AGE Control:

An Under Recognized Way to Restore Insulin Sensitivity and Improve Heart, Bone and Cognitive Health

By David D. Parrish, MD

Scientists and the general public have long been fascinated by the reasons behind why we age and the actions we can take to slow aging. A number of theories have been proposed, including The Neuroendocrine Theory of Aging, which Ward Dean, MD extensively covered in past issues of this newsletter.

The Neuroendocrine Theory of Aging was first described in 1954 in a Master’s thesis by the distinguished Russian gerontologist, Vladimir Dilman, M.D., Ph.D., D.M.Sc., who ultimately wrote a number of books about the topic. Dr. Dean obtained a copy of Dilman’s books and later co-authored with the gerontologist the book The Neuroendocrine Theory of Aging and Degenerative Disease. The Neuroendocrine Theory states that aging is caused when receptors and secretory cells in the limbic system, hypothalamus and the pituitary (important structures in the brain) are no longer sensitive to the hormones that control their function, resulting in a down regulation of the limbic-hypothalamic-pituitary axis and a subsequent down regulation of end organ receptor sites in the thymus, adrenals, thyroid, ovaries and testes. When this essential neuroendocrine axis becomes less functional, our bodies are thrown out of balance and we are at increased risk for the major diseases of aging—which include atherosclerosis, hypertension, diabetes, cancer and autoimmune disorders. Consequently, maintenance and up regulation of this vital axis is of crucial importance.1

In this article, I will take the Neuro¬endocrine Theory one step further by addressing a closely related concept that Dr. Ward Dean also has explored extensively: The Cross-linking Theory of Aging. Neuroendocrine imbalance, as mentioned above, can lead to this destructive process known as cross-linking.

It has long been known that cross-linked proteins are linked to diabetic complications. The newest research, however, reveals that cross-linking is related to a surprising number of diseases, including Alzheimer’s disease, osteoporosis, arthritis, kidney disease, cataracts and aging skin (see sidebar). Furthermore, researchers now realize that cross-linking increases the amount of LDL type B subparticles (the “bad” cholesterol).

Why We Age: One Proposed Theory

According to the Cross-linking Theory of Aging, when a sugar links with a protein molecule a harmful process called cross-linking occurs in the body. Cross-linking begins with a process called the Maillard reaction. Anyone who has toasted a slice of bread is familiar with this reaction. When the protein and the carbohydrates in the bread are exposed to heat they turn brown as a result of the chemical reaction that occurred between the proteins and carbohydrates during cooking.

The same process occurs in our bodies. When sugars combine with proteins during the Maillard reaction, it produces what’s called a Schiff base. This is then converted into another harmful substance called an Amadori product. However, the final result of this reaction—when the Amadori products are rearranged and transformed into Advanced Glycation End Products (AGEs)—is particularly destructive to the body. AGE molecules can further react with other fats, proteins and nucleic acids to form cross-links so strong that they cannot be broken apart. These Advanced Glycation End Products accumulate in many tissues as we age. This is especially true in individuals whose limbic-hypothalamic-pituitary axis is down regulated, because the body becomes inefficient at regulating normal blood glucose concentrations and maintaining proper insulin levels by blocking intracellular uptake of both insulin and glucose, paving the way for increased glycation and AGE production.

One of AGE’s best known effects is their ability to intensify diabetic complications such as diabetic retinopathy, neuropathy and cardiovascular disease. Researchers also now believe that AGE production plays a detrimental role in the onset of diabetic atherosclerosis.2 Other researchers have established a close tie between AGEs and insulin sensitivity in fat cells (adipocytes). They determined that AGEs inhibited glucose uptake and increased the production of free radicals known as reactive oxygen species (ROS) in the fat cells. AGEs also increased the expression of monocyte chemoattractant protein-1, which has been implicated in the development of obesity-associated glucose intolerance.3 These effects led the researchers to conclude that AGEs are “involved in the development of obesity-related insulin resistance.”

