Eating Carbs Doesn’t Cause Glycation and High HbA1C
Why going low-carb doesn’t protect against advanced glycation end products and can even make the problem worse
Glycation and advanced glycation end products (AGEs, for short) have become the favourite boogeyman that low-carb proponents call upon whenever trying to implicate sugar/carbohydrates as the sole source of ageing, disease, mortal sin, and all the evil in the world.
All jokes aside, I do understand the concern. Even if you haven’t heard the terms glycation or advanced glycation end products (AGEs), you’ve probably heard of HbA1C before. Glycation is what is measured by the popular HbA1C blood test, and when the test comes back high, it can be bad news.
The acronym AGE, at least in the English language, is quite fitting as AGEs do age us — and more. Uncontrollable levels of AGEs can cause some serious harm. Advanced glycation end products (AGEs) are a class of molecules capable of damaging proteins, such as collagen, impairing their function and elasticity. As such, AGEs have been especially implicated in the aging of the skin and the development of wrinkles. However, the detrimental effects of AGEs go far past cosmetic inconveniences.
AGEs activate a variety of metabolic pathways that can impair the cells’ ability to make energy, increase oxidative stress, and even cause cell death. In other words, these molecules called AGEs can in fact age us and contribute to the progression and development of diseases such as diabetes, Alzheimer’s, kidney disease, and more.
While I am in full agreement that AGEs are bad news, I need to point out some obvious flaws with the idea that the rate at which we create AGEs and the rate at which these AGEs age us is proportional to our intake of sugar. It is not, and actually, it’s likely the other way around.
AGEs - Is dietary sugar the main culprit?
Most publications would have you believe that if you eat any sugar, you will generate copious amounts of AGEs that will rapidly age you. I’ve even heard the term “sugar sag” used to describe the phenomenon of skin losing its elasticity over time, implicating sugar as the sole reason why.
For example, this article from Elle titled “Sugar and Aging: How to Fight Glycation“ writes:
“When you have sugar molecules in your system, they bombard the body's cells like a meteor shower—glomming onto fats and proteins in a process known as glycation. This forms advanced glycation end products (commonly shortened, appropriately, to AGEs), which cause protein fibers to become stiff and malformed. Much of what is known about glycation's ill effects comes from diabetes research: The connective-tissue damage and chronic inflammation resulting from diabetics' sustained high blood sugar can lead to debilitating conditions, such as cataracts, Alzheimer's, vascular tightening, and diseases of the pancreas and liver.”
By token of this idea, it should be as simple as avoiding sugar = avoiding glycation, right? Well…human physiology is nowhere near that simple.
First, I will just address that “sugar molecules” do not “bombard the body's cells like a meteor shower.” Sugars (carbohydrates) are the preferred fuel of most cells in the human body1, a widely-known concept that you can find in any biology book. And there’s a reason for that! More on this later.
Also, as a quick note, in the above sentence the words “sugar” and “carbohydrates” are being used interchangeably as all carbohydrates are sugars. Starches, such as rice or potatoes, break down to glucose during digestion, while fruit, white table sugar and honey break down to glucose and fructose. As far as the body is concerned, all carbs are sugar, and publications that insinuate that anything that tastes sweet is “sugar" are deeply misleading, especially since many sweets have 30+ ingredients, including various fats and outlandish additives, where sugar might just happen to be one of the ingredients. Anyway, back to AGEs…
The reason why dietary sugar gets blamed for glycation and the formation of AGEs is because glycation is higher in those with chronically high blood glucose levels. HbA1C measures the average blood sugar levels over the past three months by measuring the amount of hemoglobin that has been glycated. When high, HbA1C (hemoglobin-A1C) can be indicative of chronically elevated blood glucose levels and diabetes. But before you run away screaming on your way to throw your honey and all your fruit in the trash bin, let me tell you this - chronically high blood glucose levels are not caused by dietary carbohydrate consumption. Instead, they are caused by the inability to burn glucose effectively (which is, in part, a consequence of…avoiding carbohydrates. More on this later in the article). And also…the main reason why chronically high blood glucose levels go hand-in-hand with increased AGE formation is probably not what you think. As you may have guessed, this too will be explained later on.
“There are a lot of misconceptions about AGEs, and one of them is that they are mostly formed from glucose directly glomming on to proteins.” - Chris Masterjohn, PhD2
Additionally, AGEs are generated through many pathways and glucose is actually pretty mediocre as far as its protein-glycating abilities go. While glucose can bind to proteins to facilitate the early stages of glycation, these early stages are reversible. In other words, the body has ways to separate glucose from proteins to prevent the formation of AGEs. On the other hand, compounds called dicarbonyls can bypass these early glycation stages entirely and form AGEs much more quickly. Dicarbonyls are thus much more dangerous when it comes to AGE generation. And dicarbonyls are derived from metabolites of carbohydrates, proteins, fats, and ketones!
