of reactive dicarbonyl species such as methylglyoxal from dietary sources that includes the tea polyphenol EGCG, apple polyphenols phloretin and phloridzin, cinnamon proanthocyanidins, phlorotannins from brown algae, stilbene glucoside from Polygonum multiflorum Thumb. Remarkably, the researchers report that curcumin significantly and time-dependently trapped MGO (methylglyoxal) for up to 24 hours (51% reduction, p<0.05), and the effect was said to remain unchanged for up to 72 hours of incubation.1

Curcumin is readily available from turmeric root powder, an inexpensive spice which we take every day in capsules. We also take EGCG in capsules every day, too!

Reference

  1. Hu et al. Trapping of methylglyoxal by curcumin in cell-free systems and in human umbilical vein endothelial cells. J Agric Food Chem. 60:8190-6 (2012).

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