(Note that this article is cross-posted from Genetic Lifehacks)
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 links 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 to mitigate any susceptibility. In fact, one specific type of advanced glycation end product has shown to be highly determined by genetics.[ref]
Table of Contents
- Advanced Glycation End Products:
- AGEs and RAGEs…
- Genetic variants that impact RAGEs:
Advanced Glycation End Products:
The term AGEs (advanced glycation end products) refers to a lipid or protein being glycated, which means that a sugar or aldehyde binds with the protein or lipid. It is a general term that is applied to a bunch of different molecules, but the basic premise is that 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 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 forms as a side-product during glycolysis.
Decreased levels of glyoxalase I (GLO1 gene) have associations 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 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.
RAGE stands for the receptor for advanced glycation end-products. It is coded for by AGER gene. When AGEs bind to the receptor, it triggers inflammation.
RAGEs are called a multi-ligand receptor, meaning 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 initially upregulates in the early stages of Alzheimer’s. But eventually, due to glutathione depletion, the overall activity of glyoxalase 1 reduces.[ref]
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 for inflammation. Possibly, 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]
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, balancing your blood glucose levels, and boosting your body’s natural detoxification system.
Also… never smoke. 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 is 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 also are high in AGEs.[ref]
Studies show that AGEs partially absorb in the intestines from foods at a rate of 10 – 30%. The studies, though, are only looking at some of the 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…carbs 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.
Carbohydrates such as bread 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.
If you are a soda drinker, the types of soda with caramel additives (brown sodas, like Pepsi and Coke) have higher levels of AGE precursors than clear sodas (like Sprite).[ref]
Putting this into practice:
- 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.
- 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!)
Polyphenols and supplements that block the formation of AGEs:
Just as there are different types of AGEs, different natural compounds that block the formation of specific AGEs in the body. Your best bet may be to stack multiple ways of blocking the formation of AGEs in the body — along with a diet that is low in AGES.
Berberine, a plant-based supplement, is known for lowering blood glucose levels. It has shown in animal studies to inhibit AGEs formation.[ref] You can get berberine on Amazon or at your local health food store. Note that it may also reduce blood pressure a bit – something to keep in mind if you are already on medication for high blood pressure.
Quercetin is a natural compound found in fruits and vegetables. It has shown in animal studies and cell studies to decrease the formation of AGEs.[ref] Quercetin has also shown in animal studies to increase GLO1 (glyoxalase 1) levels and also increase glutathione levels.[ref] You can get quercetin as a supplement in addition to consuming it in foods. Studies show that quercetin doesn’t absorb well as a supplement, but adding a little fat to it may help absorption.[ref]
Resveratrol decrease RAGE expression in diabetic rats.[ref] It also helps decrease AGE accumulation in diabetic rats.[ref] The dosages of resveratrol were higher than what you can get from drinking wine…(I know that you were thinking that you would just have some wine alongside your grilled steak.) It is available as a supplement. Note that it can also decrease blood pressure.
NAD+ boosters, such as nicotinamide riboside (NR) and NMN, may protect against the damage caused by AGEs.[ref] You can read all about NAD+, genetics, and why I think it is important here. NR (combined with resveratrol) or NMN is available on Amazon or at other health food stores.
Glutathione is a cofactor of glyoxalase 1. Your body naturally produces glutathione as an antioxidant. You can get it as a supplement or work on activating the Nrf2 pathway.
Sulforaphane, found in broccoli sprouts and cruciferous vegetables, has shown to reduce the production of advanced glycation end products.[ref] You can get high levels of sulforaphane from growing broccoli sprouts or via a supplement.
Aspirin reduces RAGEs. This may be one way that low-dose aspirin is protective against heart disease.[ref][ref][ref] If you have questions or concerns about aspirin, talk with your doctor.
Curcumin and Gingerol have shown in a mouse study to decrease the effects of AGEs in muscle cells. Curcumin works through trapping methylglyoxal.[ref][ref] Eat your curry with some ginger?
Hesperidin, a flavonoid found in citrus fruits, helps upregulate glyoxalase 1. It does this by activating the Nrf2 pathway.[ref] You can get hesperidin as a supplement.
Studies in rats show that exercise helps to decrease AGEs in old rats. But the human studies show conflicting results on whether exercise is beneficial or not for AGEs.[ref] Some studies show staying active, in general, correlates with lower AGEs.[ref]
Perhaps as important as eating a diet with healthy vegetables is sleeping well. Getting adequate sleep was shown in a study of Japanese adults found that sleep deprivation may increase the formation of AGEs.[ref]
Men with sleep apnea have higher circulating levels of AGEs and insulin resistance.[ref] And sleep apnea also increases RAGE.[ref]
Genetic variants that impact RAGEs:
Interested in your genetic variants? You can find them on GeneticLifehacks.com here…Advanced Glycation End Products