High AGE levels have been linked to a surprising number of other conditions such as Alzheimer’s disease and osteoporosis. AGEs are known to accumulate on beta-amyloid plaques, which are linked to the development of Alzheimer’s disease, where the AGEs trigger chronic oxidative stress.4

A type of AGE known as pentosidine also increases exponentially in bone in certain areas of the body during aging, to the extent that researchers have attributed the build up of this AGE molecule as a biomarker for the degree of bone mass density loss.5

AGEs and the Diet

AGEs are produced in the body as a result of imbalanced metabolic processes. AGE molecules also are found in many regularly consumed foods, especially high-glycemic foods and, as described above, are created in carbohydrate-rich foods when they are cooked. The consumption of sugar, white bread, bakery products and other AGE-rich foods adds to the level of endogenous AGEs already produced in the body. Modern food processing also results in foods with increased AGE levels. In fact, even infant formula has high levels of AGEs, indicating that people are exposed to AGEs from a very early age.6

Dietary AGEs have been shown to initiate a number of destructive effects. They increase free radical production and deplete levels of glutathione, a critical antioxidant.7

Increased consumption of dietary AGEs can alter LDL (the “bad” cholesterol) in a way that increases its negative effects. In a study of 24 diabetic subjects, LDL from subjects consuming a high-AGE diet experienced more free radical damage (oxidation) and was more susceptible to glycation compared to subjects on the low-AGE diet. When this oxidized, glycated LDL was added to human endothelial cells from vein walls it promoted inflammation, an effect not seen with the LDL not exposed to AGEs. The LDL from the subjects consuming the high-AGE diet also significantly increased vascular cell adhesion molecule-1, a molecule that encourages blood cells to stick to the artery walls and block the arteries, providing further evidence to support the possibility that AGEs are the reason why diabetics have an increased risk of heart disease.8 The study authors concluded that exposure to dietary AGEs increased LDL-induced vascular toxicity and that “this can be prevented by dietary AGE restriction.”

In a perfect world we would be able to avoid foods that generate AGEs. However, even individuals who habitually avoid blood-sugar-raising foods find themselves “slipping off the low-glycemic wagon” from time to time by consuming the occasional treat. So while avoiding AGE-producing, blood-sugar-raising foods is important, the reality is that none of us are perfect and taking a proactive stance against AGEs is crucial. Therefore, in this article I will address nutrients that have demonstrated anti-AGE effects.

Natural AGE Blockers

N-acetyl cysteine (NAC) is one of the most potent natural AGE-inhibitors. NAC stops AGEs from initiating changes to LDL cholesterol that make this “bad” form of cholesterol even more destructive. In the study of 24 diabetic subjects mentioned above, NAC inhibited the inflammatory effects that AGE-exposed LDLs have in the body. In addition, NAC blocked the AGE-triggered production of a molecule partially responsible for increased activity of the “sticky” platelets that cause clogged arteries (vascular cell adhesion molecule-1).8

By increasing glutathione, NAC also reduces lipid peroxidation that occurs in neuronal cell lines after AGE exposure.9 This led one group of researchers to conclude, “scavengers of oxygen free radicals could be useful in protecting brain tissue from lipid peroxidation and its pathophysiological consequences that occur in Alzheimer’s disease.”

In other studies, NAC has decreased the cell death and free radical damage that occur in retinal cells after AGE exposure in vitro.10 This same AGE-triggered cell death occurs during diabetic retinopathy in humans. In cells exposed to AGEs from dietary sources and in diabetic subjects, NAC prevented the reduction of glutathione, a crucial antioxidant.11-12 NAC has an equally strong effect against AGE’s ability to cause insulin resistance in fat cells. In one study, AGE’s effects on insulin and glucose uptake by fat cells were completely reversed by NAC.3, 9-10

Studies have found that lipoic acid is also very active in inhibiting AGE formation. Rats fed lipoic acid and a high-fructose diet showed significant reductions in AGE formation.13

Another well-researched, AGE-inhibiting substance is the amino acid carnosine (beta-alanyl-L-histidine). Carnosine has been reported to retard and in some cases even reverse the glycation process.14 A large body of scientific evidence points to carnosine as powerful AGE-blocking substance. When LDL cholesterol undergoes glycation to form oxidized cholesterol and AGEs, immune cells known as macrophages phagocytize or “gobble up” the oxidized, altered cholesterol. Thus, atherosclerosis begins when macrophages engulf particles of oxidized and glycated LDL cholesterol. As this buildup continues to occur, increasing amounts of glycated and oxidized LDL cholesterol clump together, ultimately blocking the arteries. Both carnosine and its primary functional amino acid l-histidine can inhibit LDL glycation and oxidation.15

