ADVANCED GLYCATION ENDPRODUCTS REVISITED

By Dr. Bayne French

Let us define metabolism. Why? Because an unfavorable metabolism leads to the majority of diseases we will die from. So, if you want to avoid dis-ease, and stack the deck very significantly in favor of a longer (lifespan) and functional (healthspan) life, then come to understand what metabolism is and how to optimize it.

Metabolism is the vastly complicated and interwoven set of chemical processes that occur after digestion. So, you eat crap. That crap is acted on by chemicals and mechanical action in the intestine, making smaller bits of crap. These teensy bits of crap pass through the lining of the intestine and into the bloodstream. That’s when metabolism begins. What isn’t absorbed remains in the intestine, darkens from bile, and then you release a 5-pound Brown trout. Fire in the hole!

Metabolism is perturbed over the course of one’s life.

Being able to bend over and pick up your grandchildren depends on your ability to minimize the perturbation.

During the years of childbearing and raising children, we are metabolically more efficient. After that, things tend to go downhill. We have already passed on our genetic code, and in the broader sense, life has already fulfilled its purpose for us. What happens to our health after the happy phase of reproduction and child-rearing depends on what genetic cards we were dealt and how we play them. How can we nurture our genetic advantages? How can we reduce our genetic predisposition to disease? I am convinced that it depends on our eating habits, physical condition, stress management, sleep quality, and mood. Advanced Glycation Endproducts (AGEs) offer us another target, prompting us to minimize certain foods and even change how we prepare them.

Ages formed in our bodies:

I read a long article recently. Because I do stuff like that. Single-parenting is just so boring. Aragno et al. (Nutrients. 2017) put together a masterful tome on AGEs. It’s a bit frightening. “An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation End products (AGEs). AGE can be ingested with high temperature processed foods, but also endogenously formed as a consequence of a high dietary sugar intake”. Interpretation…you can eat AGEs, and you can form AGEs.

So, what in the hell is an AGE anyway? They are the products formed from sugars' interaction with other compounds, including proteins, fats, and our DNA (nucleic acids). They are considered toxic; in fact, they’re also termed glycotoxins. “The pathologic effects of AGEs are related to their ability to promote oxidative stress and inflammation by binding with cell surface receptors or cross-linking with body proteins, altering their structure and function” (Uribarri et al. J Am Diet Assoc. 2013).

Many of you are familiar with the blood test Hemoglobin A1c, particularly if you have developed diabetes. It is a very telling marker of metabolic wellness. It is a measure of AGEs! Sugars interact with the hemoglobin proteins in your red blood cells. It measures your average blood sugar for about 90 days, which is the lifespan of a red blood cell. But what about the rest of your body that isn’t turned over, replaced, and regenerated? Like your heart muscle, your brain tissue, and basically the majority of all your tissues? This interaction of sugar with these tissues, termed glycation, is largely permanent. The more AGEs, the faster you age.

Sugar is Sucrose, which is half glucose and half fructose. High-fructose corn syrup (HFCS) is a bit more fructose. Sugar-sweetened foods and drinks create a “psychological dependence” (Avena et al. Neurosci. Bioibehav. Rev. 2008). Sugar-added foods and drinks increase the risk of obesity (Schmidt et al. JAMA. 2014); cardiovascular disease (Malik et al. Circulation. 2010); fatty liver disease (Alwahsh et al. Arch. Toxicol. 2016); and cognitive decline, meaning you get un-smarterer. (Soares et al. Neuroscience 2013). I’ve written a few articles specifically about sugar, its toxic nature, and its anti-performance-enhancing effects. Re-read them because they’re just that good.

Sugar- The Antithetic Performance Enhancer.

According to Aragno et al., the formation of AGEs takes place slowly and continuously throughout the lifespan, driving AGE accumulation in tissues during aging. Yamagishi et al. (Nutrition 2016) reported that the accumulation of AGE drives many age-related diseases and that elevated blood sugar (hyperglycemia) is known to induce high rates of glycation.

