Advanced Glycation End Products (AGEs): Genetics, lifestyle, and health span

Recent research shows that advanced glycation end products (AGEs) are a causative factor in many degenerative diseases. AGEs have been linked to Alzheimer’s, heart disease, diabetes, chronic kidney disease, wrinkles and loss of skin elasticity, and more.

Like most topics covered here on Genetic Lifehacks, both genetic susceptibility and lifestyle interact to cause the problems associated with AGEs. This article will dig into genetic susceptibility and then discuss the lifehacks that can help mitigate any susceptibility. In fact, one specific type of advanced glycation end product has been shown to be highly determined by genetics.[ref] Members will see their genotype report below, plus additional solutions in the Lifehacks section. Join today. 

Advanced Glycation End Products:

The term AGEs (advanced glycation end products) refers to a lipid or protein being glycated, meaning sugar or aldehyde binds with the protein or lipid. It is a general term applied to a bunch of different molecules, but the basic premise is certain byproducts of glycolysis (producing energy from sugar) can bind with a protein or fat in the body and alter it permanently.

AGEs naturally occur in the body as a result of normal metabolism. You can also consume AGEs in foods, and their production can depend on how you cook the food.

The problems with advanced glycation end products develop when an excess is produced by the body, along with consuming a diet high in AGEs.

First, a quick food example of AGEs to give you a picture of what is going on… When you throw a steak on the grill or brown a pork chop in a hot pan, advanced glycation end products form in the process of browning of the meat. Known as the Maillard reaction, it is what makes grilled meat and vegetables taste great and smell delicious. This Maillard reaction produces advanced glycation end products in food. Think about uncooked bacon versus the taste, feel, and smell of cooked bacon – a big part of the deliciousness is the production of AGEs. It also causes the proteins to transform, linking them together to create nice, crispy bacon.

Grilled meat makes a great mental image, but AGEs also form within the body under normal conditions. In fact, the majority of advanced glycation end products come from this natural formation process in the body rather than from food.

So let me go into the formation of AGEs in the body first and then discuss ways to prevent the formation of AGEs in foods in the Lifehacks section at the end.

Where do advanced glycation end products come from in the body?

Glucose is the main fuel that your body uses for energy. (Yes, you can use fat for energy also if you are in ketosis. Stick with me here, even if you are a low carb fanatic.)

We get glucose from consuming carbohydrates, and our body breaks them down into simple sugars. The body can also create glucose via a process called gluconeogenesis, but this isn’t a big source of glucose under normal circumstances.

Inside all of your cells, glucose converts into energy in the form of ATP.

When glucose is used in the cell for glycolysis, it goes through a multi-step process to break the glucose molecule (C₆H₁₂O₆) into two pyruvate molecules plus a hydrogen ion. This process releases energy that is stored in the ATP molecule. In high school biology, it is usually just noted that glycolysis is the process of splitting the glucose molecule, forming two pyruvates and two ATP. But there are actually a bunch of intermediate steps along the way.

One of the intermediate steps of glycolysis forms glyceraldehyde-3 phosphate, which can spontaneously form methylglyoxal (MGO). Methylglyoxal is a ‘key precursor of the AGEs’.[ref]

Why are AGEs a problem?

The body has a hard time getting rid of advanced glycation end products. When a protein is bound to a carbohydrate, its structure is altered in such a way that the enzymes that would normally act on the protein can no longer break it down. Thus, the altered proteins can build up in the body.[ref]

Getting rid of AGEs is especially a problem in collagen and elastin, which have a slow turnover rate. It is also a problem when glycated proteins cross-link and form large proteins. The proteins have to be eliminated, mainly through the kidneys.

Another reason that AGEs are a problem is that they can stimulate the AGE receptor (known as RAGE), which signals a cascade of inflammatory events.[ref]

Three problems with AGES: 1) they can build up because they are hard to eliminate; 2) they trigger inflammation through their receptor; 3) they cause protein structure to be altered.

AGEs as a causal factor of aging.

If you consider aging a disease, then it makes sense to look for the causes of that disease called aging. In general, aging usually involves a loss of fitness – low muscle mass, easy injuries, and increased risk of chronic diseases. These all tie together with the increased cellular damage that happens over time. This accumulated cellular damage then causes a bunch of problems — including excess AGEs.[ref]

It can be argued that one of the causal factors of aging is your body accumulating more and more advanced glycation end products. AGEs = Aging.[ref]

For example, I mentioned AGEs forming in collagen above… Collagen is a protein that is an abundant component of bones, ligaments, skin, and muscles.

When AGEs accumulate in the collagen proteins in joints, muscles, and bones, they play a role in causing arthritis, muscle loss, and osteoporosis. All are associated with both aging and higher levels of AGEs.[ref]

The cross-linked proteins, such as collagen in a tendon, can increase stiffness and make it more prone to tearing. Think about the problems of a twisted ankle with a tendon tear when older vs when you were a kid.[ref]

This increased cross-linking in AGEs also shows up in the skin. As AGEs increase with age, you get wrinkles, thinner skin. and less elasticity.[ref]

What causes excess AGEs in the body?