Carnosine may also reduce AGE-induced cognitive dysfunction. Protein oxidation and glycation are integral components of Alzheimer’s disease. In fact, glycated protein accumulates in the cerebrospinal fluid of Alzheimer’s patients. Protein cross-links are present in the neurofibrillary tangles in the brains of Alzheimer’s patients, further building the case for a link between AGEs and Alzheimer’s. Carnosine has been shown to suppress amyloid-beta peptide toxicity, inhibit production of oxygen free-radicals and suppress protein glycation.16

Furthermore, carnosine’s ability to inhibit AGEs and cross-linking may account for its ability to reduce cataract formation in animal studies.17

Carnosine appears to “nip glycation in the bud” by causing decomposition of Schiff bases, the very first intermediate in the glycation/AGE forming process, before the Schiff bases can become AGEs.18

A lesser known AGE-blocking agent is guava (Psidium guajava extract). In a study released earlier this year, researchers determined that guava had a significant and inhibitory dose-dependent effect on LDL glycation. The researchers attributed guava’s glycation-blocking actions to its distinct abundance of polyphenolic content.19

Yerba Maté (Ilex paraguariensis extract) is emerging as another powerful AGE-blocking substance. In a recent study, Yerba maté significantly prevented AGE formation. The researchers attributed this to the fact that the polyphenol concentration in Yerba maté is about 2 to 2.5 fold higher compared with green tea, which had no effect on AGEs in the study. Yerba maté’s AGE-inhibition effects occurred during the second phase of the glycation reactions, namely preventing the free-radical mediated conversion of the Amadori products to AGEs. What’s more, Yerba Maté’s inhibition of AGE formation was comparable to that obtained by using the standard antiglycation agent aminoguanidine.20

Finally, any discussion about nutritional anti-AGE strategies would not be complete without mentioning benfotiamine, a form of vitamin B1 that is a well-researched  AGE blocker. In one study, 13 type-2 diabetic subjects were fed a high-AGE meal without benfotiamine. They then consumed the high-AGE meal together with 1,050 mg per day of benfotiamine for 3 days. When the subjects consumed the high-AGE diet without benfotiamine, their AGE levels rose. However, when they consumed the high-AGE diet with benfotiamine, AGE formation was significantly reduced.21

In diabetic mice, benfotiamine has prevented the vascular accumulation of AGEs and accelerated the healing of ischemic diabetic limbs.22

Adjunctively, ensuring that the body’s pH values are slightly alkaline (i.e. a blood pH of 7.34 to 7.36) and normalizing intracellular magnesium levels significantly increases the success of nutritional antiglycation strategies.

Conclusion

Advanced Glycation End Products (AGEs) play a significant role in a majority of the chronic, degenerative diseases associated with aging. They have long been known to be involved in complications of diabetics but new research indicates they also influence cognitive and bone health. AGEs also encourage the development of insulin resistance and elevated blood glucose transforming LDL cholesterol into harmful LDL type B subparticles, which are very destructive to the cardiovascular system. Substances such as N-acetyl cysteine, lipoic acid, carnosine, guava, Yerba maté and benfotiamine can all be used to defend against AGEs and  maintain neuroendocrine function and overall health.

David D. Parrish, MD

Dr. Parrish is a multi-specialty physician who has had extensive experience in quantum physics applications in medicine, neurology, developmental psychoanalysis, preventive endocrinology, and anti-aging medicine. He studied with Dr. Thierry Hertogue, M.D., co-founder of the International Endocrine Society and President of the World Society of Anti-Aging Medicine. Dr. Parrish is best known for his successful research identification of neurophysiologic organizers of infant development and their relation to emerging primary mental mechanisms of early childhood. Currently, Dr. Parrish devotes full time to research in the areas of neutraceuticals, pharmaceuticals and novel technologies to expand normal neurocognitive awareness.

References

1. Dean W. Neuroendocrine Theory of Aging Chapter 7. Restoring Receptor Sensitivity Part III. Vitamin Research News. Available online at www.vrp.com.