Lastly, AGEs and AGE-forming dicarbonyls can also enter our bodies directly via the foods that we eat, and no, it’s not the fruit or the table sugar that’s full of AGEs! This is explored in part two of my series on AGEs.
Instead of trying to point our finger at a single macronutrient, such as carbohydrates, implicating it as the sole cause of AGEs, we should instead investigate what contributes to the larger pathological state in our body that accelerates the formation of AGEs and inhibits our body’s defences against them. Since all food is made up of carbohydrates, proteins and fats, is the solution to avoiding AGEs to simply never eat again? I’d say not. Glycation is a normal process in the body, and there is no way to prevent it entirely. Under normal conditions, the process of glycation is slow and the body has defences in place to stop its progression. However, under pathological conditions, our defences fail, and glycation happens at a faster, uncontrollable rate.
And while this might surprise you, the best way to slow down the formation of AGEs and improve the body’s defences against them is to burn sugar well. Sugar is not the problem, the inability to use it well is. And the inability to use carbohydrates is not caused by carbohydrates.
Why am I writing this article?
I think that understanding AGEs, what causes their formation, and how they are implicated in disease is important. However, I am also writing this article to prevent you from getting bamboozled, hoodwinked, led astray, run amuck, and flat-out deceived while navigating the health and nutrition world. AGEs and glycation are complex topics, and since they are poorly understood, and since they do in fact sound scary, they make for a great supporting argument that diet gurus can bring up to back up their extremist ideologies.
My goal with this article is to demystify AGEs, providing the context, the research, and the nuance, as well as practical tips on how we can actually protect ourselves against them in ways that work, that support the body, and that don’t require cutting out carbohydrates forever.
In this article:
AGEs - what are they & how do they wreak havoc?
Diabetes, high blood sugar and AGE formation
Debunking insulin myths
How eating sugar doesn’t lead to high blood sugar
Is sugar really the main glycating villain?
How ketogenic diets increase AGE formation
How carbohydrates protect against AGEs
Actionable steps on how to glycation-proof your body
As a quick note, parts of this article do not pertain to AGEs directly but are included to provide the context for understanding AGEs better. They explain concepts such as:
What is cellular respiration
The importance of having unimpaired cellular respiration
The consequences of cellular respiration getting impaired
Why carbohydrates don’t cause insulin resistance
Basically, I promise that even if parts of this article seem off-topic, they are still relevant to understanding the matter at hand. :)
AGEs - what are they & how do they wreak havoc?
Advanced glycation end products are the end products of a reaction through which a reducing sugar (more on what exactly is a “reducing sugar” will be explained later) binds to and reacts with a protein, scrambling the protein’s structure and converting it into somewhat of a grotesque monstrosity that not only can no longer perform its job correctly but can now spread terror to and negatively affect the function of nearby cells. For example, hemoglobin’s ability to perform its core job, which is carrying oxygen to our cells so that they can use it to make energy, is greatly impaired when hemoglobin gets glycated.
A glycated protein is like a cult member that recruits other proteins to join its tribe. A glycated protein (one that has now become an AGE) can bind with other proteins in a process called cross-linking. This is the main way through which AGEs inflict damage.3 Cross-linking can be explained as a glycated protein (an AGE) binding to a nearby protein, as the two become “glued” or “melted” together. These could include the collagen proteins that make up our skin or the proteins that make up our blood vessels. This cross-linking can affect the structure and function of these proteins, making them stiffer, less flexible, and less able to perform their various jobs.
How AGEs inhibit our cells’ ability to make cellular energy
Our bodies are made up of trillions of cells, all with unique functions and jobs. However, there is one thing that all cells have in common, and that is that they all rely on energy to be able to perform their functions, repair themselves if damaged, and maintain their structure. The energy needed to do all this is created inside our cells out of the foods that we eat in a process called “cellular respiration.” The bulk of the energy generated through cellular respiration is generated in the mitochondria of our cells. As you may remember from science class “mitochondria is the powerhouse of the cell.” Many of the degenerative diseases of today, such as diabetes and Alzheimer’s, have one thing in common, which is some derangement in the cells’ ability to create and utilize energy. The term “metabolism” refers to the chemical processes through which our cells convert the food that we eat into cellular energy. This is why diseases such as diabetes are often referred to as metabolic diseases.4
As far as AGEs go, twisting our proteins into a pretzel isn’t the only way through which they exert their insidious influence. AGEs bind to their aptly-named receptor called RAGE to cause further mischief.5 The RAGE receptor is expressed on various cells, including the cells that line blood our vessels, our neurons, and the cells in our lungs, kidneys, brain and skin. When AGEs bind to the RAGE receptor, they activate multiple inflammatory pathways and cause the cell to release pro-inflammatory cytokines. These cytokines can be thought of as messages that the cell sends out to other nearby cells to tell them that something is wrong and that they should get ready to defend themselves. This can result in these same pathways getting activated in nearby cells, causing them to also divert their resources to signalling for help and bringing attention to the danger at hand. While the inflammatory signals can be helpful, telling the body to help heal or replace any defective cells, the chronic activation of these inflammatory pathways can also negatively affect the cells’ ability to make energy. The situation can get so serious that the chronic activation of the RAGE receptor and the downstream inflammatory pathways activated by it have been implicated in the death of pancreatic cells as seen in diabetes!6
“The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications.”7
Our cells power themselves by turning the electrons that enter our mitochondria from the foods we consume into cellular energy. You can think of mitochondria as little factories with a conveyor belt where pairs of electrons are chaperoned and passed from one workstation to the next until they are handed off to oxygen. This process results in the creation of little “battery packs” (called ATP8) that the cell can use to maintain itself.
