EXPLORING THE METABOLIC FURNACE: AGES IN AGING, DIABETES AND CARDIOVASCULAR DISEASE

AGEs (Advanced Glycation End Products) have been increasingly explored in the last couple of decades for their striking associations with many major lifestyle diseases. From diabetes and cardiovascular disease to wrinkles, blemishes, and aging itself, understanding AGEs could be important for leading a healthier lifestyle and improving the quality of life as we age.

The following article takes a look at AGEs, describing what they are and how they affect nearly all bodily tissues. Risk factors and tips for lowering AGE levels are also discussed below.

What Are AGEs?

AGE stands for Advanced Glycation End Product. As the name suggests, AGEs are the end result of heating proteins or fats together with sugars, causing them to become ‘glycated’. Glycation End Products are formed through the Maillard Reaction.^[1]

AGEs As Metabolic Furnace By-Products. We come across AGEs in everyday life when food is browned during heating, processing and cooking. In the body, AGEs can occur as a result of heat and cellular oxidation, which promotes the “browning” and glycation of cellular components, substrates and nutrients. In this way, energy metabolism and many other cellular activities can be viewed as a type of slow cooking process that can cause cellular proteins to become “overdone”. Under ordinary conditions, cellular respiration and mitochondrial oxidation are tightly regulated in order to prevent excessive glycation and other processes from becoming dysfunctional. Precursor by-products to AGEs are able to convert back into their basic substrates, which serves to prevent the formation of AGEs.

The Function of AGEs. Glycation is a normal cellular process that is used to create basic cellular products, such as DNA and RNA (which are glycated proteins). Ordinary glycated products in the cell are easy to break down, and like many other cellular products, their structures are often interchangeable, which is a characteristic vital to many cellular processes and functions. AGEs are the product of excessive glycation. As a result, they are typically difficult to break down and tend to stand in the way of optimal cellular function. AGEs serve as danger-signaling molecules in the context of excess oxidative stress and tissue damage, where they are formed in large quantities. DNA, RNA and several other glycated molecules are known to activate AGE receptors under these circumstances.

AGE Receptors and Inflammation. Receptors for AGEs stimulate the immune system when activated^[2] in order to promote their removal. There are nine or more types of AGE receptors, most of which signal for AGE degradation and clearance. One of these receptor types, RAGE, has been shown to increase cellular oxidative stress and inflammation, promoting many of the deleterious effects associated with tissue AGE accumulation.

Physical AGE Cell Disruption. If left to accumulate, they can form cross-links with other proteins or fats inside the cell or at the membrane.^[3] Cross-linked AGEs become larger and stand a higher chance of activating AGE receptors. Larger AGEs can inhibit major functions of the cell through binding to the membrane or to vital cellular products, thus interfering with cellular signaling, chemical reactions, and other essential functions such as nutrient uptake and waste disposal.

RAGE and Disease. AGE excess and resultant inflammation are associated with an increase in RAGE expression and a decrease in the expression of other receptors that decrease AGE clearance. In the context of disease, excessive AGE formation and RAGE activation are known to promote allergy, neurodegeneration, cardiometabolic disease, and autoimmune processes. Factors that increase AGE formation tend to increase heat, oxidative stress as well as the availability of AGE substrates, including triglycerides and blood glucose.

9 Deleterious Health Effects of AGE Accumulation

AGE excess is known to promote disease development and the acceleration of aging. The impact of AGEs on the body depends on AGE levels, the ratio of AGE receptors, the composition of the AGEs, and the site at which they form.

Deleterious effects and conditions associated with AGE accumulation are briefly discussed below.

