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AGEs and Oxidative Stress

Dangers

You might not realize it, but if you’ve ever appreciated that perfectly crispy layer of skin on a freshly roasted chicken, or admired the pattern of grill marks on your hamburger, you’ve enjoyed the results of the Maillard reaction. Discovered by French chemist Louis-Camille Maillard in 1912, this process is the reason why food browns when you cook it. Naturally occurring sugars and proteins in the food react together, producing that mouthwatering golden-brown color on everything from coffee beans to Thanksgiving turkey.

The browning of chicken

As delicious as this is on a steak, it’s much less desirable when it’s happening inside your body. Internally, chemical processes that start with the Maillard reaction can destroy the normal structure of proteins – and since protein performs so many important functions in the body, this is bad news. A similar series of reactions can do the same thing to fats, especially fragile PUFAs that are easily broken apart. Eventually, these series of reactions end up creating a group of harmful compounds called Advanced Glycation End products (AGEs).

AGEs are strongly connected to all kinds of age-related and degenerative disorders. To some extent, the accumulation of AGEs in the body seems to be a normal function of aging – they’re associated with chronic diseases like Alzheimer’s disease as well as the general decline in health associated with old age. But AGEs are also strongly associated with diabetes, especially the complications of diabetes, like vision problems, kidney failure, and cardiovascular symptoms. This gives us a clue that not all AGE-related degeneration is natural, and that it might have something to do with the metabolic damage of the modern industrial diet.

This does in fact seem to be the case: AGEs aren’t very well understood, but the evidence we have points to diet as a major contributing factor. While it’s not possible to escape aging completely, avoiding the main dietary sources of AGEs is one way to prevent premature aging, degenerative diseases, and oxidative stress.

How are AGEs Formed?

As the “Advanced” part of the abbreviation implies, AGEs are the end result of a complicated chain of chemical reactions. One way to produce AGEs is through glycation, a chemical process that results when a protein or fat molecule binds to a simple sugar without an enzyme there to control the reaction. The name “glycation” comes from “glucose,” but this is actually misleading because fructose (also a simple sugar) can be involved in the process in the same way.

Through a series of chemical changes, the new glucose-protein compound becomes something called an Amadori product, also known as an early glycation product (because it’s produced early in the process). Advanced glycation end-products are the result of further chemical changes that modify Amadori products even more. This is the classic Maillard reaction – the same process discovered in 1912.

More recently, researchers have also discovered that AGEs can also be formed through a variety of other pathways, many of which involve a process called oxidation instead of glycation (reacting with oxygen instead of glucose). Fats (especially PUFA) can be transformed into AGEs through oxidation – the results of these reactions are sometimes also called ALEs, short for Advanced Lipid Peroxidation end products. In the same way that glycation disrupts the normal functioning of the protein, oxidation destroys the normal structure of the fat.

Glucose can also be oxidized by some of the same processes. In yet another pathway, glucose is first converted to another kind of carbohydrate, sorbitol, before becoming AGEs. This is known as the polyol pathway, because sorbitol is a type of carbohydrate called a polyol (you might recognize polyols as also being a type of FODMAP, but this isn’t relevant to their role in producing AGEs). In all of these non-Maillard pathways, a group of chemicals called dicarbonyls are key players in transforming the original substances into AGEs.

All of these AGE-producing reactions can take place either in your food before you eat it or directly in your body. Food sources of AGEs are interesting to study, but the really concerning source of AGEs is internal production – which doesn’t mean that diet has nothing to do with it. On the contrary, diet has a huge effect on production of AGEs within the body, and a low-sugar Paleo diet is a safe and natural way to reduce the total damage done by AGEs in the body without needing to worry about food content or special cooking methods.

Dietary AGEs

Dietary sources of AGEs – also called exogenous AGEs, since they’re produced outside the human body – are one way to increase the total number of AGEs in a person’s body. Some foods are naturally high in AGEs, and since most of us don’t eat an entirely raw diet, it’s also possible to introduce AGEs to the food by cooking it. Certain chemicals (especially cigarette smoke) also contain noticeable levels of AGEs, but most people’s intake comes from their meals.

In terms of preparation, cooking methods that are both hot and dry tend to create the greatest spikes in AGE content. Frying or grilling, for example, will cause the number of AGEs to increase sharply, while wetter, slower methods like poaching or boiling will not. Cooking food in an acidic medium (such as vinegar or lemon juice) or marinating it in an acidic sauce beforehand will also decrease the total number of AGEs in the finished meal.