More AGEs are produced under conditions of oxidative stress. When too many reactive oxygen species (ROS) are present in a cell, it causes oxidative stress. Not only does this trigger the body’s antioxidant defenses to be produced, but the excess ROS can also escalate the production of the precursors for AGEs. This happens through increased lipid peroxidation and glycoxidation reactions, which cause more of the reactive products (like methylglyoxal) that bind with proteins to form AGEs.[ref]

More AGEs are also produced when blood sugar levels are high. Diabetes is a disease of high blood glucose levels. This excess of glucose makes it more available and thus likely for AGEs to form. A lot of the complications of diabetes, such as cardiovascular disease, retina problems, and kidney problems, are actually caused by the accumulation of AGES.[ref]

Preventing the formation of AGEs in the body:

The glucose metabolites that react to form AGEs can be stopped in multiple ways in the body. In fact, the body naturally has several ways to combat AGEs, and the key is to promote this along with decreasing production.

The enzymes glyoxalase I and II are tasked by the body to break down methylglyoxal, one of the main precursors for the production of AGEs in the body. Methylglyoxal can be formed as a side-product during glycolysis.

Decreased levels of glyoxalase I (GLO1 gene) are associated with higher AGEs in the plasma of hemodialysis patients. Another study found that upregulating the GLO1 gene (animal study) prevented AGEs formation in the presence of high blood glucose levels.[ref]

What does it take to make glyoxalase? Glutathione, one of the body’s main antioxidants, is a cofactor of glyoxalase. Low levels of glutathione can reduce the activity of glyoxalase 1.[ref]

Taking this one step further, the Nrf2 pathway stimulates glutathione production in the cells. It has been shown in recent studies that activating the Nrf2 pathway can stop the formation of AGEs by eliminating methylglyoxal.[ref]

Often, when thinking of advanced glycation end products the mind jumps to the idea that eating sugar is entirely to blame: Glycolysis is a glucose-based pathway, and the side-products of glycolysis (especially methylglyoxal) increase AGEs. High levels of glucose in the blood do increase AGEs. But one of the ketone bodies formed when eating a low-carb diet is acetone, and acetone can also be converted using the CYP2E1 enzyme into methylglyoxal.[ref][ref]

AGEs and RAGEs…

Essentially, we have two things going on here with AGEs.

First, we don’t want a build-up of AGEs in general. They are hard for the body to get rid of, and they are making my skin look old. In a general sense, we can prevent this by keeping glucose levels low and boosting glyoxalase.

Second, we don’t want a lot of AGEs to bind with the receptor for advanced glycation end products (RAGE), which causes inflammation. (more below on this…)

Genetics comes into play here, with some people having more of a problem with this than others. In other words, some people who have genetic variants in the receptor for AGEs are going to be more susceptible to the negative consequences of AGEs.

RAGEs:

RAGE stands for the receptor for advanced glycation end-products. It is coded for by the AGER gene. When AGEs bind to receptors, it triggers inflammation.

RAGEs are called a multi-ligand receptors, which means that multiple molecules can bind to it. They are located on the cell membrane in a bunch of different cell types including endothelial cells, immune system cells, muscle cells, and neurons.

RAGEs and Inflammation:

When AGEs (or another molecule) activate a RAGE receptor on the cell membrane, it transmits a signal that increases the body’s immune response. For example, in endothelial cells, which line the blood vessels, activation of the RAGE receptors causes the expression of the proinflammatory cytokines IL-1a, IL-6, and TNF-alpha. It also causes the formation of proteins needed for clotting, vasoconstriction, and cellular adhesion.[ref] This all adds up to inflammation in the blood vessels, higher blood pressure, and cardiovascular disease.

Diseases associated with RAGE activation include “inflammatory diseases, rheumatic or autoimmune diseases, infectious diseases, diabetes, metabolic syndrome and its complications, obesity, insulin resistance, hypertension, atherosclerosis, neurological diseases such as Alzheimer’s disease, cardiovascular diseases, pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and cancer.”[ref] (Yes, that is pretty much every chronic disease that I can think of — and all are associated with aging.)

Activation of RAGE (cell membrane receptor) causes an increase in reactive oxygen species as well as the increase in inflammatory cytokines. It also downregulates the cholesterol transporters, ABCA1 and ABCG1. This is important in neurodegenerative diseases.[ref]

RAGEs and Glyoxalase-1 interact:

As I talked about above, the enzyme glyoxalase breaks down one of the precursors for AGEs (methylglyoxal). Researchers have found that the receptor for advanced glycation end products also regulates glyoxalase. In animal studies, when the researchers delete the RAGE gene (AGER gene), the animals no longer accumulate methylglyoxal.[ref]

RAGEs in Alzheimer’s:

I mentioned above that RAGE is a multi-ligand receptor, which just means that there are multiple molecules that can bind to it. In addition to AGEs, amyloid-beta is another molecule that can bind to RAGE. Amyloid-beta, produced in the brain, and its accumulation is one of the hallmarks of Alzheimer’s disease.