1. Reduces Skin Vitality. AGE accumulation in the skin is known to affect all its layers and lower the skin’s vitality. Skin AGEs can cross-link with vital skin proteins, including collagen and filaggrin, which have been shown to damage the barrier, promote water loss, deplete cholesterol, and lower the skin’s capacity for repair. In a high-AGE environment, the structure of epidermal skin tissue becomes disorderly, and AGEs are known to contribute towards the slowed-down wound healing seen in patients with diabetes. The photoaging effects of UV radiation are partly attributed to promoting AGE formation, which enhances wrinkles, dehydration, and blemishes.^[4]

2. Exacerbates Neurodegeneration. A prime example of proteins that may become transformed into or cross-linked with AGEs include amyloids, which are a major protein type associated with Alzheimer’s Disease. The aggregation of these proteins eventually leads to neurofibrillary tangles, which prevent optimal neurotransmission and perpetuate neurodegeneration. Glycated fats, proteins and neurotransmitters are common components of other neurodegenerative disorders due to promoting neuronal dysfunction, insulin resistance, vascular stiffness, and chronic inflammation (as explained below). Other examples include Parkinson’s Disease and Lewy body dementia.

3. Linked with Insulin Resistance. Due to hyperglycemia, diabetic patients and those prone to insulin resistance often present with a higher level of AGEs. Glycated hemoglobin (or HbA1c) is often used as a marker to diagnose diabetes and assess its severity^[5]. AGEs are known to increase the risk for insulin resistance through promoting inflammation, pancreatic beta cell dysfunction as well as vascular damage, contributing to impaired glucose uptake and utilization.^{[6] [7]}

4. Facilitates Vascular Damage. Various preliminary studies have shown that AGE accumulation can heighten vascular permeability, inflammation, slow vascular repair, and impair the growth of new blood vessels. Cross-links of AGEs with collagen and other cell membrane components increase vascular stiffness, which has been linked to the risk for arrhythmia, heart attack, weakness of the heart, atherosclerosis and cardiovascular disease^[8]. An excess of AGEs promotes increased RAGE activation and heightened reactivity in immune cells, including macrophages that would ordinarily be involved in AGE removal. These factors lend themselves to generating more inflammation that can perpetuate the formation and accumulation of AGEs.^{[9] [10]}

5. Elevates Blood Clotting Risk. AGEs are known to promote platelet activation and substantially increase the risk for thrombosis. On top of promoting vascular stiffness, excessive AGEs have been shown to lower nitric oxide production^[11], both of which contribute towards impaired vasodilation, increasing the risk for blood clots. Additionally, AGEs can be formed from LDL cholesterol. Glycated LDL is unable to be taken up by cells and is left to accumulate in the bloodstream, able to contribute towards blood clotting.

6. Facilitates Retinal Damage. AGEs were shown to promote the release of inflammatory markers in retinal epithelial cells that are associated with retinal damage and a higher risk of developing macular degeneration. These effects are likely to be connected to the vascular effects of AGE accumulation.

7. Associated with Allergy and Autoimmunity. Large AGEs can activate mast cells by binding to RAGEs, resulting in an allergic reaction.^[12] Additionally, the body recognizes AGEs as a foreign antigen and initiates an inflammatory immune response similar to that seen in the context of food sensitivities and intolerances. Heating and glycation of common allergenic proteins (antigens) were also shown to increase their binding to RAGE as well as their capacity to trigger an allergic response.^[13] In a similar fashion, many types of AGEs appear to mimic bodily proteins and inflammatory signaling molecules, suggesting they may increase the risk of autoimmune conditions. Various AGEs have been associated with perpetuating autoimmune conditions, including multiple sclerosis^[14], type 1 diabetes^[15], and Hashimoto’s thyroiditis^[16].

8. Accelerates Aging and May Shorten Lifespan. AGEs are thought to accumulate throughout the lifespan and are linked to the severity of symptoms in diseases associated with aging, including chronic kidney disease, cardiovascular disease, and diabetes^[17]. In vitro studies show that AGEs can form cross-links with mitochondrial proteins and DNA, which interferes with energy production and can promote oxidative stress.^[18] As a result of impaired mitochondrial function, further findings suggest that AGE accumulation may shorten cellular lifespan by reducing the level of SIRT1, a biomarker associated with longevity. In animal studies, clearance of AGEs in the kidneys has been linked to longevity, while the reduction of glyoxalases (kidney enzymes that promote AGE removal) was associated with a shorter lifespan.^[19]

9. May Be Carcinogenic. Excessive AGEs have been linked to tumor formation and several types of cancer, including breast, prostate, laryngeal, and colon cancers. In large amounts, cross-linked AGEs can upregulate inflammatory signaling associated with tissue damage, cell growth, and carcinogenesis.^[20]

Risk Factors that Promote AGEs in the Body

Factors that can promote AGE formation or inhibit their clearance include:

Over Cooked Food. As explained above, AGEs can occur in foods due to excessive cooking and browning. Foods low in nutrients are more prone to browning due to having a higher degree of antioxidants that protect against heat-induced oxidation. Dietary AGEs have been shown to substantially increase AGE content in the skin and blood of both animals and humans. While only smaller AGEs are absorbable by the gut, smaller AGEs tend to avoid detection by AGE receptors and are known to increase the size of tissue AGEs.

