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Advanced Glycation End Products (AGEs): Genetics, Lifestyle, and Health Span

Key takeaways:

  • Advanced glycation end products (AGEs) build up in tissues and are a causal factor in many chronic and age-related diseases.
  • High AGE levels have been linked to Alzheimer’s, heart disease, diabetes, chronic kidney disease, joint problems, and skin aging (wrinkles, stiffness, and loss of elasticity).
  • Genetic susceptibility and lifestyle interact to cause the problems associated with AGEs.
  • Common variants in the AGER (RAGE receptor) and GLO1 (glyoxalase I) genes – combined with diet and lifestyle factors – determine how easily AGEs accumulate
  • You can lower your personal AGE burden through diet, cooking methods, smoking avoidance, sleep, activity, and specific supplements

This article will dig into genetic susceptibility and then discuss the lifehacks (solutions) that can help mitigate any susceptibility.

Members will see their genotype report below and the solutions in the Lifehacks section. Consider joining today

Advanced Glycation End Products: What are they and why are they important?

The term AGEs (advanced glycation end products) refers to a lipid or protein being glycated, meaning a 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 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 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.

Here’s an overview of where we are going here:

Topic At a glance:
What AGEs are Changes to proteins or fats when sugars/aldehydes bind to them.
Where they come from Mostly formed inside cells during glycolysis (via methylglyoxal) and through ketone metabolism (to a lesser extent); additional load comes from high‑heat cooking of protein‑ and fat‑rich foods.
Why they build up Once proteins are glycated, enzymes can’t break them down easily, so AGEs accumulate, especially in slow‑turnover tissues like collagen and elastin.
Key problems Trigger inflammation via the RAGE receptor. Cause cross‑linking and stiffness in collagen and other structural proteins.
Aging connection AGEs increase with age and contribute to arthritis, muscle loss, osteoporosis, tendon stiffness, and visible skin aging (wrinkles, thinner, less elastic skin).
Drivers of excess AGEs Oxidative stress, high blood sugar/diabetes, and, to a lesser extent, ketone metabolism (acetone → methylglyoxal) can all accelerate AGE formation.

Let’s dive into the details on the formation of AGEs in the body first, and then discuss ways to prevent the formation of AGEs in foods in the Lifehacks section.

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 is converted 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?

Simply put, 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 because they aren’t easily broken down and excreted.[ref]

Cross-linking: 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. Cross-linking in collagen and elastin causes tendons to be stiffer, more likely to tear, and less likely to repair. This adds up to injuries and joint stiffness/pain.[ref]

Neurotoxic: When AGEs bind with acetaldehyde, the breakdown product from alcohol, they can form a neurotoxic substance that can contribute to neurodegeneration in alcoholics. Other types of AGEs are thought to play a role in Alzheimer’s and neurodegenerative diseases of aging.[ref]

Advanced Glycation Endproducts Receptor (RAGE) activation: 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]

Thus, there are three significant problems with AGES:

  1. They can build up because they are hard to eliminate
  2. AGEs trigger inflammation through their receptor
  3. They cause protein structures to be altered and the crosslinking of collagen

Are AGEs the cause of aging?

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]

In general, aging usually involves a loss of fitness – low muscle mass, easy injuries – and increased risk of chronic diseases due to low-grade inflammation. These 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]

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 you’re 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 advanced glycation end products?

Oxidative stress: 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]

High blood sugar: 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 more likely for AGEs to form. A lot of the complications of diabetes, such as cardiovascular disease, retinopathy, 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 (GLO1 gene)  and glyoxalase 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 are associated with higher AGEs in the plasma of hemodialysis patients. Animal research shows that upregulating the GLO1 gene (increased breakdown of methylglyoxal) 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]

Related article: Nrf2 Pathway: Increasing the Body’s Ability to Get Rid of Toxins

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: Receptors for advanced glycation end-products.

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

RAGEs are multi-ligand receptors, which means that multiple molecules can bind to them. 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 an increase in inflammatory cytokines. It also downregulates the cholesterol transporters, ABCA1 and ABCG1. This is important in neurodegenerative diseases.[ref]

Related article: TNF-alpha: Inflammation, Chronic Diseases, and Genetic Susceptibility

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]

Related articles: Your APOE Type and Alzheimer’s Risk + Genetic Mutations that Protect Against Alzheimer’s Disease

Soluble RAGEs:

There are two forms of RAGE, a soluble form 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]

 


Advanced Glycation End Products: Genotype Report

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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.

