Aminoguanidine: AGE Inhibitor
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Aminoguanidine is a promising "new" anti-aging therapy and interest has been aroused by the fact that it may be able to prevent signs of aging before they occur.

The glucose cross-linking problem

It is believed that the cross-linking of the proteins that make up the human body plays a role in the aging process.  Everyone is familiar with the effects of cross-linking reactions, because the process causes food to turn yellow and become tough (i.e. cut an apple in half and watch in turn yellow and brown). Cross-linking may be responsible for many of the problems of old age, including senile cataracts, thickening of the arteries, some cancers and damage to the immune system.  A damaged immune system leads to increased susceptibility to infection and some cancers may arise from the effects of glucose on DNA.  DNA contains all the information necessary to create a normal cell, however it can react with glucose to produce damaged DNA, which in turn causes abnormal cells to be produced.

Cross linking, aging and the heart

Aging is associated with cardiac enlargement and arterial stiffening, one theory for this is an age-related accumulation of Advanced Glycation End products (AGEs). Glycation is the product of reaction between a sugar and the free amino group of proteins and it is referred to as cross-linking. The linking of glycosylation byproducts to proteins results in the development of large, cross-linked molecules that inhibit the ability of the cell to function normally.  One study conducted on animals showed that aminoguanidine prevented age-related cardiac enlargement.  In fact, the membrane surface area of the rats was reduced by 30%.  Furthermore, the collagen content of their arterial walls was increased by 24-30%.  Aminoguanidine is therefore acting to improve overall heart and arterial condition and not just by preventing or slowing proteins from cross-linking, but also by decreasing the AGE-induced cross-linking of the extra-cellular matrix.  Studies conducted at the University of Milan over the last 25 years have shown aminoguanidine's reduces very low density lipoprotein's (the bad form if cholesterol) ability to bind to blood vessel walls.  In turn, blood platelets are less likely to coagulate and form dangerous clots.  The Milan studies have also shown aminoguanidine's ability to open improve circulation in blood vessels constricted by atherosclerosis.  In 1992 at the University of Milan, 11 patients with peripheral vascular disease were treated with aminoguanidine.  Their blood vessels were so clogged that they couldn't walk for more than 500 yards.  But after treatment with aminoguanadine the patients blood flow improved on average by 30% and the patients exercise abilities improved by 50% to 105%.

Diabetes

Diabetes is often seen as a form of accelerated aging and research into diabetes has provided support for the idea that cross-linking causes aging.  The levels of cross-linking products in diabetics are 2X-3X greater than in non-diabetics.  It is believed that AGE is increased in diabetes and plays an important role in the development of diabetic complications.  As aminoguanidine acts to bind to sugars, thus preventing them from binding to the lysine group of proteins it was only a matter of time before various trials began.  A number of different studies with diabetic rats indicates that aminoguanidine administered rats have significantly superior survival rates than those who are untreated.  Clinical trials with diabetic humans have also highlighted aminoguanidine's ability to prevent oxidative modification of low-density lipoproteins (LDL) and inhibit the formation of atherosclerotic plaques.  Accordingly, trials conducted by the Alteon Corporation using aminoguanidine [called Pimagidine] and another drug called ALT-711 [more of that at the end of this article]), indicate that aminoguanidine can significantly reduce albuminuria (proteins present in urine, usually as a result of kidney disease), delay the onset of end-stage renal disease, and improve the cholesterol profiles of diabetic patients.

Conclusion

Research has shown that glucose is partly responsible for the cross-linking of proteins, which in turn leads to aging damage. Glucose is found in every cell of the body and is relatively stable, but it can join with protein to form a glucose/ protein combination.  It is this combination that will continue through a number of steps, to eventually cause active cross-links.  Fortunately the formation of this process is reversible. Glucose/ protein substances stay in the body for months, even years, cross-linking with the proteins around them. This continuous cross-linking may be prevented by using glycation inhibitors because their primary use is to stabilize the metabolism of glucose.  Aminoguanidine is able to join up with substances that cause links and to stop cross-links from developing. Therefore it may be able to help alleviate or prevent senile cataracts, thickening of the arteries, kidney failure, thinning bones, osteo-arthritis, skin wrinkles and many other signs of aging.  Aminoguanidine's ability to stabilize the metabolism of glucose, to help prevent and treat adult onset diabetes, it's role in reducing very low density lipoprotein cholesterol, and the evidence that it can improve blood flow, helping to reverse the conditions of atherosclerosis and blood clots, indicates that aminoguanidine has a wide reaching ability to help prevent and treat a number of aging disorders.  Aminoguanidine has the potential to slow the aging process by protecting the proteins that make up the human body, such as the skin proteins (collagen and elastin), eye lens protein, nerve protein and kidney proteins from aging damage.  All the body's proteins deteriorate with advancing age and more so in diabetes.  Aminoguanidine is able to combat some of the adverse effects of diabetes and improve the quality and duration of life.  As diabetes is an age-related disorder, and in-fact effects everyone over the age of 30 (physicians alter the parameter of the test based upon chronological age), aminoguanidine offers itself as a true anti-aging medicine.