Diet High in Calories and Low in Nutrition. Diets high in calories are usually referring to diets containing high amounts of processed foods. These are fat, sugar, and protein-heavy, and lacking in nutrition. The rise in processed food consumption indicative of the classic Western diet is associated with the rise in AGEs and AGE-related cardiometabolic diseases, serving as a substantial risk factor.^[21]

Smoking. Levels of AGEs have been proven to be elevated in smokers. Smoking tobacco offers multiple avenues that promote AGE formation, including cardiovascular inflammation and spiking blood glucose levels. Tobacco smoke itself is known to possess glycated products that can go on to form AGEs in the body once inhaled. AGE formation from smoking is thought to contribute to permanent disease-related changes in lung tissue and vasculature, as well as the development of COPD and lung cancer.^{[22] [23}

Sedentary Living. A sedentary lifestyle or lack of exercise has been linked with elevated levels of AGEs as well as an increased risk of acquiring AGE-related diseases.^[24] This could be due to metabolic inefficiency pertaining to reduced energy expenditure relative to food intake. In a similar fashion, sedentary living is connected with facilitating chronic inflammation, blood glucose fluctuations, and diabetes.

Age. AGEs are known to accumulate in the body with ages. The aging process is indicative of higher levels of oxidative stress, reduced mitochondrial repair, and lower levels of bodily antioxidants, which promote the formation of AGEs and the classic signs of aging (e.g., wrinkles). This, in turn, contributes towards faulty detection and clearance of AGEs, which is also noted to occur during aging.

Chronic or Acute Stress. While stress is known to reduce bodily inflammation, prolonged stress has been shown to cause glucocorticoid resistance, inflammation, and mitochondrial dysfunction. Inflammation and oxidative stress as a result of mitochondrial dysfunction can enhance the formation of AGEs. In the reverse context, in vitro studies suggest that AGEs can reduce the sensitivity of the cell to glucocorticoids, which promotes their inflammatory effects.^[25] Acute stress is also known to increase hyperglycemia^[26] and transient insulin resistance, which further encourages the formation of AGEs and increases the risk of developing diabetes.

Reduced Kidney Function. Receptor-bound AGEs are sent to the kidney and typically excreted in the urine. AGEs can lower kidney function and serve as a risk factor for chronic kidney disease.^[27] Kidney damage or disease can inhibit optimal AGE clearance and exacerbate their formation. A portion of AGEs is known to get reabsorbed by the kidneys, which can serve to perpetuate inflammation and kidney damage.^[28]

7 Tips for Reducing Body AGE Levels

The amount of body AGEs depends on their intake, one’s metabolism, and the body’s ability to remove them. In this way, the following suggestions may help to lower body AGEs:

1. Lowering dietary AGEs. Consumption of a diet low in AGEs was proven to reduce AGEs in the bloodstream by 30-40% in healthy individuals. In diabetic individuals, an AGE-restricted diet may enhance insulin sensitivity, although neutral results have also been reported^[29]. Foods high in AGEs include processed foods that have been heated during their manufacture, such as cheese, animal products, hydrogenated vegetable oils, and hydrolyzed protein extracts such as whey and soy isolate. Cooking also increases dietary AGEs. However, methods that include high heat, long cooking times, or the addition of excess oil, sugar, or protein will produce higher amounts (i.e., roasting, grilling, deep frying, etc.). Boiling and steaming are considered the best cooking methods in terms of lowering the AGE content of cooked foods. As AGEs can be degraded at lower pH values, consuming foods that promote optimal digestion and that aid the action of acidic digestive enzymes can help as well.

