Advanced Glycosylated Endproducts (AGEs) and Implications for Advanced Holistic Treatment

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

Research into systemic or holistic pathological processes reveals both the need for holistic Complementary and Integrative Medicine (CIM), and provides the Complementary physician access to new specific treatment protocols to aid therapy. In the last decade or two, research has revealed that Advanced Glycosylation (Glycation) Endproducts (AGEs) are integral to a variety of diseases, including Metabolic Syndrome, Diabetes, Cardiovascular disease, and neurodegenerative diseases. With glycation, or glycosylation, glucose molecules strongly attach to target proteins, lipids and nucleic acids (RNA and DNA), and the complex endproducts that arise from oxidant reactions may create a pathological level of oxidant stress when they accumulate, which may be increased with exogenous AGEs from processed and fast foods. TCM provides a holistic treatment strategy to reduce this accumulation when it occurs and prevent future accumulation.

The pathophysiological roots of chronic disease is an important subject for integrative Complementary Medicine. In Traditional Chinese Medicine, ancient physicians formulated many theories of the roots of disease, and emphasized that both the root and the branch, or symptomatic manifestation, of these diseases must be addressed in therapy. Translation of this concept into modern integrative models is a complex and difficult task, but one that is vitally important to the progress of TCM as an integrative medicine. The most important research advance to this task is the discovery of AGEs and the way that excess AGE in our bodies will generate excess receptors (RAGEs) that react to a host of chemical ligands, immunomodulators, hormones, neuropeptides, etc. This excess accumulation is a key factor in aging processes, neurodegenerative disease, atherosclerosis, diabetes, metabolic syndrome, chronic kidney failure, heart disease, cancer, etc.

Glycosylation, or glycation, is the enzymatic process that links saccharides to produce glycans, or polysaccharides (carbohydrates), to proteins, lipids, or other organic molecules. This process produces many of the essential cellular components in our bodies. The majority of proteins synthesized in the cell endoplasmic reticulum, which regulate our cellular processes, undergo glycosylation. Proteins are the large products of RNA expression, combining amino acids in such a way as to express the functional commands and produce the products that our bodies need to function in a healthy homeostasis. The glycosylation products insure that these proteins fold and unfold properly, are stable, adhere to other cells, etc. AGEs are glycosylation (glycation) endproducts that are not properly regulated by enzymatic regulation, and may be a key component of disease processes. Our modern world has changed the fundamental nature of our foods with technology, and our bodies have a long way to go to adapt to these changes.

Research has also uncovered the fact that a number of modern stressors have been created that increases the pathological effects of excess AGE and RAGE in our bodies. These include the increases in oxidants from both physiological stress and our environment. AGEs produced in the body from a variety of stress pathways create a slower disease process than AGEs introduced through the diet, and thus affect proteins with a longer life, such as albumin in blood circulation. A the effects of AGE accumulation occur, coupled with the inability to clear these complex molecules faster than they are created, chronic disease slowly progresses, and may be acutely exacerbated by AGEs introduced in the diet, increased environmental oxidant stress, and periods of higher physiological stress in the individual's life or work. As the array of common chronic diseases advance in our bodies, so too does the ill effects of AGE accumulation and RAGE expression. This is the catch-22 of chronic disease. What we need to discover is a holistic plan to reverse this pathological process that incorporates improved public dietary health, decreases in environmental stressers, prevention of chronic common disease processes, and restoration of a healthier and more natural physiology. A simple plan of inventing new allopathic pharmaceuticals to block the production of AGE and negate RAGE expression will not be effective enough, because the variety of AGEs is great, as are the pathways of cause. Medical doctors must look outside the box and incorporate an integrative and holistic approach to have an appreciable effect on this root process of common chronic disease.

