The primary exogenous AGEs: dietary AGEs (aka dAGE)
In the previous post, AGEs were classified as endogenous or exogenous depending on whether their formation occurs within the human body or originates from external sources. While factors such as smoking and exposure to pollutants or ultraviolet radiation contribute to exogenous AGEs, the largest proportion of exogenous factors is undoubtedly through food. In this post, let's delve into AGEs that enter the body directly through food.
Maillard reaction
Glycation used in food aims to visually enhance the appearance, add flavor and taste, and above all, make our mouths happy. It also has the effect of extending the shelf life. Therefore, it can be easily inferred that processed foods, which are mass-produced and can be displayed for a considerable period, contain more dietary advanced glycation end products (dAGEs) than minimally processed foods. While the term "advanced glycation end products" may be unfamiliar, you may have heard of the Maillard reaction, a technique known for searing the surface of beef on a heated pan to trap the juices inside. This Maillard reaction is, in a sense, like the godfather of AGEs.
Glycotoxins
Dietary AGEs are absorbed into the human body and can contribute to various diseases or aggravate existing conditions. That is why it is also called "glycotoxin". These substances exist more deeply in our daily lives than we might think. Crispy-looking bread with a brown crust, cookies or biscuits baked in the oven, sesame oil, and even the coffee beans used to make the coffee we love so much are all products of this Maillard reaction. These are all foods cooked at high heat in dry conditions.
Variables affecting dAGE
Variables that influence the formation of dietary AGEs include nutrient composition (high fat and protein content), presence or absence of moisture, and acidity (ph).
It has been found through various experiments that cooking in a dry state for a short period of time (such as grilling, frying, roasting, baking, and barbecuing) generates more AGEs compared to cooking in a moist state for a longer period of time (such as boiling, steaming, poaching, stewing, slow cooking) [3]. According to one study, dry-heat cooking methods promote 10 to 100 times more dAGE formation across various types of food compared to their uncooked state [2].
Foods rich in fat and protein generally contain higher levels of AGEs, while carbohydrates-rich foods such as vegetables, fruits, and whole grains tend to have relatively lower levels of AGEs even after cooking [2]. There are also test results showing significantly higher levels of AGEs when protein-rich poultry is grilled with the skin on, which has a lot of fat.[4]. Reports have mentioned the increasing trend of people adopting diets that are low in carbohydrates and high in fat and protein, and have raised concerns that such dietary habits may significantly increase dAGE and cause health issues.
Let's find methods to reduce dAGE:
1. Acidic environment
There are experimental results showing that dAGE can be reduced by half by using acidic ingredients such as vinegar or lemon. The picture below compares the levels of Nε-carboxymethyllysine (CML), which is the most stable and relatively inactive form of AGEs, in beef marinated in vinegar (A) and lemon juice (B) for one hour before grilling, compared to unmarinated beef. When comparing the 2nd and 3rd bars in both A and B, it can be observed that the acidic components effectively inhibit and reduce AGEs formation [2].
1: Raw meat. 2: Grilled beef without vinegar or lemon.
3: Grilled beef marinated in vinegar or lemon for 1 hour
This experiment supports the opinion from other reports that seasoning foods in a low pH environment may have a protective effect against dAGE uptake by reducing the formation of heat-induced AGEs during cooking. [5]
2. Natural antibiotics
According to a study with mice, Epigallocatechin-3-gallate (EGCG), a type of green tea polyphenol, is predicted to prevent AGE formation by modulating detoxifying enzymes through regulation of Nrf2(Nuclear factor erythroid 2-related factor 2).[6] This study reports not only antioxidants such as Resveratrol, Quercetin, and Curcumin but also berries (blueberries, lingonberries, bilberries, cranberries, etc.) play a role in suppressing the production of AGEs. However, it should be noted that this article focuses on the utilization of these antioxidants in the treatment of diabetes, and the direct relationship between the inhibition of dietary AGEs and these antioxidants needs to be further investigated. Additionally, the article mentions that they are preferably consumed in the form of tea or beverages, perhaps with food or meals, rather than being directly used in the process of cooking dishes.
In addition, there are papers proposing natural anti-glycation agents such as anthocyanins and ellagic acid from fruits and vegetables, garlic, resveratrol, red wine, curcumin, cinnamic acids like ferulic acid, quercetin, and coffee acid.[7] These findings emphasize the potential of natural compounds in reducing the impact of AGEs.