The inflammatory signaling from binding with RAGE exacerbates the neurodegeneration in Alzheimer’s disease. Glyoxalase 1 is initially upregulated in the early stages of Alzheimer’s. But eventually, due to glutathione depletion, the overall activity of glyoxalase 1 is reduced.[ref]

Soluble RAGEs:

There are two forms of RAGE, a soluble and a full-length form that is the receptor on the cell membrane. In contrast to the membrane receptor form, the soluble form of RAGE doesn’t signal inflammation. It is thought that soluble RAGE acts as a decoy receptor and is protective against the accumulation of amyloid-beta.[ref][ref]

One example of how soluble RAGE acts to decrease AGEs can be found in osteoarthritis. People with osteoarthritis have significantly lower levels of soluble RAGE in their synovial fluid (fluid in the joint).[ref]

Basically, you want more of the soluble form of RAGE. If soluble RAGE is floating around, it can bind with AGEs (or other molecules) and prevent them from binding to the RAGE receptor, which is on the cell membrane and activates inflammation.[ref]

Lifehacks:

The big question here is…

How do you lower advanced glycation end products?

There are several ways to decrease AGEs both through the way that you cook your food, balance your blood glucose levels, and boost your body’s natural detoxification system.

Never smoke. It is that simple.
Tobacco smoke increases AGEs in the lining of the arteries, LDL cholesterol, the lens of the eye, and collagen in the skin. Basically, one reason smoking causes wrinkles, high blood pressure, and cataracts are due to increased AGEs. Second-hand smoke is also a problem.[ref][ref]

Dietary choices to decrease consumption of AGEs:

Foods high in AGEs include meats cooked with high, dry heat. Going beyond steak or grilled chicken, AGEs also form in any food that contains proteins and fats and is browned. Cheese also contains higher levels of AGEs. One study explains that the ‘order of dietary AGEs levels in foods is found to be beef>cheeses>poultry>pork>fish>eggs’.[ref] Lower amounts of AGEs are found in uncooked foods and cooked fruits, vegetables, and whole grains. Milk is also low in AGEs (but cheese is high). In addition to broiled meats, oils heated to a high temperature and roasted nuts are also high in AGEs.[ref]

If you want to get specific with AGEs in foods, check out this study with the AGE content of 549 foods. The results show the huge differences in cooking methods on AGE formation. For example, a pan-fried steak has about 12 times the AGEs as raw steak. A microwaved steak has about 5-fold less AGE content than a pan-fried steak (but who would microwave a steak??). If you are fond of bacon, pan-fried bacon has 10-fold higher AGEs than microwaved bacon.

Studies show that AGEs are partially absorbed in the intestines from foods at a rate of 10 – 30%. The studies, though, are only looking at a couple of types of AGEs in foods because it is difficult to figure detect and quantify all of the different types.[ref]

Carbohydrates generally contain the lowest amount of AGEs.[ref] But… carbohydrates also tend to increase blood glucose levels the most. Finding a balance between foods that are low in AGEs yet don’t spike your glucose levels is important.

Funny thing – the lowest food item on the list of AGEs is sugar, which doesn’t contain any AGEs.

Carbohydrates such as bread or biscuits, though, that are heated to the point of browning have higher AGEs in the browned portion (the crust).[ref] Perhaps those picky kids who don’t eat the crust on bread actually have the right idea.

Wondering how much of a difference it makes to reduce dietary AGEs? A study of women with PCOS looked at three different dietary interventions – lowering calories, high AGEs, and low AGEs – for two months each. The diet lower in AGEs decreased serum AGEs, oxidative stress, testosterone (which is elevated in PCOS), and HOMA-IR (a measure of insulin resistance). These are pretty big changes considering the intervention was just to cook meat at lower temperatures.[ref]

Decreasing AGEs by dietary changes:

• Cut back on the grilled meat and foods cooked at high heat.
• Swap out some of your grilled recipes for crockpot (low and slow) recipes.
• Microwaving causes less AGE formation…
• Eat more vegetables, cooked or raw.
• Decrease or eliminate fried foods, and don’t go overboard on roasted nuts.
• Combine your grilled or pan-fried meats with foods high in polyphenols (e.g. have some Broccoli slaw alongside your BBQ).
• Consider sous-vide for your steaks? Or perhaps the reverse sear method (and go light on the sear!)
• Marinating meat in something acid (vinegar, lemon juice) decreases AGE formation when cooking meats.[ref]

The rest of this article is for Genetic Lifehacks members only.  Consider joining today to see the rest of this article.  

Polyphenols and supplements that block the formation of AGEs:

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