Thursday, September 14, 2017

AGEs You Know?

Do You Know Your AGE?
How and Why to
Prevent AGE Damage

Advanced glycation endproducts (AGEs) may be a
fact of life, but fighting them may extend your life.
By Will Block
f we may be so bold, which would you rather have and hold—GOLD or MOLD? OK, it’s a trick question (please don’t scold), because if truth be told, you wouldn’t want either—they’d leave you cold if you knew they were both about . . . old.
Old people, you see, are the victims of AGE—Advanced Glycation Endproducts, of which GOLD and MOLD are two prominent examples. The acronyms stand for glyoxallysine dimer and methylglyoxallysine dimer, respectively, but don’t worry—there won’t be a quiz on that. It would be wise, however, for you to become better informed about AGE (or AGEs, as they’re often called), because these chemical compounds are a key factor in the aging process.
As you will see, AGEs are formed inside your body through normal metabolism and aging, and outside your body during the preparation of some foods you eat. They’re implicated in the development or exacerbation of numerous degenerative diseases associated with aging, notably type 2 diabetes, atherosclerosis, cardiovascular disease, Alzheimer’s and other dementias, cataracts, retinal dysfunction, kidney failure, nerve damage, arthritis, and cancer.
Supplements Can Slow AGEing
It’s impossible, alas, to avoid AGEs altogether—their formation begins during early embryonic development and continues steadily for the rest of our lives. The body’s mechanisms for removing unwanted substances cannot keep up, because the AGEs are resistant to this process. Therefore, even if every other factor in the aging process could be magically eliminated, it would still be impossible to avoid aging. The good news, however, is that the “AGEing” process can be slowed down—and so, therefore, can the aging process. There are two ways to do this. Ideally, we should do both.
One way to slow AGEing involves the use of certain supplements that have been shown—in laboratory experiments, animal studies, or human clinical trials—to inhibit the formation of AGEs. Notable in this regard are: benfotiamine, a fat-soluble form of thiamine (vitamin B1); the amino acid histidine; the dipeptidecarnosine, which consists of linked histidine and beta-alanine; alpha-lipoic acid, a saturated fatty acid renowned for its potent and versatile antioxidant actions; and rutin, a flavonoid found in many plants, notably buckwheat, black tea, and apple skins.*

*Some of the evidence for these compounds was discussed in “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue.

No! Nooo!
The other way to slow AGEing is to (are you sitting down?) avoid, as much as possible, browning the foods that you cook. Just as the colors red, orange, yellow, blue, and purple are usually signs of exceptional healthfulness in fruits and vegetables (these colors come mostly from flavonoids), the color brown should be considered a “red flag” warning ofunhealthfulness in the crusts of bakery products and in meats or vegetables that have been baked, roasted, broiled, grilled, fried, sautéed, etc. It’s better for your health to steam, boil, or stew the meats and veggies.1
I can hear you now: “No! Nooo!” I know, I knooow. Forgoing the most delicious preparation methods seems almost insane—like giving up sweets. But it does have its rewards: better health and longer life.

†For some good news on the sweets front, see the article on page 11 of this issue. That article and this one share an emphasis on the importance of glycemic control for maintaining good health.