Role of Kidneys and Liver
Kidney and dAGE
The two most important organs that play crucial roles in detoxification by processing harmful substances absorbed into the body are the kidneys and liver. It would be meaningful to examine the impact that AGEs from food can have on these two organs and the relationship between them.
The glomeruli of the kidneys filter waste products from the blood and excrete them through urine on a daily basis. However, when it comes to dAGE, there are potential risks associated with their accumulation in the kidneys, in that dAGE molecules are not only chemically toxic but can also negatively impact blood flow, leading to cell damage. If dAGEs are not processed in a timely manner and continue to accumulate, the function of the renal tubules may deteriorate, leading to disruptions in the normal functioning of the kidneys. This situation can be particularly problematic for individuals who already have kidney disease due to causes such as diabetes. There are reports indicating that the accumulation of AGEs in the glomeruli can lead to progressive renal sclerosis [4].
The relationship between dAGE and kidney disease is undesirable, as they can exacerbate each other. The accumulation of AGEs in the kidneys can lead to impaired kidney function, and individuals with pre-existing kidney conditions may be more vulnerable to the detrimental effects of dAGE.
Reabsorption of AGEs in the kidneys
Several studies have shown that the rate of clearance of AGEs from the kidneys is slower than that of creatine.[4] This suggests that instead of being excreted in the urine, AGEs are reabsorbed back into the body in significant amounts in the proximal tubule. Creatinine, a waste product generated from muscle metabolism, is used as a measure to evaluate kidney function, and a higher removal rate indicates better kidney function. The fact that AGEs can be reabsorbed and circulated in the body means that more AGEs are accumulated, so to prevent this, the production of AGEs must be reduced as much as possible regardless of the type of AGEs.
To investigate the effects of long-term consumption of dAGE on overall health and disease, an experiment was conducted where mice were fed food containing much more dAGE than normal for 12 months. [4] The results showed that the kidneys and liver became enlarged, and pigmentation was deposited in these organs and that chronic infusion of AGEs accelerated vascular and kidney lesions similar to those seen in diabetes. The underlying causes could be related to increased detoxification activity due to excessive dAGE intake, or it may result from oxidative stress and an exaggerated inflammatory response triggered by the binding of AGEs to RAGE receptors.
Even in humans, continuous intake of AGEs from food is believed to act as a persistent source of toxins, adding burden to the body on a daily basis. Therefore, efforts should be made to significantly reduce the burden of these toxins by taking appropriate measures, such as reducing foods or cooking methods with the highest dAGE content.
The liver, another key organ involved in the metabolism and elimination of glycotoxins.
Another mouse experiment showed that AGEs modification can seriously impair the LDL clearance mechanism, which is mediated by LDL receptors. [8] AGEs cross-link with LDL and modify it, slowing down the rate of LDL removal. As a result, the circulating amount of LDL that remains uncleared in the body increases, leading to elevated plasma LDL levels.
Liver LDL Removal Mechanism and AGEs
The liver, which plays a critical role in lipid metabolism, not only synthesizes lipoproteins but also removes circulating low-density lipoprotein (LDL) through specific receptors when there is an excess of cholesterol in the bloodstream. One important mechanism is the uptake of LDL by hepatocytes, which express receptors that recognize and bind to apolipoprotein B (ApoB), a component of LDL. Once bound to these receptors, LDL is internalized into hepatocytes via receptor-mediated endocytosis. Within the cells, cholesterol from the internalized LDL can be utilized for various metabolic processes or stored as hepatic triglycerides. After processing within hepatocytes, remnants of modified or degraded lipoproteins are either recycled back into circulation as smaller lipoproteins or excreted into bile for elimination from the body through feces.
However, this normal mechanism for LDL removal is disrupted when the receptors fail to recognize LDL that has undergone modifications due to binding with AGEs. As a result, abnormal LDL accumulates excessively in the body, potentially leading to dyslipidemia, and persistent impairment of the removal mechanism can ultimately cause severe damage to the blood vessels. If food-derived AGEs are consumed on a daily basis, they can act as a permanent source of toxins, and long-term repetitive intake of dAGEs can have serious pathological implications.
The relationship between the kidneys and the liver is closely intertwined. AGEs that are not properly filtered or reabsorbed by the kidneys can circulate in the body and crosslink with LDL in liver cells, potentially damaging the liver. This, in turn, can lead to an increase in circulating AGEs, placing an additional burden on the kidneys. This vicious cycle can be particularly noticeable in patients with diabetes.