AGEs are one example of a pathological process that can be reversed and prevented effectively with a medical protocol that is inclusive of Complementary Medicine. The first significant attention to these metabolites occurred with the pharmaceutical focus on new diabetic or metabolic therapy and testing. The A1C index is now a universal test to accompany circulating blood sugar and triglyceride levels to evaluate and treat Metabolic Syndrome, which is still unfortunately referred to as type 2 diabetes. A1C is the nonenzymated glycated product of the hemoglobin beta-chain at the valine terminal residue, and excess indicates a complex metabolic dysfunction of unregulated sugar and protein coupling that leads to many of the health risks in metabolic syndrome. While a pharmacological allopathic approach has produced the glitazones Actos and Avandia to lower the A1C index, these drugs have produced alarming systemic side effects that have prompted stern FDA warnings in 2007 of increased cardiovascular risk. The drugs also produce weight gain, water retention, anemia, inhibition of steroidogenesis and androgen production, and in a 5 year efficacy study, the various metabolic drugs failed in 15-34% of cases.

The research that has resulted from these pharmacological studies has opened a pandora's box of information related to unhealthy metabolism and its consequences on public health issues. AGEs are now implicated as a root disorder in the etiology of diabetes, metabolic syndrome, atherosclerosis, heart failure, age-related diseases, neuroendocrine disorders, and possibly cancer. These metabolic endproducts appear to relate to neuroendocrine receptors in most organ systems in our bodies, and require a robust oxidative and immune metabolism to counter ill effects of excess. The food industry has gravitated toward processed foods that are high in these AGEs, and also stimulate endogenous production, while inhibiting the essential nutrients needed to counter the ill effects. What we see here is a scientific explanation of a holistic approach to pathology.

"Advanced glycation end-products (AGEs) are molecules formed during a non-enzymatic reaction between proteins and sugar residues, called the Maillard reaction. AGEs accumulate in the human body with age, and accumulation is accelerated in the presence of diabetes mellitus. In patients with diabetes, AGE accumulation is associated with the development of cardiac dysfunction. Enhanced AGE accumulation is not restricted to patients with diabetes, but can also occur in renal failure, enhanced states of oxidative stress, and by an increased intake of AGEs. Several lines of evidence suggest that AGEs are related to the development and progression of heart failure in non-diabetic patients as well." Department of Cardiology, Thoraxcenter, University Medical Center Groningen and University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Scientific study of advanced glycosolation endproducts represents a field of research that points to a need for a holistic approach to a number of serious health problems. Not only age and diabetes associated heart failure, but atherosclerosis itself has been linked to excess AGE and AGE receptor stimulation. Complementary medicine must play a large role in the standard of care devoted to normalizing homeostasis and decreasing excess production of AGEs, as well as providing reliable dietary information to decrease excess intake in the diet, reducing oxidative stress, and insulin resistance. Simply applying pharmaceutical drug therapy to block excess production of these endproducts of normal sugar metabolism is unwise and may engender excess health risk greater than benefit for many patients. Use of Complementary Medicine has shown promise as an adjunct therapy to pharmaceutical drugs in this realm, as a reducer of risks from side effects, and as a first line conservative care for patients with less risk.

AGEs have been implicated in the formation of atherosclerotic plaque independant from a diabetic state. AGEs have also been implicated in health problems associated with aging, and probably future research will implicate this unhealthy metabolic mechanism in many chronic diseases affecting our population. The problem involves a combination of dietary habits, unregulated processed foods, environmental stresses, increased oxidative stress in the population, decreased immune efficiency, metabolic dysfunction, insulin resistance, hepatic and renal dysfunction, and normal aging, all of which may contribute to a significant cause of the most threatening chronic health problems in the United States today.

