AGE in Food: Are You What You Eat?
When I started medical school my biochemistry professor used to tell my class, “Oxidation is the consequence of eating and breathing.” I felt this sentiment was darker than how one should view food and breath, however for some people (including those with diabetes), considering the already oxidized materials in food - and reducing them - may have health benefits!
Oxidation of food occurs during the cooking process in the presence of oxygen, i.e. air. One of the most common reactions occurs between carbohydrates (e.g. sugar and starch) reacting with proteins at high temperatures. However oxidation of oils also occurs. This process forms little chemical bridges or bonds that alter the way food is treated inside the body.The resulting particles are called advanced glycosylation endproducts or AGE.
So who cares? Perhaps we all should. It turns out AGE products are absorbed into the body and can bind to AGE-receptors, i.e. they stick around inside of us and stick to things they shouldn’t stick to. High consumption of AGE in food appears to affect kidney function and blood vessel disease in people with diabetes. Can anything be done to fight off AGE? The simple answer is yes, but you have to keep reading!
AGE Content in Food
Nutrition researchers Goldberg et al. published the most comprehensive list of the AGE content of food in the literature and provided tables of food AGE content1.
Foods with the highest AGE content:(in decreasing order)
- high fat foods (particularly butter, cream cheese, mayonnaise and cooking oils)
- high protein foods (meat and meat substitutes including tofu)
- carbohydrate-dense foods
Foods with the lowest AGE content:
- low-fat dairy
How food is prepared also determines AGE content:
- High AGE: oven frying, deep frying and broiling
- Lower AGE: stewing, boiling, poaching and microwaving
- Processed boxed/pre-cooked foods had the highest AGE content for carbohydrate dense foods.
I suspect many of you are now thinking, “Wonderful. One more thing to add to list of concerns about my diet. Now I have to watch carbs, fat, glycemic index, glycemic load, total calories, saturated fat and cholesterol.” I agree it is confusing and I too get burdened by the quest for the “perfect” diet. Please remember, knowledge is power and empowerment helps us all make better decisions about our health and the health of our family.
AGE in Diabetes
AGE does appear to matter in diabetes. Specifically the published research suggests dietary AGE products do enter the blood stream, bind receptors, and stimulate inflammatory processes known to cause blood vessel disease in diabetes.
High intake of AGE products by people with diabetes leads to increased oxidation of LDL cholesterol compared to low AGE intake; oxidized LDL stimulates inflammation (increased C-reactive protein and NF-kappa B activity) leading to calcification of blood vessels, i.e. atherosclerosis or “hardening of the arteries” (See Cholesterol: The Good, the Bad, and the Ugly).
Of note, because AGE intake increases various receptors, or adhesion molecules, on the inner lining of the blood vessels, high AGE intake may have lasting effects beyond one isolated meal!
AGE in Kidney Health
One of the most debilitating complications of diabetes can be reduced function of the kidneys. If untreated by improving blood glucose and blood pressure, kidney disease can lead to kidney failure requiring dialysis or kidney transplantation. Although it is too early to say definitively, research suggests dietary AGE intake may also affect kidney function in people with diabetes.
Kalousova et al. have published reviews discussing the role of AGE products in kidney disease3. In additional to the inflammatory process discussed above, AGE-effects in the kidney also include direct reductions in kidney filtration due to blood vessel disease and fibrosis.
Can Eating Less AGE Products Impact These Processes?
Human studies investigating the effects of low AGE intake on long term blood sugar control or blood vessel disease are nonexistent to date, however animal models of diabetes give us some information of what may be possible if people with diabetes limit AGE intake.
Specifically, Hofmann, et al. published research demonstrating reduced body weight and improved insulin sensitivity in diabetic mice fed a low-AGE diet compared with a high-AGE diet4. The low-AGE fed mice also had improved functioning and shape of the cells in the pancreas that produce insulin! “Good” cholesterol (HDL) was also increased in the low-AGE mice.
Similarly, animal studies by Zheng et al. demonstrate that low dietary intake AGE products in animals with either Type 1 or Type 2 diabetes prevents kidney disease and increased survival5.
How to Stop AGEing?
The evidence is accumulating that dietary consumption of advanced glycosylation end products (AGE products) has implications in health and disease, possibly including the development of heart and kidney disease in humans. Although still untested, the background research in animal models of diabetes suggests AGE intake may also contribute to the development of insulin resistance and reduced insulin secretion known to be important in the development of diabetes. So can you stop AGEing?
Based on the research by Goldberg and Vlassara, the most direct method for reducing the damage cause by high AGE product intake is to reduce AGE product intake from the diet from a combination of choosing different foods and cooking methods!
Fortunately for all of us, the dietary changes needed to reduce AGE intake are very similar to a “whole-foods” diet recommended for diabetes and heart disease.
A Low AGE Diet:
Processed foods (boxed foods,
frozen meals, etc.)
Fish (except fried or breaded)
Some may consider these changes to be impractical or difficult to incorporate into daily life. I agree these changes may take some time to get accustomed to, however I also believe small choices can have a big impact on AGE intake. For example:
- A hard-boiled egg has about 1/100th of the AGE content as a fried egg
- A homemade pancake has about ? the AGE content of a frozen, toasted pancake
- Puffed rice cereal has 120 times the AGE content of puffed wheat cereal
- Using avocado as a spread in place of butter reduces AGE intake 3-fold
(Values abstracted from Goldberg et al. 2004)
Small changes may lead to large long-term health gains!
Can Supplements Help?
Although we lack long-term clinical studies that show using supplements changes the long-term impact of AGE products in the body, there are several nutrients and nutrient derivatives that have demonstrated reductions in the inflammatory changes that result from AGE intake.