2. He R, Qu AJ, Mao JM, Wang X, Sun W. Synergistic proliferation induced by insulin and glycated serum albumin in rat vascular smooth muscle cells. Sheng Li Xue Bao. 2007 Feb 25;59(1):1-7.

3. Unoki H, Bujo H, Yamagishi S, Takeuchi M, Imaizumi T, Saito Y. Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen species in adipocytes. Diabetes Res Clin Pract. 2007 May;76(2):236-44. Epub 2006 Nov 13.

4. Gasic-Milenkovic J, Loske C, Münch G.  Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y. J Alzheimers Dis. 2003 Feb;5(1):25-30.

5. Odetti P, Rossi S, Monacelli F, Poggi A, Cirnigliaro M, Federici M, Federici A. Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci. 2005 Jun;1043:710-7

6. Elliott RB. Diabetes--a man made disease. Med Hypotheses. 2006;67(2):388-91.

7. Cai W, Gao QD, Zhu L, Peppa M, He C, Vlassara H. Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction. Mol Med. 2002 Jul;8(7):337-46.

8. Cai W, He JC, Zhu L, Peppa M, Lu C, Uribarri J, Vlassara H. High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients. Circulation. 2004 Jul 20;110(3):285-91.

9. Gasic-Milenkovic J, Loske C, Münch G. Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y. J Alzheimers Dis. 2003 Feb;5(1):25-30.

10. Kowluru RA. Effect of advanced glycation end products on accelerated apoptosis of retinal capillary cells under in vitro conditions. Life Sci. 2005 Jan 14;76(9):1051-60.

11. Cai W, Gao QD, Zhu L, Peppa M, He C, Vlassara H.  Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction. Mol Med. 2002 Jul;8(7):337-46.

12. Ozkilic AC, Cengiz M, Ozaydin A, Cobanoglu A, Kanigur G. The role of N-acetylcysteine treatment on anti-oxidative status in patients with type II diabetes mellitus. J Basic Clin Physiol Pharmacol. 2006;17(4):245-54.

13. Thirunavukkarasu V, Anitha Nandhini AT, Anuradha CV. Lipoic acid improves glucose utilisation and prevents protein glycation and AGE formation. Pharmazie. 2005 Oct;60(10):772-5.

14. Szwergold BS. Carnosine and anserine act as effective transglycating agents in decomposition of aldose-derived Schiff bases. Biochem Biophys Res Commun. 2005 Oct 14;336(1):36-41.

15. Rashid I, van Reyk DM, Davies MJ. Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Lett. 2007 Mar 6;581(5):1067-70.

16. Hipkiss AR. Could carnosine or related structures suppress Alzheimer’s disease? J Alzheimers Dis. 2007 May;11(2):229-40.

17. Guo Y, Yan H. [Preventive effect of carnosine on cataract development] [Article in Chinese]. Yan Ke Xue Bao. 2006 Jun;22(2):85-8.

18. Szwergold BS. Carnosine and anserine act as effective transglycating agents in decomposition of aldose-derived Schiff bases. Biochem Biophys Res Commun. 2005 Oct 14;336(1):36-41.

19. Hsieh CL, Yang MH, Chyau CC, Chiu CH, Wang HE, Lin YC, Chiu WT, Peng RY. Kinetic analysis on the sensitivity of glucose- or glyoxal-induced LDL glycation to the inhibitory effect of Psidium guajava extract in a physiomimic system. Biosystems. 2007 Mar;88(1-2):92-100.

20. Lunceford N, Gugliucci A. Ilex paraguariensis extracts inhibit AGE formation more efficiently than green tea. Fitoterapia. 2005 Jul;76(5):419-27.

21. Stirban A, Negrean M, Stratmann B, Gawlowski T, Horstmann T, Götting C, Kleesiek K, Mueller-Roesel M, Koschinsky T, Uribarri J, Vlassara H, Tschoepe D. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care. 2006 Sep;29(9):2064-71.

22. Gadau S, Emanueli C, Van Linthout S, Graiani G, Todaro M, Meloni M, Campesi I, Invernici G, Spillmann F, Ward K, Madeddu P. Benfotiamine accelerates the healing of ischaemic diabetic limbs in mice through protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. Diabetologia. 2006 Feb;49(2):405-20.