"The normal aging process is often accompanied by arterial wall stiffening and by a decrease in myocardial compliance. These processes contribute to isolated systolic hypertension and diastolic heart failure, which lead to substantial morbidity and mortality among older individuals. Patients with diabetes manifest arterial stiffening and diastolic dysfunction at a younger age. This leads to the concept that the mechanism that underlies changes in vascular mechanical properties during aging is accelerated in diabetes. The Maillard reaction or advanced glycation of proteins occurs slowly in vivo with normal aging and at an accelerated rate in diabetes. Advanced glycation end-products (AGEs) that form during the Maillard reaction are implicated in the complications of aging and diabetes. The formation of AGEs on vascular wall and myocardial collagen causes cross-linking of collagen molecules to each other. This leads to the loss of collagen elasticity, and subsequently a reduction in arterial and myocardial compliance. Aminoguanidine, an inhibitor of AGE formation, is effective in slowing or preventing arterial stiffening and myocardial diastolic dysfunction in aging and diabetic animals. In aged and diabetic animals, agents that can chemically break pre-existing cross-linking of collagen molecules are capable of reverting indices of vascular and myocardial compliance to levels seen in younger or non-diabetic animals. These studies suggest that collagen cross-linking is a major mechanism that governs aging and diabetes-associated loss of vascular and cardiac compliance. The development of AGE cross-link breakers may have important role for future therapy of isolated systolic hypertension and diastolic heart failure in these conditions." - Department of Cardiology, Rambam Medical Center, POB 9602, Haifa 31096, Israel.

The receptors for Advanced Glycation Endproducts (RAGEs) are often overexpressed when an excess of AGEs accumulate, and recent research has shown that these receptors are implicated in chronic skin problems as well. A study by the University of Amsterdam, in 2015, showed that RAGEs are implicated in regulation of immune responses to bacteria, and that they are related to common Staph infections that are chronic on distal limb skin. This study (see link below) showed that in this case, the expression of RAGE did not affect the immune mediators to common skin bacteria such as Staph, but did facilitate bacterial growth on distal limb skin (PMID: 26086798). Studies in 2014 at the University of Sydney and the University of Queensland, in Australia, found that the pathway of RAGE and HMGB-1 (high mobility group box ligands) is also implicated in chronic allergic reactivity in bronchioles and sinus membranes (PMID: 24506934). While this research presently is exploring the novel implications for drug targets to block disease processes, such research shows that a pathological accumulation of AGEs and expression of RAGE is implicated in an array of chronic diseases that are difficult to treat, and that normalization of AGEs and RAGE expression would surely improve these conditions. Further studies will be designed to see if this can be proven.

The pathological implications of AGEs and RAGE is leading to much research of novel chemicals that may inhibit AGE accumulation and excess expression of RAGE. Aminoguanidine is a chemical inhibitor of nitric oxide synthase. Recent research has shown that this pharmaceutical does not inhibit AGE formation, as was believed. Scientific data is available at the end of this article in additional information, with links to study summaries. Herbal chemicals that achieve this same inhibition of inducible nitrix oxide synthase include wogonin, baicalin, and baicalein from the Chinese herb Huang qin, berberine from Huang bai, and polydatin from Hu zhang. Studies at Taipei Medical University found that these herbal chemicals effectively inhibited nitric oxide production without directly effecting the inducible nitric oxide synthase enzyme activity, and without noticeable cytotoxic effects on the cell. Alone, or as complement to chemical iNOS, Huang qin presents a dose-dependent treatment to effectively block the effects of excess AGE on arteries and heart muscle. Fang feng is another studied herb found to inhibit nitrite production. Imperatorin and deltoin from this herb were found to be potent NO production inhibitors via inhibition of nitrite production, as well as inhibition of the expression of iNOS protein. As the implications of AGE accumulation and excess expression of RAGE become more evident, research is growing into pathways of herbal chemicals that may reduce AGE accumulation, with novel herbal therapy proven to work well, such as Korean thistle extract. What is important to consider as this research progresses is that we need to find a more comprehensive treatment strategy for this widely variable disease, not just a single herb.