2. Maintaining Regular Blood Glucose Levels. As high blood glucose levels can increase AGE formation, it is important to keep blood glucose levels stable and within healthy ranges. A diet high in calories is linked with AGE formation as well as hyperglycemia. Eating balanced meals can help to regulate blood glucose levels, as well as eating smaller amounts at set times of the day, in line with one’s metabolism. Hyperglycemia can also be controlled if careful attention is paid to the order of one’s meal. Additionally, Caloric restriction has proven to lower the formation of AGEs in rats as well as control blood glucose levels and inflammation in humans. Despite this, a diet high in AGEs is still known to increase body levels, whether restricted in calories or not. Thus, while controlling blood glucose levels is important for lowering body AGE formation and preventing hyperglycemia, a low AGE diet is still required in order to reduce the risk of AGE-induced insulin resistance.

3. Being Careful About Sun Exposure. As explained above, sunlight can increase skin inflammation, aging, and the formation of AGEs in response to UV and heat. The intensity of UV the sun emits changes throughout the day, with certain types of UV known to generate more inflammation in the skin than others. Getting sun at the right times of the day can help to lower skin inflammation, photoaging and resultant AGE accumulation. The morning sun is generally known to be less harmful than the mid-afternoon sun.

4. Regular Exercise. Some studies suggest that exercise helps to lower body AGE levels. However, these results are likely to be due to improving other facets of health, such as body fat and glycemic control.^[30]

5. Kidney Health. Maintaining optimal kidney health can help to promote better AGE clearance from the body. Lowering AGE intake is a major component of improving kidney function,^[31] with fewer bodily AGEs being conducive to their clearance. Protein intake ought to be balanced with higher consumption of plant-based fiber-rich foods.^[32] Keeping hydrated is another important aspect of kidney health.

6. Consuming a Nutrient-Dense Diet. A diet high in nutrients with balanced ratios of macronutrients can help to reduce the formation of dietary AGEs as a result of cooking, as well as promote their removal from the body. A nutrient-dense diet is typically plant-based, which facilitates a healthy gut microbiome and optimal nutrient absorption. Phytochemicals (plant-based nutrients) often have antioxidant properties that collectively serve to combat oxidative stress and inflammation, especially if frequently consumed, as they can accumulate in the body. In many animal studies, antioxidant administration helped to lower AGE accumulation and could partially ameliorate the associated deleterious effects. A specific class of phytochemicals known as flavonoids was shown to protect against the effects of AGE accumulation. Resveratrol and hesperidin are two flavonoids that are known to enhance glyoxalase levels (an enzyme that removes AGEs) and promote AGE removal.

• Anti-Coagulants such as aspirin  and heparin  are known to inhibit glycation and the formation of AGEs, as well as their binding to RAGE receptors. Lowered binding of AGEs to RAGEs decreases AGE-associated inflammation and increases the chances of AGE clearance via other pathways.
• Metal Chelating Agents have been proposed to reduce AGEs through lowering levels of metals that catalyze cellular oxidation reactions and resultant inflammation. 
• B Vitamins Thiamine (B1) and Pyridoxamine (B6) are both capable of inhibiting the formation of AGEs and lower AGE levels via chelation and lowering oxidative stress.
• ACE inhibitors, commonly prescribed to treat hypertension, appear to have chelating and AGE-inhibiting properties which may contribute towards their antihypertensive effects.  
• Carnosine is a dipeptide found throughout the body that can lower blood glucose levels, enhance AGE clearance and reduce the formation of AGEs when supplemented.  Evidence suggests that it confers anti-diabetic effects and is supportive of cardiovascular function. 

Conclusion

Advanced Glycation End Products (AGEs) are a natural part of the aging process. However, their premature accumulation can contribute to the progression of many diseases. AGEs are formed in the body when glucose levels are too high, when there is an abundance of fats and proteins, and when there is excessive cellular oxidation or heat to facilitate glycation. Risk factors for AGE formation include factors that promote bodily inflammation, unbalanced diet plans, and an elevated intake of dietary AGEs, which are found in larger amounts in processed or overly cooked foods. Leading a healthy lifestyle and consuming a nutrient-dense diet goes a long way towards lowering body AGE formation.

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