Dietary AGEs and intestinal absorption
Approximately 10% of dietary advanced glycation end products (AGEs) are known to be absorbed into the body's circulatory system. However, about 80% of Amadori products (early glycation products) are broken down by intestinal bacteria and do not reach the stage of AGEs[9]. When formulating hypotheses to study the intestinal absorption of the various AGEs that have been discovered, the absorption pathway of AGEs should be considered in terms of properties such as their molecular size, hydrophilicity, and charge.
In addition, how much and how AGEs are actually absorbed from the intestines depends on various conditions, such as the possibility that proteins have been modified during the cooking process, when intestinal permeability is weakened due to metabolic disorders, or when the integrity of the intestinal wall is questionable due to leaky gut syndrome. It may vary depending on the situation, however, research results in this area are still rare.
Several factors have been identified that are expected to inhibit the absorption of AGEs in the intestines. Foods rich in antioxidants can prevent the intestinal absorption of Maillard reaction products and certain AGEs. Pectin oligosaccharides have been shown to decrease the generation and absorption of AGEs in vitro experiments, and catechins and chlorogenic acid have been found to interfere with AGEs absorption in vitro experiments as well. Intestinal microbes play a crucial role in the breakdown of all nutrients, and AGEs are no exception. Recently, Lactococcus lactis bacteria have been shown to significantly decrease the absorption of dietary CML by breaking it down mainly through β-galactosidase activity in the intestines of healthy subjects.
In recent years, aminoguanidine, pyridoxamine, N-acetyl cysteine (NAC), resveratrol, and sulforaphane have been identified as promising compounds for removing the toxicity of AGEs. However, there are few reports on whether these compounds can remove the toxicity of dAGEs absorbed through food. Although this area is a promising topic, the current knowledge is still insufficient, so it is expected that more specific and extensive research will be conducted in the future.
Future dAGE studies
Currently, there is a lack of sufficient understanding regarding the absorption, bioavailability, and physiological effects of AGEs in the human body. Moreover, there is a notable shortage of reliable methods for accurately measuring AGEs in both food and the human body. Although there have been some reviews focusing on AGEs in relation to food, a report highlights the need for future research that comprehensively integrates the fields of food science, food chemical analysis, and human nutrition.[10] Conducting such integrated studies is essential for critically evaluating the importance of AGEs in terms of their impact on health outcomes, as no comprehensive study has been undertaken in this area so far.
Questions for us
In an experiment conducted under the assumption that urban populations with high accessibility and availability of processed and ultra-processed foods would have much higher levels of dAGEs in their bodies, the results turned out to be completely unexpected [11]. The level of dAGE intake in rural areas of Pakistan, a developing country with low access to processed foods, was found to be very similar to that of the New York City population. (For reference, their average daily dAGE intake was 14,464 kU in these rural areas, 14,311 kU in Mexico, 14,700 kU in healthy New York City residents, and 9,686 kU in urban areas of Iran). This result suggests that even in rural areas where it is expected that people consume a significant amount of fresh and natural foods, the levels of dAGEs can still be high depending on the cooking methods used.
As mentioned earlier in the post, processed foods will naturally contain dAGE due to the Maillard technique, which is a good way to increase taste, flavor, and shelf life, so reducing these foods will definitely have a desirable effect. The problem does not stop there, and this experiment suggests that even for fresh and natural foods, dAGE can be reduced by paying as much attention to the cooking method as possible.
[References]
[1] Tobacco smoke is a source of toxic reactive glycation products
[2] Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet
[3] Current perspectives on the health risks associated with the consumption of advanced glycation end products: recommendations for dietary management
[4] Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy
[5] Intake of dietary advanced glycation end products influences inflammatory markers, immune phenotypes, and antiradical capacity of healthy elderly in a little‐studied population
[6] Dietary natural products as a potential inhibitor towards advanced glycation end products and hyperglycemic complications: A phytotherapy approaches
[7]] Toxicity of advanced glycation end products (Review)
[8] Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency
[9] Gut Metabolism of Sugars: Formation of Glycotoxins and Their Intestinal Absorption
[10] Advanced glycation end products in food and their effects on health
[11] Intake of dietary advanced glycation end products influences inflammatory markers, immune phenotypes, and antiradical capacity of healthy elderly in a little‐studied population
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