Coming of AGEs

Cooking food is something that many people don’t think much about. Yet human beings have cooked food since prehistoric times. Prehistoric man caught and cooked wild game, and the tradition of heating food has continued through the eons. While a minority of people today espouse the notion of eating food only in its raw state—the food, not the people—given the choice, most people want their food cooked.

Food can be cooked by various means: boiling, grilling, roasting, frying. Besides changing food in ways that increase aroma, flavor and color, cooking offers a few practical benefits. Heating destroys bacteria that could cause food poisoning or other ills. Potentially toxic compounds found in raw food, such as lectins and protease inhibitors that could interfere with protein digestion, are destroyed by heat. While many plant-based foods are eaten raw, often to conserve certain nutrients, other plant foods release their bounty of protective nutrients when cooked. Take, for example, tomatoes. Lycopene, a protective nutrient linked to lower rates of cancer and cardiovascular disease, is more available in cooked tomato products than in raw tomatoes.

While cooking is the preferred mode of food preparation, it produces substances that could harm your health. The heterocyclic amines produced when meat is barbecued are linked to colon cancer. They are more of a factor, however, when meat is cooked to the well-done stage. Other substances that result from the heat of cooking are collectively known as advanced glycation end products, or AGEs.

AGEs result when sugars react with proteins, and their production also occurs in the human body. In fact, the process that results in AGEs is considered a leading theory of aging. Recent studies even suggest that most causes of aging have an AGEs link. In the body, the process that results in AGEs production is known as “nonenzymatic glycation” because no enzymes are involved, although other enzymes protect against the process. The process itself is complex and consists of two early stages marked by the interaction of sugar molecules with amino acids. The result is the generation of the advanced product, or AGEs.

In the body, AGEs are thought to result from a long-term interaction between glucose, the only sugar that circulates in the blood, and proteins. Glucose, however, is the least reactive of all sugars, and that may be the reason it evolved as the primary sugar in the blood. A far more reactive sugar is fructose. Vegetarians, who eat little or no cooked foods, take in a lot of fructose, which explains why vegans have high concentrations of AGEs in their bodies.1 AGEs prematurely age proteins, including the proteins that make up skin, and that explains why many long-term vegans look older than they are.

The process of producing AGEs also releases large amounts of free radicals, which are substances that have unpaired electrons. Free radicals seek to combine with other electrons, but when that happens, the paired electrons malfunction. That typically occurs in fat tissues, such as cell membranes. The body deals with free radicals by neutralizing them with built-in antioxidant systems and with the antioxidants it gets from food. The extensive free-radical release involved in AGEs formation can overwhelm the body’s defenses, leading to degenerative diseases and faster aging.

Diabetics have elevated blood glucose, and as you might expect, that relates to greater production of AGEs and more rapid aging. In fact, diabetics age about five times faster than other people, and it’s all because of increased AGEs production. Rapid aging is not confined to diabetics, however. Exposure to glucose leads to some degree of glycation in anyone who lives long enough. Markers of glycation in the body increase fivefold from infancy to old age.2 Diabetics are particularly prone to the effects of AGEs not only because of higher blood glucose but also because of decreased kidney function. Excess AGEs are excreted through the kidneys, and that avenue of elimination is impaired in diabetics.

Insulin sensitivity is known to decline with age. While much of that decline is related to a loss of lean mass, or muscle, due to inactivity, AGEs also come into play. Both AGEs and the free radicals they produce interfere with insulin receptor functioning, which alters both glucose and glycogen metabolism.

Another theory suggests that aging is caused by the gradual destruction of mitochondria, the energy-producing structures in cells and where the immediate source of cellular energy, ATP, is produced. Fat is also oxidized in mitochondria in a process called beta-oxidation. With age, AGEs can accumulate in mitochondria. One reason for that is long-term high blood sugar. That leads to more free-radical production in mitochondria, overwhelming the built-in defense system. It eventually leads to the destruction of mitochondria, which in turn results in cell death and aging.

One reason AGEs accumulate with aging is the loss of kidney function. Most older people retain 40 percent of their kidney function. As noted above, the kidneys are essential for the elimination of AGEs, whether naturally made in the body or derived from food. The retention of AGEs in older people makes them more prone to certain diseases, including Alzheimer’s disease.3 In blood vessels AGEs inactivate nitric oxide, leading to hypertension, or high blood pressure. AGEs become incorporated in low-density lipoprotein—the bad kind of cholesterol—leading to its oxidation and decreased clearance from the blood. That results in cardiovascular disease. In the eyes, AGEs interact with protein in the lens to produce cataracts.

Another reason AGEs accumulate in the body with age relates to immune-system components called macrophages, which are types of white blood cells found primarily in the blood and connective tissue. They destroy foreign invaders, such as bacteria, by engulfing them and digesting them in a process known as phagocytosis. The relationship to AGEs is that macrophages are attracted to AGEs receptors, known as “RAGEs,” and prevent the accumulation of AGEs in the body. The problem is that the older a body is, the more immune response becomes blunted, as does the AGEs protection offered by macrophages. That’s another reason AGEs damage shows up more often in older people.