These herbs just described not only inhibit excess nitric oxide production, one of the harmful endproducts of AGEs, but exert potent antioxidant activity, lower cholesterol, inhibit harmful prostaglandins and COX-2 enzyme, and lower blood sugar. The herbs, unlike synthetic pharmaceuticals, often have a modulatory effect, with a host of chemicals in the herb that protects the body from excess effects. These modulatory approaches are important, as inducible nitric oxide synthase has beneficial effects as well as toxic effects in our bodies, inducing healing of skin and intestinal mucosa, killing of certain bacteria, regulating of T-cell proliferation and differentiation, and control of leukocyte recruitment. The pathways uncovered in pharmaceutical research present useful evidence for parts of the holistic protocol that is needed to reverse AGE accumulation and prevent progression of chronic disease.

A host of Chinese herbal chemicals have been studied as potent inhbitors of nitric oxide synthase. Nitric oxide production by inhibition of nitrites was found to be an activity of angelicin, pimpinellin, sphondin, byakangelicol, oxypeucedanin, oxypeucedanin hydrate, xanthotoxin, and cnidilin, from the Chinese herbs Bu gu zhi, Bai zhi, Bai xian pi, and Chuan xiong. Various herbs attenuate the AGE accumulation and pathology via various biochemical pathways, and some of this research is available in the section of this article entitled Additional Information.

When clearing bitter herbs, or circulatory herbs, are not used, scientific research has found tonic herbs that also inhibit excess AGE formation. Huang qi, astragalus, was found to inhibit AGE formation and exert significant antioxidant activity. The professional TCM/CIM physician is able to develop an individualized step-by-step treatment protocol to help clear AGE accumulation with no adverse effects. The only side effect from this type of persistent therapy is better overall health, and TCM therapies do not have to be taken daily forever, like pharmaceutical medications. Short course of such therapy will help stimulate the body to work better in the natural clearance of AGE accumulation.

A 2015 multicenter research study at the University of Oxford, in the UK, The Icahn School of Medicine at Mount Sinai, New York, the University of Sydney, in Australia, and the Institute for Global Health concluded that "high serum AGEs, a modifiable risk factor for insulin resistance, may indicate risk for the Multiple Sclerosis, type 2 diabetes, and cardiovascular disease. High dietary AGE consumption and serum AGE levels may link healthy obesity to at-risk obesity (as well)" (PMID: 25695885). Pharmaceutical reduction of circulating AGEs is problematic, and integration of Complementary Medicine and a holistic approach with patient education and public health regulation is very important to achieve this goal. TCM/CIM offers such a holistic approach now, and is increasingly evidence-based.

Such research as cited in this article points to importance of using a variety of treatment modalities in Complementary and Integrative Medicine (CIM/TCM) to prevent disease associated with AGEs. Research shows that metabolic syndrome, commonly called type 2 diabetes, which now affects a high percentage of our youth, and accounts for more than 60% of health care expenditure on patients under the age of 15, accelerates the effects of harm from excess AGEs. The first step in reducing harm from excess advanced glycation endproducts (AGEs), and preventing harm from cardiovascular problems, diabetes and metabolic syndrome, is to decrease dietary intake of these molecules.

Nutritional medicine to reduce excess AGEs

Scientific study has found that a number of healthy nutritional supplements and herbal chemicals help to reduce AGE (advanced glycosylation endproducts). P5P, the active form of Vitamin B6, helps inhibit AGE formation and platelet clumping. Vitamin B1 thiamine, and the metabolite of thiamine, benfotiamine, both protect cells from excess AGE, and inhibit superoxide radicals and excess inflammatory mediators called nuclear factors (NFKbeta). There are many different antioxidants, and some of them are particularly effective in inhibiting AGE formation and accumulation. These include L-Carnosine, N-acetyl cysteine, and alpha-lipoic acid (ALA). Of course, dietary changes, such as eating less simple carbohydrates, or refined foods, and more real whole grains, fresh vegetables and whole beans and legumes, will also help. Specific nutrient chemicals, such as betanin in red beets have been proven in studies to inhibit non-enzymatic glycation, or the Maillard reaction, as well, and reduce the collagen cross-links associated with AGE accumulation in organ tissue of laboratory animals fed a high fructose diet. Proanthocyanidins from grape seed extract were also proven to reduce AGE accumulation and provide other benefits to reverse oxidative and inflammatory damage in a variety of cells. Studies have also shown that pomegranate extract significantly inhibits AGE formation and provides potent tissue antioxidant effects. An array of these nutrient medicines provides a very potent strategy for inhibition and clearance of AGE accumulation, as well as the adverse effects generated by AGE accumulation.

