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AMINOGUANIDINE - AN AGE INHIBITOR

Posted on June 29, 2003, 9:43 a.m. in Aging

AMINOGUANIDINE: AN AGE INHIBITOR!
By Phil Micans PharmB

Aminoguanidine (pronounced a-mean-o-gwan-I-din) is a “new” anti-aging therapy and recent interest has been aroused by the fact that it may be able to prevent some of the signs of aging from occurring.

THE GLUCOSE CROSS-LINKING PROBLEM

It is believed that the cross-linking of the proteins that make up the human body play a role in the human 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. watch what happens after you cut an apple in half).

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 (AGE).

Glycosylation 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 by-products 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 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 ability to do two things. Firstly, in tests on animals, aminoguanidine has reduced the ability of very low density lipoprotein, (the bad form if cholesterol), to bind itself to blood vessel walls. In turn, blood platelets are less likely to coagulate and form dangerous clots.

Secondly, aminoguanidine has an ability to treat patients whose blood vessels are constricted by arteriosclerosis. 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 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 two to three times those than their equivalent “normal” 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 indicate that aminoguanidine administered rats have significantly superior survival rates than those who are untreated.

Diabetic clinical trials with humans have also highlighted aminoguanidine’s ability to prevent oxidative modification of low-density lipoproteins (LDL) and inhibit the formation of atherosclerotic plaques.

Trials conducted by the American corporation, Alteon Corporation (who are using aminoguanidine under the name of Pimagidine) and another drug development 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. But the formation of this process appears to be 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 glycosylation 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 arteriosclerosis 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

Both animal and human trials indicate that aminoguanidine has very low toxicity and appears safe to use with “normal” dosages. Side effects in human trials have been limited to nausea and headache, but as presently there is still relatively little human data and clinical trials, aminoguanidine use is probably best undertaken whilst under the supervision of a physician.

LATEST NEWS

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.

It is becoming clear that agents that can slow, prevent and even reverse the effects of cross-linking will have a major impact in the role of preventative medicine, and indeed could be one of the keys to true anti-aging medicine.

Copyright 2003. This article may not be reproduced for public broadcast in any form, without the written permission of: International Antiaging Systems

REFERENCES
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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.
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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.
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