Advanced Glycation End products

Advanced glycation end products (AGEs), also known as glycotoxins, are highly oxidant compounds with pathogenic significance in diabetes and in many other chronic diseases. In the recent years the role of advanced glycation end products (AGEs) is also discussed in aging. And logically this has led to finding potential strategies against the effects of AGEs.

Advanced glycation end products (AGEs) are a complex group of compounds that are formed when reducing sugar reacts in a non-enzymatic way with amino acids in proteins and other macromolecules. This occurs both exogenously (in food) and endogenously (in humans). It is also known that greater concentrations of AGEs are found in older adults. In the last twenty years, there has been increased evidence that AGEs could be implicated in the development of chronic degenerative diseases of aging, such as cardiovascular disease, Alzheimer’s disease and complications of diabetes mellitus. AGEs are also involved in skin aging, the human’s largest organ. In addition it has been suggested that AGEs are involved in the loss of bone density and muscular mass associated with aging. Results of studies in animal models and humans show that the restriction of dietary AGEs has positive effects on wound healing, insulin resistance and cardiovascular diseases. More recently it has been reported that restriction in AGEs consumption as part of food increases the lifespan in animal models.

One of the harming mechanisms of AGEs is additional cross-linking on collagen (whose normal structure already contains crosslinking) by glycation of its free amino acids. The collagen-AGEs cross-linking for example produces stiffness of blood vessels. Therefore, accumulation of AGEs could be an explanation for some or part of the cardiovascular changes associated with aging, such as vascular stiffening, diastolic dysfunction and endothelial dysfunction. A study with long-term (24–30 weeks) administration of aminoguanidine (an inhibitor of AGE formation) showed prevention of the age-related cardiac hypertrophy and arterial stiffness.

The extracellular matrix (ECM) proteins are also among the main victims of glycation. In the skin collagen it is not only used as a supportive framework for mechanical support for cells and tissues, but it also is an active component able to interact with cells and affects various cellular functions such as migration, differentiation and proliferation. Collagen glycation impairs its function in various ways. Intermolecular crosslinks of adjacent collagen fibers change its biomechanical properties leading, again, to stiffness and decreased flexibility. In addition the change of its charge and the formation of AGEs on side chains of collagen affect its contact sites with cells and other matrix proteins and inhibit its ability to react with them. The modified collagen resists degradation by MMP enzymes and as result inhibits its removal and replacement by newly synthesized and functional collagen.

The accumulation of AGEs in tissues is also suggested to contribute to increased oxidative stress, and as a final outcome, impair organ function. Recent work suggests a mechanism that shows detoxification by the body of an AGEs precursor is significantly diminished in older mice, allowing AGEs to increase faster when older. Additionally, slowly diminishing renal function with age could affect the ability to excrete AGEs. These are possible explanations as to why high levels of AGEs are found in older age groups. All together this suggest an important negative role of dietary and circulating AGEs for healthy aging and anti-aging efforts.

As said before AGEs are created through a nonenzymatic reaction between reducing sugars and free amino groups of proteins, lipids, or nucleic acids. This reaction is also known as the Maillard or browning reaction. The formation of AGEs is a part of normal metabolism, but if excessively high levels of AGEs are reached in tissues and the circulation they can become problematic. Among the better-studied AGEs are the stable and relatively inert Nε-carboxymethyllysine (CML) and the highly reactive derivatives of methyl-glyoxal (MG). Both these AGEs can be derived from protein and lipid glycoxidation. In addition to AGEs that form within the body, AGEs also exist in foods. AGEs are naturally present in uncooked animal-derived foods, and cooking results in the formation of new and more AGEs within these foods. In particular, grilling, broiling, roasting, searing, and frying vreates new AGE formation. Recent studies with the oral administration of AGE-rich food to humans and animals show that AGEs are absorbed and contribute significantly to the body’s AGE pool.

A persistent AGE form in humans is glucosepane which forms an ever-increasing number of cross-links between macromolecules in the extracellular matrix and so far there are no approved drugs known today that can break these links. Therefore a strategy to lower the impact of AGEs maybe to interfere in the earlier steps in the formation of these very hard to break cross links thus preventing them to be formed as much as possible. It is however not for a lack of trying, for example both aminoguanidine (AG) and the thiazolium derived compound ALT-711 (algebrium) have been tested and have shown potential as drugs that inhibit AGE formation, but in both cases further clinical development was discontinued due to safety and/or efficacy concerns.

Therefore easiest starting point is to adjust our eating. Databases show that reduced intake of dietary AGEs can be achieved by increasing the consumption of fish, legumes, low-fat milk products, vegetables, fruits, and whole grains and by reducing intake of solid fats, fatty meats, full-fat dairy products, and highly processed foods.

In addition an increasing list of natural antioxidants and chelating agents such as ascorbic acid, α-tocopherol, niacinamide, pyridoxal, sodium selenite, selenium yeast, trolox, rivoflavin, zink and manganese have been shown to inhibit glycation of albumin in vitro. Green tea, vitamins C and E and a combination of N-acetylcystein with taurine and oxerutin could inhibit skin collagen glycation in mice. Another compound, the green tea-derived polyphenol and flavonoid epigallocatechin-3-gallate revealed also promising in vitro effects by antagonizing AGE-induced proinflammatory changes. In healthy human subjects, supplementation of vitamin C significantly decreased serum protein glycation.

Many spices and herbs have also been shown to inhibit glycation of albumin in vitro, among them ginger, cinnamon, cloves, marjoram, rosemary and tarragon. Their protective effects correlated with their phenolic content. Other promising compounds include blueberry extract and naturally occurring flavonoids, such as luteolin, quercetin and rutin, which can inhibit various stages of AGE formation.

On this section of the blog you will find recent research articles related to the impact of AGEs and developments of possible anti-glycation compounds. The preference will go to nutraceuticals as those have an inherent safety profile and are often available already (but in in use for other purposes).