by Phil Micans PharmB
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
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 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 the patients blood flow improved on average by 30% and the
patients exercise abilities improved by 50% to 105%.
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.
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
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 (in
other words the HCL version may be preferable). Aminoguanidine HCL is also
more soluble than the bicarbonate form, and therefore is less irritating. 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 into split doses.
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.
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
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.
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.
Skamarauskas JT, McKay AG, Hunt JV, "Aminoguanidine and its pro-oxidant
effects on an experimental model of protein glycation." Free Radical Biol.
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.
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,
16. "Pimagidine, an investigational drug for the prevention of
diabetic complications." Med. Sci. Bulletin, Issue 245, Feb. 1998.
"Aminoguanidine prevents age-related arterial stiffening and cardiac
hypertrophy." Proc. Natl. Acad. Sci. USA, Feb. 3, 1998.