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Physiology of the Skin: The Impact of Glycation on the Skin, Part 2

By Peter T. Pugliese, MD
Posted: April 14, 2008, from the April 2008 issue of Skin Inc. magazine.

page 2 of 2

       Supplements. There are a few supplements that help to prevent glycation from occurring. The ones with the best record are the following:

     Aminoguanidine—150–300 mg a day, best taken with food. Higher dosages are usually required for diabetic patients, around 300–600 mg daily, or even higher,
since aminoiguandine last only four hours it should be taken in divided doses. It is best to consult with your physician before taking aminoguanidine since it tends
to deplete B-6.
     Benfotiamine—100 mg twice a day
     Carnosine—500–1,000 mg/day
     Pyridoxamine—100 mg/day

       Carnosine is a dipeptide consisting of alanine and histidine that has been shown to counteract free radicals and help prevent peroxidation of cell membranes. Pyridoxamine is a form of pyridoxine or vitamin B-6, but it does not have the side effects of B-6 and is an excellent glycation inhibitor.20 Benfotiamine is a lipid-soluble thiamine or B-1 vitamin. It also is an excellent glycation inhibitor. Aminoguanidine has a long use as a glycation inhibitor, but of late, there are some reports of low toxicity, mainly coupling with vitamin B-6.21 It cannot couple with pyridoxamine, however. It is widely used in animal studies with glycation products and has been shown to be very effective. The dosage for humans is 150–300 mg/day in divided doses. There are many suppliers for these products.
  Even though glycation has been known about for more than 20 years, the information is only now becoming available to the general public, and very few doctors in the United States have heard of it. Antiglycation agents are widely used in Europe to treat both diabetes and heart disease. So far, the products on the market for topical treatment of glycation are few and not very effective. Actually, the extent of glycation in the skin can be measured with an instrument that measures a fluorometric chemical called pentosidine. Pentosidine accumulates in a linear fashion over time. A consumer can actually determine if a topical product is effective with this method and can monitor the progress of treatment in a client. The current instrument is only a research model that costs about $35,000, but as the treatment becomes popular, a more inexpensive version will become available. This could open a whole new era of skin care and anti-aging treatment.

AGE breakers
        Once the glycation product is formed, it is hard to break because there are no natural enzymes in the body that can dissolve the bond. There are products developed that have been shown to be effective in breaking AGE-associated links. Alt-711 is one of these products that improved the vascular system of older Rhesus monkeys.22 Known now as C16, a second type studied in rats was found to restore diabetes-associated cardiovascular diseases. This product was also a thiazolium type similar to Alt-711.23 A third product uses a different approach; an enzyme specific for glycation called an amadoriase. There are actually two enzymes—fructosyl lysine oxidase and fructosyl lysine 3-phosphokinase—isolated from bacteria that are capable of breaking glycation link proteins.24 Although not commercially available or tested on humans, it presents a possible method that could be a great addition to future treatment modalities in anti-aging.

Summary
        Glycation is the non-enzymatic joining of a sugar and a protein, or a lipid. It is a process that occurs naturally in foods, especially when cooked. The Maillard reaction is one of these processes that starts by forming a Shiff base and proceeds to forming multiple chemicals called advanced glycation end-products, or AGEs, that have adverse effects on a person’s biological processes. AGEs can link up with many proteins and denature them or alter them to be nonfunctional, cross-linked collagens, which is an AGE protein complex responsible for stiffness of the skin.
       Skin collagen has a long half-life; these cross-linked forms do not go away and are not fully reversible at present. Elastin is another long-lived protein that is easily glycated and lasts a long time. Denatured elastin is associated with slackened skin. AGEs have cellular receptors known as RAGEs that initiate inflammatory reactions when activated by an AGE complex. These reactions tend to be chronic and are associated with arterial diseases, metabolic disorders and rheumatoid arthritis. Once they are started, the AGE-RAGE system will accelerate and perpetuate itself. 
     In the skin, glycation accounts for accelerated aging, yellowing and stiffness of the skin, and decreased circulation. Skin cannot look young and healthy with glycation products. Treatment is best started with prevention by diet control, reducing total calories, avoiding high sugar foods and not cooking at high temperatures. Supplements such as aminoguanidine, pyridoxamine, carnosine and benfotiamine are excellent glycation preventors. A new class of drugs called glycation breakers is being developed to correct the existing glycation protein complexes associated with many chronic diseases. They will truly be the youth drugs of the future.


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3.  VM Monnier et al, Accelerated age related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci 81, 583–587 (1987)
4.  S Reinhard et al, Advanced Glycation End Products in End-stage Renal Disease and Their Removal. Nephron 87, 295–303 (2001)
5.  ME Williams, Clinical studies of advanced glycation end product inhibitors and diabetic kidney disease. Current Diabetes Reports 4(6), 441–446 (2004)
6.  S Nobuyuk et al, Advanced Glycation End Products in Alzheimer’s Disease and Other Neurodegenerative Diseases. Am J Pathol 153(4), 1149–1155 (Oct 1998)
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8.  AS Duhaiman, Glycation of human lens proteins from diabetic and (nondiabetic) senile cataract patients.  Glycoconjugate Journal 12(5), 618–621 (1995)
9.  K Mizutari et al, Photo-enhanced modification of human skin elastin in actinic elastosis by N(carboxymethyl) lysine. One of the glycation products of the Maillard reaction. J Invest Dermatol 108, 797–802 (1997)
10.  DG Dyer et al, Accumulation of Maillard reaction products in skin collagen in diabetes and aging.
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17.  M Peppa et al, Fetal or neonatal low glycotoxin environment prevents autoimmune diabetes
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18.  C Cerami, Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci 94, 13915–13920 (1997)
19.  B Levi and MJ Werman, Long-term Fructose Consumption Accelerates Glycation and Several Age-Related Variables in Male Rats. J of Nutrition 1442–1449 (1998)
20.  JM Onorato et al, Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions. J Biolog Chem 275, 21177–211884 (2000)
21.  KC Chang, Aminoguanidine prevents age-related deterioration in left ventricular-arterial coupling in Fisher 344 rats. British J of Pharmacol 142, 1099–1104
22.  PN Vaitkevicius et al, A cross-link breaker has sustained effects on arterial and ventricular properties in older Rhesus monkeys. Proc Nat Acad Sci 98, 1171–1175 (2001)
23.  G Cheng et al, C16 a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental rats. Acta Pharm Sinica 12, 1460–1466 (2005)
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Recent Articles by Peter T. Pugliese, MD:
Physiology of the Skin: The Impact of Glycation on the Skin, Part 1 (March 2008)
Parabens: Paradox or Paranoia (January 2008)

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