Many of these nutrients are available as nutritional supplements, however, as always, I discourage self-prescription of nutritional supplements or the prescription of nutritional supplements by store clerks. Many of the supplements which may improve AGE effects have not been studied for long-term safety and the medical community really has no idea how safe many of these substances are for long-term human consumption.
My recommendation is always to fix the real problem - reducing high dietary AGE intake - rather than looking for a quick-fix, patch.
Although most of the data we have on alpha-lipoic acid and AGE product formation is limited to animal studies, both the density of the research and the continuity of the research makes alpha-lipoic acid one the more favorable supplements to consider.
Both Midaoui et al. and Thirunavukkarasu et al. have published research in animals demonstrating alpha-lipoic acid as an effective inhibitor of AGE formation in diabetes
N-Acetylcysteine (NAC) is an antioxidant precursor to a natural antioxidant called glutathione; glutathione is known to be depleted in people with diabetes.
In the animal research performed by Cai et al. cited above, administration of NAC prevented the inflammatory changes observed from high AGE intake. This finding is consistent with the findings of De Mattia et al. who demonstrated reductions in pro-atherosclerotic vascular adhesion molecules from NAC supplementation in patients with Type 2 diabetes7.
NAC is relatively safe, though stomach irritation and agitation have been reported.
Benfotiamine is a derivative of the B-vitamin thiamine. Some data suggests high dose thiamine may have similar actions but benfotiamine appears to be better absorbed.
Recent publications suggest Benfotiamine may prevent inflammation caused by AGE intake. Specifically, Stirban et al. administered 1050 mg benfotiamine per day to patients with Type 2 diabetes and demonstrated reduced inflammatory markers, improved circulation and reduced pro-atherosclerotic adhesion molecules8.
Recommended doses and confidence in safety are still elusive due to a lack of long-term, large clinical studies.
Various on-line supplement companies (in some cased representing themselves as researchers or health-professionals) heavily market L-carnosine as the answer for preventing AGE-induced damage.
Scientific reviews suggest carnosine is a potent inhibitor of the formation of AGE products, and therefore carnosine has therapeutic potential in a variety of conditions including diabetes and diabetic complications9.
However clinical studies of carnosine are virtually non-existent in the U.S. literature and therefore it is nearly impossible to recommend a dose. Also, the lack of rigorous studies in humans make it very difficult to discuss the safety of the substance.
Although carnosine is present in food, specifically meat, the safety of taking high doses of carnosine in isolation is unknown.
Vitamin C and Vitamin E
Data is inconclusive on the effects of antioxidant vitamins on the development of AGE products. Preliminary animal research suggests a combination of vitamin C and vitamin E may prevent AGE product formation10, however this effect has not been demonstrated in humans. In fact, Konen et al. supplemented twenty-two people with diabetes with vitamin C and vitamin E for one year and did not observe a reduction in AGE content of skin samples11.
Advanced glycosylation endproducts (AGE) are an important factor in health and disease and appear to be particularly important in people with diabetes at risk for complications.
Although in diabetes, AGE formation occurs as a consequence to chronically elevated blood sugars, AGE products are also directly consumed by all of us in our diets.
There are dramatic differences in AGE content of food determined both by the nutrient composition of food, as well as by the degree of processing and method of cooking.
Dietary intake of AGE appears to affect blood vessel inflammation and oxidation of “bad” cholesterol, leading to increased atherosclerosis or “hardening of the arteries.”
Although supplements may be beneficial, few have been rigorously tested and therefore self-prescription without physician oversight is discouraged.
Alternatively reductions in the negative consequences of AGE products can be achieved by eating a “whole-foods” diet free of highly-processed, high-fat foods and by avoiding fried or broiled foods.
Alpha-lipoic acid (ALA), an antioxidant supplement, gained additional footing in the quest for legitimacy as effective treatment of painful diabetes neuropathy this past month.
Ziegler et al. published a dose-finding study in patients with diabetes and neuropathy randomized to three different doses of ALA (600, 1200 or 1800 mg/day) or placebo.
Patients in all three ALA groups experienced significant reductions in stabbing and burning pain as well as reductions in standardized symptom questionnaires compared to placebo.
Reductions in symptoms were similar for all groups suggesting 600mg per day is an adequate and effective dose.
Previous studies suggested higher doses around 1200mg/day may be necessary because absorption has been questioned.
Side effects were dose dependent and included nausea, vertigo and vomiting.
(Reference: Zeigler et al. “Treatment with Alpha-Lipoic Acid Improves Symptomatic Peripheral Neuropathy”. Diabetes Care. 2006. 29: 2365-2370.)
Ryan Bradley, ND, MPH is a naturopathic doctor, clinical researcher and epidemiologist in San Diego, CA. He is an Associate Professor and Assistant Director of Research at the National University of Natural Medicine in Portland, OR and an Assistant Professor in the Department of Family Medicine and Public Health at the University of California, San Diego.
1. Goldberg et al. J. Am. Diet. Ass. 2004
2. Cai et al. Circulation. 2004 and Vlassara et al. Proceedings National Academy of Science. 2002.
3. Kalousova et al. Kidney and Blood Pressure Research. 2004
4. Hoffman et al. Diabetes. 2002
5. Zheng et al. Diabetes/Metabolism Research and Reviews. 2002
6. Midaoui et al. Am J Hypertens. 2003 and Thirunavukkarasu et al. Pharmazie. 2005
7. De Mattia et al. Diabetelogia. 1998
8. Stirban et al. Diabetes Care. 2006
9. Guiotto et al. Curr Med Chem. 2005
10. Yatoh et al. Diabetes Met Res Rev. 2006
11. Konen et al. J Nutr Health Aging. 2000