AGEs and Nutrition

While AGEs produced in the body are a major cause of some of the effects of aging, they are also in foods. In fact, many of the foods most common and popular in typical bodybuilding diets are loaded with AGEs, mainly because of cooking. Cooking foods produces a process known as the Maillard reaction, named after the scientist who first described it in 1912. The Maillard reaction is caused by heat browning food and leads to a reaction between naturally occurring sugars and proteins in the food. The AGEs formed by cooking are released into the blood during the digestive process. Some emerging evidence shows that the Maillard reaction offers protection against prions, which are protein particles suspected of causing fatal brain diseases, such as variant Creutzfeldt-Jakob—that is, mad cow—disease.4

AGEs can adversely affect protein digestion, making them a special concern to bodybuilders and other athletes. In one study, 21 subjects followed either heated or unheated high-protein diets—three grams per kilogram of bodyweight—for one week each.5 Both diets contained the same amounts of energy, protein and carbohydrates. The heated diet produced high markers of AGEs, while the unheated diet produced nearly none. Those on the high AGEs diet gained more weight and had increased insulin insensitivity. They also showed early signs of kidney problems.

Another study examined how diets rich in Maillard reaction foods affect protein digestion in boys aged 11 to 14. The 18 boys in the study followed two different diets for two weeks, each separated by a 40-day washout period, in which no diets were followed. One diet contained more fried, broiled and baked foods and so was higher in Maillard reaction products. When eating that diet, the boys showed higher markers for those products, which are known to interfere with the activity of protein digestive enzymes. They had a 47 percent higher fecal nitrogen excretion rate, 12 percent lower nitrogen absorption and 6 percent lower nitrogen digestibility. Nitrogen is found solely in protein, thus linking greater intake of Maillard reaction products or AGEs to an interference with normal protein digestion.

Certain amino acids in protein are particularly susceptible to the effects of AGEs. Examples include lysine and arginine. When lysine, an essential amino acid, is altered by AGEs, it reduces the uptake and digestibility of other essential aminos. A study that examined commercial whey protein supplements found that some showed markers of AGEs related to a breakdown of lysine in the product. Whether that occurred depended on how much heat was used to process the product and how much sugar the product contained. The study suggested that whey protein powders that aren’t subjected to excess heat treatment and are low in sugar, are okay to use and provide full potency. Another amino acid, taurine, protects against the formation of AGEs in the body.

As noted above, AGEs are found in many popular foods. One study looked at markers of AGEs production in 250 foods.7 Foods high in fat showed the most AGEs, followed by meat and meat-substitute products. Carbohydrate foods, including milk, bread, pancakes and fruits, were the lowest. The AGEs content of any food related to how it was cooked; the higher the temperature, the greater the presence of AGEs. Thus, broiling and frying led to the most AGEs, followed by roasting and boiling. The study noted that methods of cooking that apply less heat, such as boiling and stewing, reduce AGEs formation by 50 percent while retaining the same amount of nutrients. The authors suggest that you can reduce AGEs intake by cutting back on high-fat cheeses, meats and highly processed foods and increasing fish, grains, lowfat milk, fruits and vegetables.

Not every scientist accepts the notion that AGEs are dangerous to health. Skeptics note that they have been eaten ever since man first began cooking food, and purposeful Maillard reactions are used in the generation of flavors and colors and the modification of food properties. Those researchers don’t deny the effects of AGEs produced in the body as a cause of disease, but they argue against the idea that AGEs in food are hazardous to health.

One reason is that AGEs produced in the body are bound to proteins in tissues, while those found in foods are absorbed in a free, or unbound, state. The difference is that free forms are rapidly excreted by normal kidneys, while those in the body must first be degraded. Even glycated proteins in the body are detected and broken down by a special enzyme system. That system is impaired both in the aged and in those who have decreased kidney function, such as diabetics. Some dietary AGEs even have antioxidant effects and can activate phase-2 detoxifying enzymes in the liver. Since most of the potentially toxic effects produced by dietary AGEs are related to increased oxidation, that effect can be blocked by the body’s antioxidation system, as well as dietary antioxidants—or so say the skeptics.

Complicating that view is a study that measured dietary AGEs in both young and older people.8 One hundred and seventy-two healthy men and women were divided into two age groups: 18 to 35 and 60 to 80. Blood tests showed that AGEs were 35 percent greater in those over 65. More important, however, was the finding that the AGEs in the blood directly correlated with what the subjects got from food. In addition, higher measures of AGEs showed a relationship to markers of inflammation, which is now known to be the cornerstone of most major diseases, including cancer and cardiovascular disease. AGEs release inflammatory substances in the body. The study also found high counts of AGEs in some younger subjects comparable to counts in diabetics. The authors suggest that the higher rate of AGEs in the young is related to increased diabetes and cardiovascular disease.

