Advanced Glycation End Products

Recent research shows that advanced glycation end products (AGEs) are a causative factor in many degenerative diseases - including almost all of the diseases associated with aging. 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 the genetic susceptibility and then discuss the lifehacks that can help to mitigate any susceptibility. In fact, one specific type of advanced glycation end product has shown to be highly determined by genetics.[ref]

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 a Maillard reaction, it is what makes grilled meat and vegetables taste great and smell delicious. This Maillard reaction is producing advanced glycation end products in the 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 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 multistep 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 for 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, 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 bone, 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 in 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 causes 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 by 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 the receptor, it triggers inflammation.

RAGEs are called a multi-ligand receptor, 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 that is on the cell membrane which activates inflammation. [ref]

 


Genetic variants that impact RAGEs:

This section explains how your genetic variants impact advanced glycation end-product formation in your body. Genetic variants that alter AGEs and RAGEs can increase the risk of Alzheimer's, diabetic retinopathy, and inflammatory-related conditions.

 


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