Dietary sources of advanced glycation endproducts or AGEs

The most significant source of these harmful AGE molecules is found in processed foods. High fructose corn syrup is the most common commercial sweetener and contributes heavily to AGE in the diet. This is because high fructose corn syrup is a more reactive acyclic form of fructose that induces greater AGE fluorescence compared to glucose. Commercial baked goods, snacks, and many processed foods are also a big dietary source of AGEs. A variety of baked goods and processed foods are made with proteins cooked with sugars in the abscence of water. Proteins are found in most food sources, not just meat, and when the cooking or preparation of these foods is accomplished with little water, the sugars bind to the proteins and form excess AGEs. This type of processing is used in commercial food production to save money and extend shelf life, as well as to produce sweeter foods. Carmelized foods are one example, as are grilled and charred commercial meats, such as hamburgers. Ground beef is often now processed with mild heat treatment in commercial processing even before it is prepared, and studies have shown that this accelerates formation of AGEs as well (PMID: 25442623). Fastfood that is grilled or barbecued with a commercial sauce is particularly high in AGEs, as is meat that is breaded and fried. French fries would be a good example of a mixture of potato protein with added commercial sugar, fried in the abscence of water. Often commercially processed, or cooked, foods will utilize fructose or dairy sugar (galactose), which undergoes glycation at a rate of about 10 times that of glucose. Products made in small quality bakeries and restaurants often use old fashioned sugar, honey or maple syrup, and food preparation is often natural and healthy. Investing a little more money in your food may save your life down the road. Avoidance of commercially prepared foods or attention to the label contents will help reduce dietary AGEs drastically.

Healthy and intelligent choices in your diet help in three ways. One, you take in less of these harmful AGEs, two, the healthier dietary choices help insure that your body, especially your liver, does not produce an excess of AGEs, and three, your body is nourished properly with essential nutrients needed to clean up these excess endproducts of glycosolation. In times of increased oxidative stress, healthy foods that help with antioxidant cleaning are important. Diet is not the only concern here, though, improved function of the liver and kidney systems, improved metabolism, and reversal of diabetic or metabolic dysfunction is also important. Acupuncture, herbal formulas, and nutrient medicine may all help in this regard. Today, scientific evidence helps the physician choose the right evidence-based medicine to take care of these specific problems.

Many patients may make healthy choices in diet changes and tell themselves that they are now immune from dietary harm. This is not necessarily the case, and attention to healthy dietary education is always valuable. Vegetarian diets do not guarantee health in this regard. Vegetarian diets with high fructose intake, or chronic deficiency of lysine and lack of balanced protein may also lead to excess AGE production and accumulation. AGEs are produced in the body as an endproduct of a non-enzymatic reduction of carbohydrates with lysine side chain molecules and N-terminal amino groups of macromolecules, and a lack of lysine, poor and unvaried sources of protein, and a problem with enzyme metabolism may contribute to excess AGE accumulation. As stated, fructose is a carbohydrate that is more difficult to process in AGE metabolism. Excess intake of sweeter fruits, sweet fruit juices, and dried fruits in the diet may also contribute to an excess fructose intake. Apples, for instance, are often very high in fructose compared to glucose content. A choice of fruits that are less sweet, and care in controlling excess consumption of sweet fruits, especially with juices and dried fruit is important. Even though our palates are trained in the United States to desire sweet foods, acquiring a taste for foods that are sour, pungent and bitter are important to a healthy balanced diet. These various tastes occur in foods because they are high in various important nutrients. A person concerned with health will work to change their appetite by acquiring a natural desire for these types of foods.