How does hyperglycemia develop? There are spikes in blood sugar that occur during the day related to high carbohydrate eating and sugar consumption. These blood sugar extrusions are very unhealthy and drive diabetes, hypertriglyceridemia, obesity, joint inflammation, and basically feeling like absolute crap. Depending on your genetic predilections, these blood sugar excursions ultimately lead to insulin resistance and type 2 diabetes.  

Let me be clear: the pandemic disease of type 2 diabetes is one of excessive carbohydrate consumption… human animals consistently eat non-human animal food. In my experience, patients who choose to eat and drink differently than every other member of their family who have developed Type II Diabetes basically NEVER develop the disease. To restate, even with a strong family history of diabetes with different lifestyle choices, it is exceedingly rare to develop diabetes. Many other metabolic diseases are also far less, like cancer and heart disease. Think about the culture, though, of eating. The event of a meal runs so deep within families that it is the rare individual who can break free of that diabetic and obesity-prone familial system.

Stay with me. Recall that sugar is half glucose and half fructose. When we’re talking about AGE formation (glycation), fructose is WAY more potent than glucose. Bunn et al. (Science 1981) found that fructose glycated 7.5 times more than glucose. Other authors found over 10 times more potency of fructose than glucose at permanently sticking to our tissues, gumming up our cellular machinery and basically creating metabolic mayhem and creating glycotoxins. Just picking an exercise fuel, and a source of sweet that doesn’t involve fructose is a huge improvement. Sugar is just so bad in so many ways. Thus, among the numerous “sugars” used for sweetening drinks and foods, fructose (in the form of sucrose or high fructose corn sugar) likely represents the most hazardous for AGE accumulation and your health in general. 

Here's something interesting: we’ve developed proteins (enzymes) that help degrade (remove) AGEs. This is why I wrote largely permanent above. Of all the ways AGEs develop, from high-temperature cooking to interaction with a variety of carbohydrates, AGEs that develop from fructose are the hardest to remove (Mastrocola et al. Am. J. Physiol. Gastrointerst. Liver Physiol. 2013). Sugar then exerts a twofold contribution on glycation through both enhanced production and by reducing the bodies’ ability to detoxify them. Again, an exercise-fueling source or dietary form of sweets that isn’t sugar is just a better long-term choice.

Brownlee et al. (Ann Intern Med. 1984) detailed the three-stage formation of AGEs. The first stage involves a blood sugar elevation after a meal. This sugar interacts with other tissues in a matter of hours. It represents a “shot across the bow” because it is reversible. The occasional and mindful blood sugar excursion, no problem. The second stage becomes a bit more serious. Amadori products are made. These chemicals result from actual molecular rearrangement of our normal tissues. Are you getting an idea of how potent and sinister sugar is? Yet you have another chance. These Amadori products are not permanent. But…when they accumulate, the permanent third stage occurs, with the irreversible formation of AGEs. This process, depending on the degree of blood sugar abnormality and individual predilections, can occur over weeks or just in a few hours (Stirban et al. Mol Metab. 2014).

Ages formed in our diet:

Uribarri et al. (J Am Diet Assoc. 2013) wrote an article on dietary AGEs (dAGEs). These are advanced glycation endproducts already formed in the foods that we eat. Different foods and how they’re cooked make a big difference in the amount of dAGEs consumed. In this article multiple foods and cooking methods were studied and will be discussed later.

Animal-derived foods, even when uncooked, already possess naturally accumulated AGEs. Cooking creates more, especially with dry, high heat. Moist heat with lower temperatures with the addition of an acid like lemon juice or vinegar results in dAGEs being “significantly reduced”.

Let’s take a look at mice. What happens to them correlates with what happens to us. Maybe I’ll write a book one day. I’ll title it Of Mice and Men or something like that. Will probably win a Pulitzer like some of my other stuff. Anyway, it was thought for a long time that these nasty dietary AGEs are not absorbed into our bloodstream. Koschinsky et al. (Proc Natl Acad Sci USA. 1997) showed decades ago that mice clearly absorbed these nasty chemicals—poor little reptiles.

Multiple researchers have since shown that mice fed a high dAGE diet developed cardiovascular and kidney disease. And restricting dAGEs in the mice diet prevented cardiovascular and kidney disease, and the development of both type 1 and 2 diabetes. Cai et al. (Am J Pathol. 2008) reported two very interesting things: First, mice that ate less (time-restricted feeding/intermittent fasting) lived longer. Second, mice that ate less dAGEs also had a longer lifespan.

But what about humans? There’s been a study on us, too. Uribarri et al. (J Gerontol A Biol Sci Met Sci. 2007) showed that consumed dAGEs correlate with how much AGE is in our bloodstream. So, we, like mice, absorb these toxic compounds quite well.

There are lab tests that measure inflammation and oxidative stress. Elevated levels correlate with a much higher incidence of numerous diseases. Numerous authors have shown that minimizing dAGE’s results in reductions in these abnormal lab tests. “Together, the findings from animal and human studies suggest that avoidance of dAGEs in food helps delay chronic diseases and aging in animals and possibly in human beings” (Uribarri et al. J Am Diet Assoc. 2013).

Now, more on cooking. I recently learned how to do this out of necessity. Uribarri et al. at Mount Sinai School of Medicine studied the effects of boiling (100 degrees C), broiling (225 deg C), deep-frying (180 deg C), oven-frying (230 deg C), and roasting (177 deg C). The numbers below are a measure of AGEs and illustrate that raw food already possesses AGEs and how cooking increases the AGE burden:

• Chestnuts raw 817; roasted 1,606
• Beef frank boiled 6,736; broiled 10,143
• Beef steak raw 720; pan-fried with olive oil 9,052
• Chicken raw 769; grilled 4,848
• Salmon raw 527; pan-fried with olive oil 3,083; broiled with olive oil 4,334

Here’s a frustrating bit of trivia…many foods I consider to be metabolically unfavorable, like bread, ice cream, juice, and beer, have a very low amount of dAGEs. Easy now, think this through. The damage these substances cause occurs endogenously, meaning after they’re consumed and absorbed into our bloodstream.

The effect of marinating was also examined. Remember several paragraphs above:  …with the addition of acid like lemon juice or vinegar results in dAGEs being “significantly reduced”. 

The amount of dAGE in raw meat, marinated cooked, and non-marinated cooked meat were compared: 

The raw meat clearly has the lowest dAGE content (#1). The take-home here I think, is in #3. Simply marinating for 1 hour in an acidic solution like vinegar and lemon juice resulted in much less dAGE formation.

To summarize Uribarri et al. findings, animal products had the highest dAGE content. Fruits and vegetables are the lowest. In all food categories, exposure to higher temperatures and lower moisture levels coincided with higher AGE levels for equal weight of food as compared to foods prepared at lower temperatures or with more moisture. As an example, scrambled eggs cooked on medium heat had half as many dAGEs as those cooked on high heat. Poached and steamed chicken had less than a fourth of dAGEs compared to chicken that was roasted or broiled.

Grilling, roasting, broiling, and frying yielded more dAGEs compared to stewing, steaming, boiling, and poaching. 

Also observed is that higher fat foods had a higher level of dAGEs. As an example, full-fat dairy had higher dAGE than low-fat dairy. There are numerous benefits to the consumption of dietary fat. It is satiating, a great source of energy, results in weight loss, and generates ketones. The modest increase in dAGEs in higher fat foods needs to be reconciled with these other benefits.

Type 2 diabetes:

Let’s do a little diabetes in-service.  It is a metabolic disease from chronically elevated blood sugars. The main categories are type 1 and type 2. For our purposes, it’s ALL about type 2 and, according to Salazar et al., represents “one of the most massive epidemics of the twenty-first century.” If your goal is just to be left alone in your later years, then one of the best ways to achieve this is not to develop type 2 diabetes. And it IS dramatically preventable by human animals usually consistently eating human food.