They further note that while the body can excrete dietary AGEs, it can be easily overwhelmed by excessive intake of fried, broiled and grilled foods. Over time, that can result in disease or premature aging. Once in the body, AGEs are increasingly difficult to eliminate, especially as you get older. You see it in the aging of muscle tissue. Studies show that while the contractile proteins in muscle remain stable with age, the connective tissue that surrounds muscle fibers is highly susceptible to AGEs.9 One study found a 200 percent increase of a marker of AGEs in collagen protein in muscle connective tissue. That would translate into increased muscular stiffness and loss of flexibility with aging, an effect more common in people who don’t exercise. In fact, some studies show that aerobic exercise can help prevent the negative effects of AGEs in cellular mitochondria.

What can you do to offset the effects of AGEs in your body? Since much of the damage results from oxidative effects, it’s vital to ensure a rich supply of dietary antioxidants, such as vitamins C and E and green tea. Some experts consider calorie restriction to be the only way of slowing down the aging process—the mechanism of decreasing AGEs formation by keeping down blood glucose counts. Since calories need to go down by 30 percent to impact the body, calorie restriction is impractical for most people. Intermittent fasting, or eating less every other day, can produce most of the health benefits attributed to calorie restriction, including fewer AGEs.10

You would want to avoid using drugs classed as methamphetamines, or “speed,” since recent research shows that those commonly abused drugs are potent initiators of glycation. Long-term use leads to out-of-control inflammation, which may explain their destructive effects on the brain.

A flavonoid in citrus products called rutin was recently found to exert potent antiglycation effects.11 Carnosine, a dipeptide consisting of beta-alanine and histidine, helps prevent glycation and AGEs in the body.12 Since supplemental beta-alanine is the direct precursor of carnosine production in muscle, its long-term use may exert an antiaging effect in muscle tissue. Polyamines—substances produced from the amino acid L-arginine—also protect against AGEs, as does creatine. A form of vitamin B6 called pyridoxamine is clinically shown to block AGEs.14 It’s more potent than a drug called aminoguanidine, which was the first substance found to prevent AGEs damage. It fell out of favor because of potential long-term toxicity; it tended to produce a vitamin B6 deficiency.

Another drug, referred to as ALT-711, shows promise in preventing the damaging effects of AGEs, as does a fat-soluble form of vitamin B1, or thiamine, known as benfotiamine. The oral antidiabetic drug metformin has shown antiaging effects in animals because it lowers sugar levels but also has an independent effect on preventing formation of AGEs. Small amounts of a metabolite of alcohol called acetaldehyde form a complex with the glycation products that results in AGEs, which then blocks AGEs formation. That helps explain some of the benefits of moderate alcohol intake. Aged garlic extract supplements also appear to offer protection against the damage induced by AGEs.15 A new study found that cinnamon contains factors that help prevent the formation of AGEs.16

A study of worms found that upgrading the activity of glyoxalase-1, an enzyme also found in humans, diminishes the glycation process—extending worm life, anyway, by 40 percent. When the activity of the enzyme was decreased, the worms’ life span was shortened. The enzyme converts the damaging reactive products derived from glucose into harmless compounds. In another study, normal mice that got a lifelong diet containing a 50 percent reduced level of AGEs over normal showed no increase in age-related oxidative stress, no insulin resistance with increased age, less organ and tissue damage and, most important, a longer life span than mice put on diets that had more AGEs.17

While the effects of AGEs remain controversial, few would argue that they play a major role in the aging process, and recent studies suggest that they can accumulate in the body over time. Good evidence also shows that if you can keep the production of AGEs to a minimum, you’ll retain the appearance, strength and movement associated with youth far longer.

Editor’s note: Jerry Brainum is the author of the e-book Natural Anabolics, available at www.JerryBrainum.com.

References

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2 Dyer, D.G., et al. (1993). Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest. 91:2463-2469.

3 Vitek, P., et al. (1994). Advanced glycation end products contribute to amyloidosis in Alzheimer’s disease. Proced Natl Acad Sci. 91:4766-4770.

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11 Laurean-Cervantes, D., et al. (2006). Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites. J Nutr Biochem. 17:531-40.

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13 Gugliucci, A., et al. (2003). The polyamines spermine and spermidide protect proteins from structural and functional damage by AGE precursors: A new role for old molecules. Life Sci. 72:2603-2616.

14 Voziyan, P.A., et al. (2005). Pyridoxamine: The many virtues of a Maillard reaction inhibitor. Ann NY Acad Sci. 1043:807-16.

15 Ahmad, M.S., et al. (2007). Aged garlic extract and S-allyl cycteine prevent formation of advanced glycation endproducts. Eur J Pharmacol. 561:32-38.

16 Peng, X., et al. (2008). Cinnamon bark proanthocyanidins as reactive carbonyl scavengers to prevent the formation of advanced glycation endproducts. J Agric Food Chem. 56(6):1907-11.

17 Cai, W., et al. (2007). Reduced oxidant stress and extended lifespan in mice exposed to a low glycation diet: Association with increased AGER1 expression. Am J Pathol. 170:1893-1902.

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