Biggest impact: 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. Secondhand smoke is also a problem.[ref][ref]

Reversing AGEs with drugs:
A 2026 paper announced a breakthrough in the development of an enzyme that can reverse one type of advanced glycation end product –  Nε-carboxymethyl-lysine (CML), which is abundant in aging tissue. This is something to keep an eye out for new research and products.[ref]

Dietary choices to decrease the 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:[ref]

beef > cheeses > poultry > pork > fish > eggs

Raw or low heat: 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 a 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 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 want the crust cut off their sandwiches actually have the right idea.

Ultraprocessed foods:
Many ultraprocessed foods are baked at high heat or extruded with heat, causing the formation of dietary AGEs. One reason that ultraprocessed foods are associated with so many detrimental chronic conditions is the high levels of AGEs.[ref]

How much of a difference does it make 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]

Practical ways to decrease dietary AGEs:

  • Cut back on the grilled meat and foods cooked at high heat.
  • Marinating meat in something acidic (vinegar, lemon juice) decreases AGE formation when cooking meats.[ref]
  • 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 ultraprocessed foods.
  • 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 or low and slow clooking methods for meats.

Polyphenols and supplements that block the formation of AGEs:

Just as there are different types of AGEs, different natural compounds 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 been shown to inhibit AGEs formation in animal studies.[ref] You can get berberine online 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.

Related article: Berberine: Research, Benefits, Absorption, and Genetics

Quercetin is a natural compound found in fruits and vegetables. It has been shown in animal studies and cell studies to decrease the formation of AGEs.[ref] Quercetin has also been shown in animal studies to increase GLO1 (glyoxalase 1) levels and glutathione levels.[ref] You can get quercetin as a supplement in addition to consuming it in foods. Studies show that quercetin is not all that well absorbed as a supplement, but adding a little fat to it may help absorption.[ref]

Related article: Quercetin: Scientific Studies + Genetic Connections

Resveratrol decreases 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.

Related article: Resveratrol: Genetic Interactions and Bioavailability

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. And you can get NR (combined with resveratrol) or NMN online 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. A 2016 study in mice found that N-acetyl‑L‑cysteine (NAC), which is a precursor your body needs to produce glutathione, “reduced the inhibitory effects” of AGEs. [ref]

Related article: Glutathione synthesis genes

Sulforaphane, found in broccoli sprouts and cruciferous vegetables, has been 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.

Related article: Sulforaphane research studies

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 been shown in a mouse study to decrease the effects of AGEs in muscle cells. Curcumin works by trapping methylglyoxal.[ref][ref] Eat your curry with some ginger?

Hesperidin is a flavonoid found in citrus fruits that can help upregulate glyoxalase 1. It does this by activating the Nrf2 pathway.[ref] You can get hesperidin as a supplement.

Related article: Hesperidin  | Nrf2 genes

Melatonin: A 2025 randomized placebo-controlled trial found that 5mg of melatonin taken nightly reduced cellular markers of AGE. [ref]

Related article: Melatonin: Key to Health and Longevity

Exercise – or even just staying active?

Studies in rats show that exercise helps to decrease AGEs in old rats. But human studies show conflicting results on whether exercise is beneficial or not for AGEs.[ref] Several studies show that staying active, in general, is correlated with lower AGEs.[ref]

Sleeping well is also essential:

Perhaps as important as eating a diet with healthy vegetables is sleeping well. Getting adequate sleep was shown in a study of Japanese adults that 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] Plus, sleep apnea also increases RAGE.[ref]

Focusing on a regular sleep schedule, fixing sleep apnea if you have it, and prioritizing a strong circadian rhythm may be as important as diet when it comes to AGEs and RAGEs.

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Related Articles and Topics:

Quercetin: Scientific Studies + Genetic Connections

Problems sleeping? Your genes can point to individualized solutions


References:

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About the Author:
Debbie Moon is a biologist, engineer, author, and the founder of Genetic Lifehacks where she has helped thousands of members understand how to apply genetics to their diet, lifestyle, and health decisions. With more than 10 years of experience translating complex genetic research into practical health strategies, Debbie holds a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. She combines an engineering mindset with a biological systems approach to explain how genetic differences impact your optimal health.