Aminoguanidine Review Article
Aminoguanidine also known as Pimagedine is a drug that is capable of slowing down the aging process. It is commonly regarded that age-related changes in body are due to the cross-linking or glycosylation of protein. This drug is capable of protecting body-making-up proteins including the skin (elastin and collagen), nerves, eye lens, and kidney proteins from linking by means of combining itself with the substances that cause links. This way, it stops the aging of the body and prevents thickening of the arteries, senile cataracts, age-related yellowing and toughening of the skin, some cancers, and damage to the immune system. The effects of Aminoguanidine show that it may be capable of at least slowing the development of the aforementioned age-related conditions. It is proven that this drug has the ability of reducing the capacity of very low density lipoproteins (VLDL), otherwise known as “bad cholesterol”, to stick to the wall of blood vessels which result to a less likely coagulation of blood platelets and avoidance of dangerous atherosclerotic plaques formation. Aminoguanidine is also able to inhibit age-related heart enlargement and irregular glucose metabolism which results in development of diabetes in old age. To a large extent, the visible effects of skin ageing owes to the formation of AGEs.
Aminoguanidine (aka Pimagedine) is a drug highly recognised for its anti-aging benefits.
One of the main causes of mammalian aging is known to begin with a reaction between glucose and other reducing sugars and the amine residues of proteins. This is a reaction that is not regulated by any enzymes and is called glycation (or Maillard reaction; this reaction is quite known in cooking as a form of “browning” and it gives a distinctive taste and a caramel colour to foods). The resulting glycoprotein (i.e. the sugar + protein formation) can further react with other proteins to form cross-links that are difficult for the body’s enzymes to break; so aggregations are gradually formed in various places inside the body. These aggregations are called AGEs (Advanced Glycation End Products). Continue reading...
The Maillard reaction causes a "browning" effect on food. The reaction is similar to what takes place in our body. Actually many foods are sources of AGEs which are added using food processing methods for their distinctive colour, odour and taste.
While the process of glycation and the formation of AGEs is a normal metabolic process, it is now understood to be accelerated during aging, where its clinical symptoms begin at around the age of 30 in humans (Gasser et al, 2011).
The aggregation of AGEs understandably has a number of harmful effects for our body. First, the aggregation of proteins alters their conformation and their mobility and can render them dysfunctional. Second, their accumulation in cells, tissues and blood vessels can cause these to become rigid and increasingly dysfunctional. This can in turn lead to various age-associated diseases; including, among others, atherosclerosis, myocardial hypertrophy and other cardiovascular disorders (due to AGE accumulation in the arteries and the myocardium), nephropathy (due to accumulation of AGEs in the kidney) that can also lead to proteinuria (excretion of protein through the urine), retinopathy (due to AGEs accumulation in retinal vessels), Alzheimer’s disease (due to accumulation of AGEs in the brain), and osteoarthritis (due to accumulation of AGEs in the articular cartilage) (Goh and Cooper, 2008, Takedaa et al, 1996). All these effects can be even more prevalent during diabetes (because of the elevated glucose levels associated with this disease), which is another age-associated disease.
A diagram illustrating how the formation of plaques stuck on the inside of the arterial walls can cause a reduction of blood flow (in addition to sclerosis of the blood vessels) that can lead to hypertension and other cardiovascular complications.
Because the process that leads to the formation of AGEs includes a number of steps that may span over months or years (Vasan et al, 2003), the proteins most prone to aggregations of AGEs are long-lived proteins such as collagen and elastin.
Collagen and elastin are also the main constituents of the dermis (the inner layer of the skin), so it should be expected that aging would also influence the skin, which is indeed the case. One of the major causes of skin aging, apparent by hardening of the skin and formation of wrinkles, is glycation and the formation of AGEs; AGEs can activate metalloproteinases (these are proteases, i.e. enzymes that break down proteins, that work only in presence of a metal) (Nah S-S et al, 2007) which are known to break down proteins of the extracellular matrix (ECM) such as collagen (Choe et al, 2003) and thus contribute to skin aging.
AGEs also bind on specific receptors, called RAGEs (Receptors for AGEs), which is an event that can lead to induction of oxidative stress that can increase the risk for atherosclerosis and inflammation (Baynes and Thorpe, 2000, Goh and Cooper, 2008). Reactive oxygen species caused by the AGE-RAGE interaction can also stimulate the apoptosis of cells which can lead to further complications (Goh and Cooper, 2008).
AMINOGUANIDINE'S ANTI-AGING EFFECTS
Aminoguanidine (AG) is a nucleophilic reagent that can inhibit the formation of AGEs by reacting with reactive carbonyl groups of proteins (that could otherwise be intermediates to the formation of AGEs) to form relatively non-toxic adducts (thus it is said to “trap” carbonyls). Experiments on animal models have repeatedly shown that by this mechanism of action AG can combat a great number of age-related symptoms including but not limited to all of the ones mentioned above (cardiovascular complications, retinopathy, nephropathy, Alzheimer’s disease complications, proteinuria, osteoarthritis, and skin aging) (Bolton et al, 2004, Corman, 1998, Wilkinson-Berka et al, 2002, Picard, 1992, Li et al, 1996, Kern, 2001).
In general, the inhibition of AGE formation is important in anti-aging medicine for three main reasons:
1) It prevents the aggregation of AGEs thereby allowing proteins to function normally and preventing the scleroses of cells, tissues and blood vessels:
2) It prevents the degradation of collagen that is caused by AGE-induced metalloproteinases (Choe et al, 2003:
3) It reduces reactive oxygen species (ROS) formation that is caused by AGEs binding on RAGEs thereby reducing the rates of oxidation-induced cell apoptosis (Giardino et al, 1998)
The chemical structure of aminoguanidine
AG was clinically trialled for its potential benefits in suppressing the progression of renal disease in patients with diabetic nephropathy (Bolton et al, 2004). The trial focused on diabetes mellitus type 1 and was called ACTION I (A Clinical Trial In Overt Nephropathy of Type 1 Diabetics). It was a randomized, double-masked, and placebo-controlled trial. It involved 690 patients (of both genders, aged 22–50 years) with the diabetes-associated complications nephropathy and retinopathy. 236 of the patients took a placebo pill, 229 took AG in low dose (150 mg/day) and 225 took AG in higher dose (300 mg/day).
AG reduced proteinuria significantly and the results were more prevalent in patients who took the low dose (150 mg/day). The reduction was probably caused by the inhibition of formation of AGEs (it's known that AGEs accumulate in the kidney and result in increased permeability to blood proteins and proteinuria).
Another effect of AG was a reduction of triglycerides and total cholesterol, and an increase in high-density lipoprotein cholesterol; again, the effects were more apparent in patients receiving the lower dose.
Based on the ETDRS (Early Treatment of Diabetic Retinopathy Study) scores, it was also evaluated that the AG-treated patients had a reduced progression of retinopathy.
The high dose (300 mg/day) was associated with a few side effects, that included induction of autoantibodies, a flu-like syndrome, mild elevations of liver enzyme levels, and a mild anemia of unknown cause that was also induced in the placebo-treated though in a milder form. All these effects were reversible and quickly resolved, sometimes without requiring a discontinuation of the drug. With the high dose there were also three cases of glomerulonephritis, but the lower dose (150 mg/day) was not associated with any toxicity at all.
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Aminoguanidine Review Article