AGEs created from grilling meat

In the second category (foods that are high in AGEs even before they’re cooked), the specific numbers are disputed depending on which method of measuring AGEs you take as the standard, but it’s relatively clear that meats and fats have higher levels of AGEs than vegetables and carbohydrates. This should be alarming to Paleo dieters: meat and fat are two Paleo staples, but how can they be so healthy if they’re so high in AGEs? Can it really be true that plant sources of protein (such as beans and legumes) and a carbohydrate-based diet would contribute less to oxidative stress and chronic disease?

Fortunately, there’s no need to swear off grilled hamburgers and pan-fried chicken, because the total amount of AGEs in the diet isn’t actually a useful measure of the total number of AGEs in the body. Most dietary AGEs are excreted within a few days of eating them, and don’t stick around to cause oxidative stress or any other negative consequences.

It’s easy to spend a lot of time and energy choosing and preparing meals to minimize the total AGE content of your diet. But with any kind of dietary intervention, it’s also important to look at the gains – what kind of results do you get for all your hard work, and are they worth it? Is there a less laborious way to get the same benefits.

Endogenous AGE Production: Fructose Strikes Back

In the case of AGEs, it turns out that there’s a much less painful way to reduce free radical damage to your body than to drive yourself crazy with special food restrictions and preparation methods. The real damage from AGEs comes not from the ones on your plate, but from the ones you synthesize inside your own body (a process technically known as endogenous AGE production).

This is clear from a study comparing four different groups. One group ate the standard modern diet, another group ate a strict vegan diet, the third group ate a vegetarian diet (including eggs and dairy), and the fourth group ate a vegetarian diet including fish, but no other type of meat. Sine meat and fats are the foods highest in AGEs, it would be logical to expect that the vegans would have the lowest total AGE content in their bodies, and that the omnivores would have the highest. But in fact, the opposite was true. No matter how you measure AGE content, the omnivores had the lowest, even though they were eating a diet much higher in AGEs.

This study makes it very clear that the number of AGEs in the diet isn’t actually the most important factor that determines the number of AGEs in the body. It does make some difference (several studies have found a reduction in total AGEs in people eating an AGE-restricted diet), but clearly it’s not the only issue at play.  The real determining factor seems to be how many AGEs your own body produces – and that number depends on much more than how many AGEs you eat.

One of the most important determiners of endogenous AGE production is blood sugar. Specifically, people with high blood sugar produce many more AGEs, and by far the worst type of sugar seems to be fructose. Even though AGEs are named after glucose, fructose reacts to form them much more readily: the same researchers who found that vegetarians have a much higher concentration of AGEs in the blood remarked that AGE production increased linearly with an increase in glucose, but exponentially with an increase in fructose.

This accounts for the difference between the vegetarians and the meat eaters, and explains why the people with the lowest dietary intake of AGEs had the highest levels in their bodies. Since vegetarians had a much more carbohydrate-based diet, and a much higher amount of fructose in the diet overall, their endogenous AGE production was greater. The strong relationship between blood sugar and AGE production also fits with the evidence from a number of studies that show very high levels of AGEs in people with diabetes (more on this below).

Dietary sugar intake can influence the creation of AGEs through the Maillard reaction process, but dietary fat can also play a role in generating AGEs (or ALEs) through oxidation. Specifically, the fats most susceptible to oxidation are PUFA. Remember that PUFAs are dangerous in large amounts because they’re very chemically fragile, so when they’re exposed to stressors like light, heat, and oxygen, they tend to oxidize (which transforms them into AGEs). The PUFAs in modern processed food have been chemically processed and heated, and then left to go rancid at room temperature – they’re oxidized before they even get to your mouth. But just keeping the peanut oil in a cool, dark place won’t cut it either: even unoxidized PUFA increases the levels of oxidative stress in the body, because the oxidation reaction can occur internally as well. This may be another reason why the non meat-eaters in the study had higher levels of AGEs: while the omnivores could cook with lard, tallow, or butter, vegans with much more limited options would be more likely to cook with seed oils high in PUFA.

The upshot is that endogenous AGE production is the source of AGEs you should really be worrying about. While dietary AGEs do have some effect on the total level of AGEs in the body, it’s simplistic to say they’re the only cause. More accurately, certain elements of the modern diet (especially fructose and PUFA) tend to support the production of AGEs in the body, which is a much more serious problem.

AGEs and Diabetes

Since the formation of AGEs is so closely tied to blood sugar, it’s easy to see how people with diabetes can suffer from extreme forms of AGE-related damage. In fact, much of the research into AGEs has been done on diabetics, because AGEs and diabetes are so closely related. One of the major tests for diabetes is actually a measurement of glycation (the chemical process that kicks off the formation of AGEs). It’s called the A1C test, and it measures what percentage of hemoglobin (a protein in your blood) has gone through the first stage of the Maillard reaction. The higher the percentage, the higher your blood sugar is – and the more AGEs are concentrating in your body.