Dosages and Side Effects

Aminoguanidine has shown to have very low toxicity in both human and animal trials.. Side effects in human trials have been limited to nausea and headache, but presently there is still relatively little human data. Therefore dosages should not be exceeded unless under the close supervision of a physician.  It should be noted that most anti-aging research has been carried out using a hydrochloride (HCL) derivative, not the more commonly available bicarbonate, which may be a lot less bio-available.  An effective anti-aging dosage of aminoguanidine is 150mg to 300mg a day, taken with food. Diabetics may require dosages in the range of 300-600mg daily or even higher. Aminoguanidine has a half life of only 4-hours, so these dosages would be best administered over the day in split doses.

Update

The Alteon Corporation in the USA currently has aminoguanidine (Pimagidine) in stage III trials for diabetes.  Interestingly it has also developed ALT-711 (thiazolium salt) which is now in stage II trials. Whilst aminoguanidine and other agents (such as Carnosine and Acetyl-L-Carnitine) have been shown to help prevent cross-linking, ALT-711 is claimed to break existing links. If this is substantiated, this could be a major anti-aging medicine of the future.

References

1. R.R. Kohn: "Principles of Mammalian aging" Prentice Hall Englewood cliffs NJ 1978 

2. D.E. Harrison: J.R. Archer "Exp Gerontol" 13:75 1978 

3. J.W. Baynes "Methods in Enzymology Post Transitional Modifications" F would & K Moldave (Academic press NJ 1984) Vol 6, PP 88- 98. 

4. H.B. Mortensen & C Christophersen "Clin. Chim. Acta" 134:317 1983 

5. M. Brownlee: H. Vlassara: A. Cerami: " Diabetic Complications & Scientific and Clinical aspects" Pitman London 1986. 

6. V. Monnier: R.R. Kohn: A. Cerami: "Proc Natl Acad Science" USA 81:583 1984. 

7. Verzar F: "Exp Gerontol" 3: 69- 75 1968. 8. Aminoguanidine- Drug evaluation monograph, Micormedex Inc., October 2000. 

9. Cameron NE, Cotter MA: "Rapid reversal by aminoguanidine of the neurovascular effects of diabetes in rats: modulation by nitric oxide synthase inhibition." Metabolism 1996; 45(9): 1147-52. 

10. Friedman EA, Distant DA, Fleishhacker JF, et al. "Aminoguanidine prolongs survival in azotemic-induced diabetic rats." Am. J. Kidney Dis. 1997; 30(2): 253-9. 

11. Makita Z, Yanagisawa K, Kuwajima S, et al. "Advanced glycation end-products and diabetic nephropathy." J. Diabetes Complications 1995;9(4): 265-8. 

12. Skamarauskas JT, McKay AG, Hunt JV, "Aminoguanidine and its pro-oxidant effects on an experimental model of protein glycation." Free Radical Biol. Med. 1996;21(6):801-12. 

13. Zimmerman GA, Meistrell 3rd, Bloom O, et al. "Neurotoxicity of advanced glycation of end-products during focal stroke and neuroprotective effects of aminoguanidine." Proc. Natl. Sci. USA 1995;92(9):3744-8. 

14. Klandorf H, Zhoq Q, Sams AR, "Inhibition by aminoguanidine of glucose-derived collagen cross-linking in skeletal muscle of broiler breeder hens." 1996 Poultry Sci. 75:432-437. 

15. Fa-Yauh Lee, Sun-Sang Wang, Yang-Te Tsai, Hwai-Jeng Lin, Han-Chieh Lin, Chi-Jen Chu, Shwu-Ling Wu, Chung-Ching Tai, Shou-Dong Lee, "Aminoguanidine corrects hyperdynamic circulation without ameliorating portal hypertension and portal hypertensive gastropathy in anaesthetized portal hypertensive rats." J. Hepatlogoy Vol. 26, Issue 3, 687-693. 

16. "Pimagidine, an investigational drug for the prevention of diabetic complications." Med. Sci. Bulletin, Issue 245, Feb. 1998. 

17. "Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy." Proc. Natl. Acad. Sci. USA, Feb. 3, 1998.

ALL INFORMATION IS EDUCATIONAL AND SHOULD NOT REPLACE THE ADVICE OF YOUR PHYSICIAN.

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