Some helpful tips in your diet to reduce excess AGEs include increased comsumption of slightly bitter green leafy vegetables, boiling, steaming, lightly sauteing, or braising, instead of using high heat and dry frying. Cooking meats slower, as in stews and soups, and eating broiled or grilled meats rare or medium rare, will help. Experimentation with recipes that steam fish etc. is helpful. Barbecuing with sweet commercial sauces and charring the meats will produce the most AGEs. Avoidance of commercially prepared barbecued meats is helpful. Sometimes, our choices of food at lunch or on the go are particularly unhealthy. Commercial snack foods are often prepared by combining proteins and sugars without water in the cooking process, such as with corn chips, etc. Be careful of excess consumption of these foods as snacks. If your like to drink juices and eat dried fruit, choose fruits that are less sweet. Many people just drink orange and apple juice, and avoid less sweet fruit choices. Start eating sour cherries, apricots, tart apples, berries, etc. and experiment with and acquire the taste for more varied foods. Raw vegetable juicing is one healthy choice, but beware of juices that are again too sweet. Excess consumption of sweet carrot juice, and commercial vegetable juices with a high content of sweet apple or banana should be avoided.

Information Resources

  1. The Center for Cardiology du Nord Saint-Denis, in France, outlines how important AGEs are in cardiovascular and metabolic disease, playing "a central role in complications of both type 1 and type 2 diabetes mellitus" and non-diabetic patients as a marker of cardiovascular disease, regardless of the degree of glycemic control. These doctors in cardiac surgery note that many compounds are being investigated to prevent or treat these diseases by regulated Advanced Glycation Endproducts and their receptors:
  2. Insulin resistance and increased duration of circulating insulin has been found to be a potent modulator of chronic vascular tone, activating protein kinase C in vascular tissues and inhibiting an important enzyme mediator PI-3 kinase, affecting endothelial nitric oxide synthase expression adversely. Chronic enhancement of nitric oxid production may be linked to atherosclerosis, hypertension and myocardial dysfunction.
  3. A 2015 study at Southern Medical University, in Guangzhou, China found that overexpression of RAGE (repceptors for advanced glycation endproducts) is a useful marker to predict gastric cancer progression, showing the link between AGEs and cancer causation:
  4. A 2015 study at the University College London Medical School, and Ramathibodi Hospital, in Thailand, showed that accumulation of AGEs were a strong predictor of higher risk of death in patients with kidney disease undergoing dialysis:
  5. A 2015 study at Stellenbosch University, in South Africa, showed how Advanced Glycation Endproducts (AGEs) may supply the explanation for the array of effects involved in progression of diabetes, linked to oxidative damage to fat cells and other tissues. A focus on AGEs involving the protein albumin, a major transporter in the blood, especially of essential fatty acids and calcium ions. You may click on a PDF link to read the full study:
  6. A 2015 study at Fudan University, Tongji University School of Medicine, in China, and the University of Melbourne School of Medicine, in Australia, found that up-regulation of RAGE and metalloproteinases were highly associated with amyloid beta protein migration through the blood brain barrier, a potential contributor to Alzheimer's disease:
  7. Studies have cast doubt on the ability of aminoguanidine, one of the early pharmaceuticals studied to inhibit AGE formation in diabetes, to inhibit AGE formation, and the findings of harsh side effects ended its development in 2001:
  8. Effects on nitric oxide inhibition by chemicals in Huang qin, studied at Taipei Medical University:
  9. Effects on nitric oxide inhibition by chemicals in Hu zhang, Polygonum cuspidatum, studied at Sungkyunkwan University in South Korea, Department of Biological Science:
  10. Effects on nitric oxide inhibition by Fang feng, studied at Taipei Medical University:
  11. Effects on nitric oxide inhibition by a number of chemicals found in Chinese herbs, studied at Taipei Medical University:
  12. Effects on inducible nitric oxide synthase that are beneficial point to a problem with drug protocols that block all iNOS to counter excess AGE harmful effects:
  13. Effects on inhibition of AGE formation, as well as significant antioxidant activity was found in the herb Huang qi, or Astragalus:
  14. A 2007 study at the Manchester Metropolitan University School of Biology, in Manchester, United Kingdom, found that the active chemical S-allyl cysteine, found in the herb prepared aged garlic extract, significantly inhibited AGE formation and and protected against harmful cardiometabolic effects:
  15. A 2015 study at the Korea Institute of Oriental Medicine, in Daejeon, South Korea, found that the herbal chemical Myricetin inhibits the pathology in diabetic retinopathy. Myricetin is found in Huang lu (Cotinus coggygria), Gou mei (Myrica rubra), and Man shan hong (Rhondodendron dahuricum):
  16. A 2014 study at Zhengzhou University and the Jiangsu Academy of Chinese Medicine, in China, found that the herb Smilax glabra, Tu fu ling, could significantly attenuate AGE-induced endothelial dysfunction in diabetic cardiovascular disease:
  17. The systemic effects of AGE excess on receptors (RAGE), and the overexpression of RAGE and subsequent interaction with the various chemicals that may overstimulate the receptors, is found to be an important factor contributing to a host of important chronic disorders, including Alzheimer's:
  18. A 2010 study at Tohoku University in Japan found that AGEs may play a role in the development of various diabetic complications, including neuropathy and retinopathy, and confirm that P5P and benfotiamine both inhibit AGE formation and are found to inhibit the development of these diabetic health problems:
  19. The biochemical reasons that benfotiamine acts to reduce AGEs, and how AGEs are implicated in a number of chronic inflammatory diseases:
  20. A multicenter study in 2014, at the University of Sydney and the University of Queensland, in Australia, implicated RAGE, or AGE receptors in the pathway of allergic sensitivity and reaction in the lung and sinus:
  21. A 2015 study at the University of Amrsterdam failed to find a direct causative effect of RAGE for dysfunction of immune responses to Staph bacteria, but did find that RAGE expression was related to the growth of bacteria on distal limb skin, implicated AGEs and RAGE overexpression in chronic skin conditions:
  22. A 2015 study in South Korea, at Chonbuk University and Pukyong National University, as well as th University of Daegu College of Pharmacy, showed that the herb Cirsium maackii, or Korean thistle, may be significant inhibitors of advanced glycoylsation endproducts (AGEs):
  23. A 2015 study at Shenyang University in China showed that a chemical in red beets, betanin, was effective in inhibiting AGE formation and also in reducing AGE-induced cross-links of collagen in heart tissues:
  24. A 2007 study at Shandong University in China showed that proanthocyanidins in grape seed extract significantly reduced AGE formation in laboratory animals with induced diabetes, and also reduced the expression of RAGE, NF-kb, and TGF-beta, showing the potential as part of a holistic regimen to prevent cardiovascular disease:
  25. A 2014 study at the University of Rhode Island, U.S.A. showed that pomegranate extract, a well known tissue antioxidant with an array of benefits, significantly inhibits AGE formation and reduces AGE accumulation via antioxidant effects:
  26. A 2015 study of herbal medicines that could significantly inhibit AGEs, by experts at Chulalongkorn University, in Bangkok, Thailand, found that Rhinacanthus nasutus, Syzygium aromaticum, and Phyllanthus amarus (Ye Xia Zhu) could reduce AGE formation via the methylgloxal pathway: