AGEs formation pathway
1. Maillard reaction
The most representative method by which AGEs are produced.
1-1 Initial glycation product (reversible)
It is formed through a complex molecular process that occurs through both simple and multi-step reactions. The electrophilic carbonyl group of glucose or other reactive sugars reacts with the free amino group of amino acids (especially basic lysine or arginine residues) to form a Schiff base. The unstable Schiff bases then undergo additional chemical rearrangements to form more stable ketoamine intermediates (Amadori products). It may take as little as a few days to several weeks to get to this point, but the process is still reversible, and these can be understood as early glycation products, a precursor to AGEs.
1-2 Advanced glycation products (irreversible)
The Amadori products undergo various processes such as dehydration, degradation, oxidation, reduction, condensation, and polymerization. These processes lead to the transformation of Amadori products into highly reactive carbonyl compounds, specifically dicarbonyls, a molecule containing two carbonyl (C=O) groups. If these compounds are exposed to persistent oxidative stress and inflammatory reactions over a prolonged period, they undergo further chemical modifications and reactions, ultimately becoming the final glycation products. As the name suggests, these final glycation products are irreversible. This process can take months to years to complete.
Once formed, AGEs can further cross-link with neighboring proteins, lipids, and DNA nucleic acids, remaining in the tissues for an extended period. For example, when AGEs cross-link with collagen, a structural protein that supports the mechanical load, it alters the mechanical properties of tissues and leads to stiffening and loss of elasticity in blood vessels and articular cartilage [1].
Schematic representation of Maillard reaction [2]
2. Lipid peroxidation
Lipid peroxidation is a process in which free radical molecules, such as reactive oxygen species (ROS) and other oxidants that cause oxidative stress, attack and damage polyunsaturated fatty acids in our body. These free radical molecules are unstable and highly reactive because they have one or more unpaired electrons. These free radicals can trigger and initiate lipid peroxidation by stealing electrons from polyunsaturated fatty acid molecules in cell membranes
Once lipid peroxidation is initiated, the newly formed lipid radicals react with oxygen to generate another type of radical called a peroxyl radical, which in turn attacks the surrounding lipids, continuing the chain reaction. This process occurs repeatedly between free radicals and lipids, resulting in the increase of lipid peroxidation chain reactions. Eventually, antioxidants present in our body terminate the chain reaction by donating electrons to these free radicals and neutralizing them. As a result of this process, significant oxidative damage can occur to cellular components containing lipids such as cell membranes, proteins, and DNA and lead to the disruption of cellular function and integrity.
Regarding the formation of AGEs, during lipid peroxidation, lipids undergo oxidative damage, and through oxidation reactions, dicarbonyl compounds, such as methylglyoxal and glyoxal, are formed. These dicarbonyl compounds serve as precursors for AGEs. In situations where there is an excess of glucose, these dicarbonyl groups ultimately forms AGEs.
Additionally, it's worth mentioning that the reactive dicarbonyl compound generated during the lipid peroxidation process not only reacts with sugar to form AGEs in high blood sugar conditions, but also reacts with amino groups of proteins to produce advanced lipid oxidation end products(ALEs). Malondialdehyde (MDA), a representative aldehyde produced through lipid peroxidation, combines with protein lysine residues to generate malondialdehyde-lysine (MDALys) through Shiff base reaction without enzymatic intervention. [3]
Although these protein-lipid oxidation product referred to as advanced lipid oxidation end products (ALEs) are not as extensively studied as AGES, they have been reported to not only modify proteins and interfere with normal cellular function but also be associated with various conditions such as atherosclerosis, diabetes, neurodegenerative diseases like Alzheimer's and Parkinson's, cancer, chronic inflammatory diseases, and early aging.[4]
3. Polyol pathway
The polyol pathway refers to a two-step process that occurs when blood glucose levels are high. In the first step, excessive glucose is converted to sorbitol through the activity of aldose reductase. Then, in the second step, sorbitol is converted back to fructose through the action of sorbitol dehydrogenase.
In situations where the amount of glucose is normal, only a small amount of glucose is converted to sorbitol because the level of aldose reductase is low in most tissues. However, in high blood sugar situations, the expression and activation of aldose reductase increase, leading to a greater conversion of glucose to sorbitol.
Sorbitol, a sugar alcohol, cannot easily come out of cells, so it accumulates within cells and can cause problems. First, when sorbitol accumulates within cells, intracellular osmotic pressure increases and water flows into the cells, which can cause cell swelling and damage. Additionally, the metabolic byproduct of sorbitol metabolism, fructose, can interact with specific compounds or undergo the Maillard reaction, further contributing to the formation of additional AGEs.
AGE formation pathways [3]
The twist of fructose
We have examined the three major pathways through which AGEs are formed, but there is one more aspect I would like to emphasize. While the majority of sugars in our body exist in the form of glucose, a small amount of fructose, a type of monosaccharide, is also present in the bloodstream after being metabolized in the liver. The issue lies in the chemical structure of fructose, specifically its open-chain structure, which makes it much more reactive with other molecules such as amino acids. Therefore, in terms of triggering the Maillard reaction, fructose is 8 to 10 times more reactive than glucose, meaning it has a significantly higher probability of generating AGEs.
It's important to note that the AGEs derived from fructose should not be confused with the third pathway mentioned earlier because the polyol pathway converts excess glucose in the body into fructose. This is something you must think about when consuming fruit juice with added sugar, as well as various processed foods and beverages sweetened with high-fructose corn syrup.
[References]
[1] Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabeteshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975757/
[2] Advanced glycation end products
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583887/
[3] The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696601/
[4] Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199390/
[5] Toxicity of advanced glycation end products (Review)
https://www.spandidos-publications.com/10.3892/br.2021.1422
[6] Formation of Fructose-Mediated Advanced Glycation End Products and Their Roles in Metabolic and Inflammatory Diseases
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227984/