This disease is a microcosm. Not that I know what microcosm means exactly, but it’s a way of viewing what’s in store for most humans that are habitual consumers of carbohydrates, especially sugar. It is driven by consistently eating what we are not designed to eat, consistently.

Salazar et al. (Int J Environ res Public Health. 2021) put together a super cool review of recent data in regards to AGEs and how they are pivotal in all the problems as a result of diabetes.

There are different ways of diagnosing type 2 diabetes, like a couple of blood sugars over 126 and/or a hemoglobin A1c of 6.5 or higher. What’s most important to know, however, is that the diagnosis comes from many years of metabolic dysfunction. And when the diagnosis is made, the metabolic dysfunction is dramatically accelerated. It is very unusual to actually die of type 2 diabetes. Those acute deaths are a result of extremely low or high blood sugars, and the death is sudden. The majority of individuals with type 2 diabetes will meet their premature death through complications of the disease.  The elevated blood sugars cause large blood vessel problems like cardiovascular disease (heart attacks and strokes) and also numerous small vessel problems like kidney disease and neuropathy.  The burden of cancer is also dramatically higher in patients with type 2 diabetes.  The principal player in all these type 2 diabetes-related complications is AGEs.

Goldin et al. (Circulation. 2006) authored a review article detailing the biochemical mayhem behind how AGEs cause arterial injury in patients with diabetes. It is well established that the burden of cardiovascular disease, both in small (microvascular) and large (macrovascular) arteries in patients with diabetes, is very high. AGEs, primarily those created in the body as a result of a high blood sugar environment, are at the forefront of arterial damage.

Conclusion

There are many mechanisms behind this damage. A primary one appears to be the interaction between AGE and RAGE. Yep, I can’t make this stuff up. RAGE stands for Receptor for Advanced Glycation End products. A receptor is a “docking port” that the AGE connects with. When RAGE is triggered, a host of unfavorable cellular signaling messages occur. The result is that the inside slippery lining (endothelium) of arteries becomes more permeable, allowing the influx of white blood cells, foam cells, macrophages, and cholesterol. This, then, is the crux of accelerated atherosclerosis, thus cardiovascular diseases like strokes, heart attacks, and kidney disease.

Once an AGE is formed, it is largely irreversible. When an AGE fits the RAGE like a lock and key, dramatic and unfavorable signaling takes place. Compounds like tumor necrosis factor are then created. I couldn’t even make up that name, and my imagination is freaky, as I’ve already said a few times. And there are dozens of scary chemicals that are created as a result of RAGE being activated. The result is disease, suffering, and early death. It’s all driven by what we eat, and how we cook it.

I’ve written extensively about the unfavorable metabolic actions that result from regular and excessive carbohydrate and sugar consumption. These compounds exert biological activity by numerous mechanisms.  A major mechanism appears to be the formation of AGEs and the resultant cauldron of unfavorable actions that ensue.

We want to prevent exactly what AGEs cause.  And to do so we must prevent the formation and consumption of AGEs themselves. 

Sun Tzu was a Chinese military strategist.  He also dabbled in philosophy, like me. He hated burpees but was hell on wheels with a sword.  He said, “Know thy enemy…”. We know it here. We have a very good idea about what causes AGEs, and about the damage that they then cause.

Simple action items involve cooking at a lower heat and with moisture. The fat content of an animal that did not eat their native food is much different than a grass-fed, wild-caught, wild game animal. Although I could not find any research comparing the amount of AGEs in animals depending on their feeding practices, it makes sense to me that animals that eat their native foods have a much less inherent burden of AGEs, to begin with. Grass just has a hell of a lot less carb than corn, sorghum, and oats. 

It is paramount to avoid repetitive blood sugar excursions. With every blood sugar spike, there is a potential for glycation.  The irreversible sticking of sugar to other compounds results in AGEs. Fructose, which comprises 50% of sugar, is a potent former of AGEs. I highly advised it not being a staple, and certainly not a fuel for exercise. Reserve it for a special occasion, like celebrating my mullet.