Since so many complications of diabetes are largely driven by AGEs, diabetes symptoms provide a useful (if depressing) way to study the most extreme effects of long-term oxidative stress and AGE production in the body. By damaging proteins and cells, AGEs disrupt the structural building blocks of major organs and physical systems: in diabetic patients, increased numbers of AGEs are strongly associated with virtually all major complications of diabetes, including cardiac problems, vision damage, kidney failure, and heart disease.

The good news is that diabetes also offers some support for controlling blood sugar as a way to reduce AGE-related damage. In diabetic rats, control of blood sugar levels resulted in a noticeable decrease in both AGEs and ALEs. Many studies have also suggested a low-AGE diet for diabetics, but since the measurement of AGEs in different foods is so imprecise, and since a low-AGE diet is likely to be high in carbohydrates (which would do much more harm than good to diabetics), this isn’t a particularly useful treatment from a Paleo standpoint.

The connection of diabetes-related high blood sugar and AGEs has caused many people to focus exclusively on the classic Maillard reaction (monosaccharide + protein = AGE), but it’s important to remember production of AGEs in the body is much more complicated: AGEs can also be formed from several other types of oxidizing reactions. They are strongly linked to diabetic complications, but diabetes involves many types of metabolic and hormonal damage besides high blood sugar, so it’s quite unlikely that hyperglycemia is the only problem involved. As diabetes becomes an increasingly prevalent public health crisis (and hopefully as researchers begin to realize that the officially recommended low-fat, high-carb diet is doing nothing to help), new research on AGEs will probably uncover further connections to the symptoms and causes of diabetes.

Oxidative Stress

One of the more interesting aspects of AGEs is their relationship to oxidative stress. Oxidative stress is a kind of cellular damage caused by very unstable molecules called reactive oxygen species (ROS). Healthy and normal cells do produce some ROS, but the oxidative stress caused by too many ROS is a major contributor to aging and degenerative diseases: exactly the same conditions that are also linked to AGEs.

High levels of AGEs and high levels of oxidative stress are definitely related, but the relationship between them isn’t a simple cause-and-effect chain. Instead, the evidence suggests that AGEs and oxidative stress can create something of a vicious circle. Higher levels of oxidative stress may contribute to the formation of some chemical compounds necessary for the formation of AGEs. At the same time, reactive oxygen species (the molecules behind the development of oxidative stress) are by-products of AGE formation, so AGEs also increase oxidative stress.

This seems to be a depressing vicious cycle, but it also offers a useful insight: controlling your oxidative stress (by getting enough sleep, eating a healthy and non-inflammatory Paleo diet, and avoiding modern food toxins, you can also help prevent the formation of AGEs.

AGEs and Antioxidants

With any dietary danger, the temptation to go hunting for a magic super-supplement to “make up for” the damage is strong. In the case of AGEs, that magic bullet is antioxidants: if oxidative stress is so closely related to AGEs, couldn’t antioxidant supplementation help stop AGE formation in its tracks?

It seems like a great idea at first, but over-supplementing with antioxidants can actually cause more harm than it cures. Eating fresh fruits and vegetables (which contain antioxidants) is always a healthy idea, because fruits and vegetables are whole foods that contain balanced levels of several important vitamins and minerals. But commercial antioxidant supplementation isn’t a magic bullet for AGEs or anything else – it’s better to reduce the endogenous formation of AGEs in the first place by keeping dietary fructose and PUFA low, minimizing oxidative stress, and controlling your blood sugar.

Conclusion

It’s painful, but true: human beings just aren’t designed to live forever. Our life cycle includes a period of declining physical abilities as we get older, and accumulating AGEs in the body is a natural and unavoidable part of this. The raw materials that drive the production of AGEs and ALEs (amino acids, sugars, and fats) cover all the necessary food groups: trying to restrict them is likely to end your life much faster than any amount of AGEs.

That said, premature aging isn’t on anyone’s to-do list, nor is it natural. And the complications of diabetes are definitely the product of the artificial modern food environment, not some innate human destiny. The high amounts of fructose in the modern diet and the prevalence of inflammatory and unstable PUFAs contribute to the abnormally high concentration of AGEs in patients with diabetes, the trademark disease of the modern diet and lifestyle. By avoiding oxidized fats and keeping your fructose intake to a level that your body can reasonably metabolize, you can avoid the systemic symptoms of oxidative stress without making any extreme changes in diet or lifestyle.




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