A Prediction Ignored, Then Verified

Louis Camille Maillard
To understand AGEs (about which there is much confusion in the popular literature), we need to go back a century, to prewar Paris. In 1912, a young French physician and chemist named Louis Camille Maillard (Mah·YAHR) began investigating the chemical reactions between nutrient sugars (such as glucose and fructose) and amino acids, the building blocks of proteins.
When Maillard heated aqueous solutions of sugars and amino acids for a few hours, they turned a yellow-brown color, the result of a series of reactions that yielded a witches’ brew of products. Significantly, the same phenomenon occurred, albeit much more slowly, when he simply allowed the solutions to sit for a few weeks under physiological conditions (37ºC, pH 7.4).
Maillard had discovered a series of complex and important chemical reactions that now bear his name:Maillard reactions. He predicted that they would occur in the human body, especially in diabetic patients because of their chronically high glucose (blood sugar) levels. This prophetic insight went unnoticed for half a century, however, and he did not live to see it realized.
In 1971, scientists investigating the blood of diabetic patients discovered that some of the hemoglobin wasglycated. Glycation—the first step in the Maillard reactions—is the chemical attachment of a sugar molecule (either free or bound in a polysaccharide, such as starch) to an amino acid (either free or bound in a protein, such as hemoglobin). As the ensuing reactions advance through numerous complex stages, they can lead to a great variety of endproducts, most of which are harmful to us. These are the “advanced glycation endproducts” we now call AGEs.
AGEs Make Diabetes a Kind of Accelerated Aging
The sugar of greatest importance to us is glucose, because it’s the principal product of carbohydrate digestion, and it’s our principal fuel for energy metabolism. Glucose is among the least reactive of the nutrient sugars in the Maillard reactions. This may have led, through natural selection, to its being the evolutionarily favored sugar in mammalian species.2,3
The glycation reactivity of fructose (fruit sugar), on the other hand, is about ten times higher than that of glucose. Fructose is found in honey and many fruits, and it’s also one-half of the sucrose (table sugar) molecule, the other half being glucose. The exceptional propensity of fructose to produce AGEs is another reason why we (diabetics especially) should minimize our intake of sucrose and high-fructose corn syrup.
Because diabetics tend to have higher glucose levels than nondiabetics, they also have higher AGE levels at any given age, compared with nondiabetic individuals. And because AGEs form earlier in life and more rapidly in these patients, diabetes can be thought of as an accelerated form of aging. Much evidence suggests that AGEs are involved in almost all the complications of diabetes, which arise from damage to blood vessels throughout the body.4
AGEs—A Haphazard Process
Unlike most biologically important reactions, which are catalyzed by enzymes, glycation is not catalyzed. It’s a nonenzymatic version of a common and necessary biochemical process calledglycosylation, which is tightly controlled as to the time, place, and extent of its occurrence. The lack of enzymatic control over the glycation process means that this reaction can occur haphazardly—anytime, anywhere, to an extent limited only by the availability of the reactants—and it does, with generally harmful results that tend to accumulate over time.
Now you get the picture: there’s nothing to restrain glucose from reacting with amino acids and proteins, which are everywhere in the body. Since we can’t live without glucose, we can’t avoid AGEs—but we can slow down their formation. Another bit of good news is that not all glucose will react similarly with all proteins (of which there are about 25,000 different kinds in humans)—the extent of the reaction depends on a myriad of factors that can vary greatly throughout the body. But, as we saw above, the list of “hot spots” is large, and the long-term consequences are horrendous.
Most AGEs Are Incredibly Yummy
So much for the AGEs that form in our bodies as a result of normal metabolism. What about the ones we ingest with our food? Isn’t it adding insult to injury to eat the very kinds of compounds we’re trying to minimize the formation of in our bodies? Of course it is, but if you’re the kind of person who likes food, you probably love dietary AGEs (which should be called DAGEs), because they happen to be among the tastiest compounds known. (This is another of Ma Nature’s cruel jokes at our expense.)
It’s no accident that many AGEs are found in commercial food flavorings designed to make all kinds of foods taste even better, as though they’d been browned. (The Maillard reactions are, in fact, the basis of the flavoring industry.) Nor is it an accident that the bits of browned stuff left over in the frying or roasting pan, which celebrity chef Emeril Lagasse calls “yum-yums,” are yummy because of the Maillard browning, which is the principal source of DAGEs.
Oh, What a Tangled Web Maillard Wove
Over 1000 DAGEs are currently known, and there are probably many more. They’re the products of Maillard reactions occurring under dry conditions at temperatures above about 120ºC (248ºF). The tangled web of chemical reactions is so complex that many chemists have spent their whole lives trying to unravel it. The caramelization (browning) of sugar, by the way, may appear to be a Maillard-type process, but it’s not—the chemistry is entirely different.
In books on the chemistry of cooking, the Maillard reactions are portrayed in a good light because of the gustatory wonders they produce. Chefs love them, naturally, and they’re not about to commit professional suicide by shunning them just because some scientists recommend it. In any case, the books claim that the Maillard reactions occur only with high, dry heat, not at the lower temperatures involved in cooking with water, where the maximum is 100ºC (212ºF). That may be true in the kitchen, where time scales are usually very short, but in real life, as Maillard himself showed, the process does occur—very slowly—even under cool, wet conditions.
You Are So Cool (and Wet)
Not to get too personal, but your body, compared with an oven or barbeque, is rather cool and wet, and the Maillard reactions will proceed, slowly but surely, for all the days of your life. You could, however, resist this slow tide by taking antiglycating supplements every day.
And given a choice between eating browned foods that are high in Maillard products, or water-cooked foods that have virtually none . . . well, that too is a choice that only you can make. (Let’s hope the federal health police don’t someday try to make it for you.)
AGEs Large and Small
There are hundreds of known, naturally occurring AGEs produced by the Maillard reactions in our bodies. Some of these are very large molecules produced by the chemical cross-linking—induced by sugars—of proteins that were never intended to be linked. This produces a kind of cellular “gunk,” which in principle is not unlike the crud that builds up in your car’s engine over time. In both cases, performance is impaired, and the system can be brought to a premature halt if suitable measures are not taken.
One example of the slow damage due to cross-linking is the gradual stiffening of the protein collagen, which is the principal component of our connective tissue and cartilage. The resulting loss of tissue elasticity can occur in the heart, blood vessels, skin, eyes, kidneys, joints, etc., with results that older people know all too well.
Many other AGEs are relatively small degradation products of the Maillard reactions, and some of these contain a reactive chemical group called the carbonyl group, R2C=O. [The carbonyl is the C=O part; the two Rs can be almost anything but hydrogen atoms, as, e.g., in acetone, (CH3)2C=O, which contains two methyl groups.]
Carbonyl compounds are common in organic chemistry, and many of them instigate harmful chemical reactions in living organisms. In fact, the glycation reaction that begins the Maillard process involves a carbonyl group on the sugar molecule reacting with the amino group of an amino acid. The spectrum of damage caused by carbonyl compounds is calledcarbonyl stress. It’s analogous to the oxidative stress caused by reactive oxygen species, including free radicals.
AGEs of a sort can also be formed, by the way, by the reactions of sugars or other reactive carbonyl compounds with two other important types of biological molecules: lipids (fats) and nucleic acids (DNA and RNA). These AGEs too are deleterious to our health.
  1. Harding A. How food is prepared important to health: study. Reuters Health, May 7, 2007.
  2. Ahmed N. Advanced glycation endproducts—role in pathology of diabetic complications. Diabetes Res Clin Pract 2005;67:3-21.
  3. Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res 2001;56:1-21.
  4. Peppa M, Uribarri J, Vlassara H. Glucose, advanced glycation end products, and diabetes complications: what is new and what works. Clin Diabetes 2003;21(4):186-7.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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