When the electrons from food pass through this entire cascade without any impairments, we are able to make the energy needed to power, maintain, and repair our cells. This is the energy that keeps us alive and functioning. However, when the pathways that release inflammatory signals are chronically activated, they can impair the proper flow of electrons.
What is oxidative stress and how it impairs our ability to make energy
As an example, imagine that at our electron-carrying factory, the fire alarm goes off, and the whole factory staff needs to evacuate. If the fire alarm only goes off once, the staff comes back and simply picks up their jobs where they left off. Now imagine that the fire alarm goes off every 5 minutes for the entirety of the workday. This is what it’s like when the inflammatory pathways are chronically activated by something like an AGE binding to the RAGE receptor. In other words, the various inflammatory pathways stimulated by AGEs disrupt cellular respiration.
The workers are scrambling, running back and forth every time the alarm rings, as electrons pile up on the conveyor belt. Since the belt isn’t moving efficiently, the electrons can start leaking out/escaping from the conveyor belt, reaching oxygen all unsupervised. Now, when electrons are paired up, as they tend to be when their flow through the mitochondria is controlled, they are pretty well-behaved. However, when electrons start leaking out, they escape unpaired. Once an unpaired electron reaches oxygen, it reacts with it to form a free radical. The unpaired electron in a free radical really wants to be in a pair again, so it will try to steal an electron from another molecule, such as a strand of DNA, or from one of the fats in the membrane of the cell (especially if the fat is unsaturated, more on this later). This can damage the cell, and this is what’s called oxidative stress.
The body has its antioxidant defences that can help to donate an electron to a free radical to neutralize it and prevent it from destroying everything in its path like a toddler with a hammer. However, these defences can get overwhelmed, as their function too depends on having adequate energy (ATP). This is why excessive oxidative stress can result in inhibited energy production, as the cell “closes down” parts of the factory (parts of the energy-making assembly) to prevent further damage from uncontrollable free radicals.
In short, the activation of these inflammatory pathways by AGEs binding to the RAGE receptor can increase inflammation and oxidative stress and overwhelm the body’s antioxidant pool, inhibiting the cells’ ability to create energy, to the point of being able to cause cell death. Not good.
Oh and if this wasn’t enough, remember how AGEs can cross-link proteins? Well, AGEs can also cross-link with mitochondrial proteins involved in cellular respiration,9 reducing their ability to create energy directly, and increasing oxidative stress as the proteins responsible for chaperoning the flow of electrons get glued up like a fly to a fly trap.
“AGEs can also cause the crosslinking of mitochondrial proteins in the respiratory chain, reducing the synthesis of ATP and promoting the production of oxidative free radicals. The pathways described above may cause a vicious cycle that leads to intracellular damage, impaired cellular function, and ultimately cell death, resulting in aging and the development of various age-related chronic diseases, such as cancer, Alzheimer's disease, cardiovascular disease, diabetes and other chronic diseases.”10
In summary, AGEs are insidious in the sense that while issues with cellular respiration (such as seen in diabetes and other metabolic diseases) can contribute to AGE creation, AGEs themselves contribute to derangements in the structure and function of cells, including their ability to make energy. This creates a dangerous feedback loop. And when cells’ ability to make energy is impaired, so are their defences against AGEs, as these defences are powered by cellular energy.
Diabetes, high blood sugar and AGE formation
After hearing all the ways in which AGEs can be a nuisance to our health, you are probably ready to avoid them at all costs. Also, hearing that AGEs can be formed when sugar reacts with a protein might make you want to avoid carbohydrates at all costs. However, as mentioned earlier, human physiology is not as simple as eating sugar = high blood sugar, as high blood sugar is usually the result of impaired sugar metabolism, which is something that sugar restriction can contribute to. On top of that, I will argue that it’s not even the high blood glucose itself that’s the main culprit behind AGE generation, but rather the in-between metabolites of glucose oxidation that accumulate and escape when glucose metabolism is impaired.
To understand the above statement, let’s take a look at the disease of diabetes. Those who suffer from diabetes tend to experience chronically high levels of blood glucose. Their blood tests also often come back with a high HbA1C value, indicating high levels of glycation.
The key question that we should be asking is “Why is blood glucose high in those suffering from diabetes?”