Fighting the 8th AGE: the mandatory panacea metformin and other natural supplements.

Exciting new anti-aging evidence has been published this year:

The Bard  spelled out the 7 ages of man. Now we know we have to deal with more AGEs – Advanced Glycation End Products- , and more evidence to prolong the healthy ages of man.

GLYCATION: some of us are fudge addicts. Fortunately with the natural supplements available, we can have  a little of our cake and safely eat it.

But as Wiki details,  such  lethal exogenous glycations and (AGEs) Advanced Glycation Endproducts “are typically formed when sugars are cooked with proteins or fats (eg fudge, baked puddings, sweet crackling/baked beans !). Temperatures over 120°C (~248°F) greatly accelerate the reactions, but so do  lower temperatures with longer cooking times. These compounds are digested with about 30% efficiency. Browning reactions (usually Maillard type reactions – like fudge, crackling!) are evidence of pre-formed glycations. Indeed, sugar is often added to products such as french fries and baked goods to enhance browning. Glycation may also contribute to the formation of acrylamide, a potential carcinogen, during cooking. Until recently, it was thought that exogenous glycations and AGEs were negligible contributors to inflammation and disease states, but recent work has shown that they are important.”

“Although most   research work has been done with reference to diabetes, these results are important for all, as exogenous AGEs are implicated in the initiation of retinal dysfunction, cardiovascular diseases, type II diabetes, cancer and many other age-related chronic diseases. Food manufacturers have added AGEs to foods, especially in the last 50 years, as flavor enhancers and colorants to improve appearance. Foods with significant browning, caramelization, or with directly added preformed AGEs can be exceptionally high in these proinflammatory and disease initiating compounds. A long list of foods with very high exogenous AGEs includes:  donuts, barbecued meats, cake, and dark colored soda pop”

This explanation of one of the root causes of the multisystem degenerative diseases of aging dispels the myths that the fast food chain and what the  Drug Industry promotes are healthy, that we need a patent drug per disease eg statin for lipidemia, antihypertensives for hypertension, anti thrombotics for thromboses,  anti-inflammatories  for pain, etc.

GALEGA METFORMIN: THE LONGEST-USED ANTIGLYCATION MEDICINAL:  The longest randomized controlled drug trial RCT ever, the UKPDS (Holman 2008) in type 2 diabetes DM2 showed that long term metformin double-blind for up to 20 years (mean 13.6yrs) (and up to 30years open use), lowers all-cause morbidity and mortality by about 1/3.  Other anti-diabetic drugs eg Sulphonylureas by contrast do little but lower hyperglycemia – without reducing mortality, but adding major risk of hypoglycemia – increasing the risk of dementia long term..

According to Schnider and Kohn from Ohio in 1980 (via Pubmed) , the concept of advanced  glycation/glycosylation in human aging and diabetes was  already well described, so the clinical concept is over 35 years old — but metformin has been under intensive research since 1922 ie for over 85years, and in human use (as the parent herb galega officinalis) for thousands of years – although the first mention on Pubmed of metformin as a blocker of glycation end products was in 1995. .

A new Dutch study (Kooy 2009) in humans has confirmed that metformin (850-2550mg/d) in the medium-term (a mean of 4.3yrs) added to insulin in DM2 lowers macrovascular endpoints by 39% p.02, weight by a mean of 3kg, and insulin requirement by 20iu/d.

A Buenos Aires study (Schurman 2009) notes that “AGEs  are implicated in the complications of diabetes and aging, affecting several tissues: in bone cells in culture, metformin treatment of osteoblastic cells prevented these AGE-induced alterations.”

There can be no doubt that,  given that the lethality of advanced obesity and  DM2 is as bad as smoking, it is crucial to reverse early ie prevent from developing all the mechanisms of obesity- diabetic damage including from hyperglycema itself; wasting from intracellular energy deficit due to insulin resistance; oxidation, nitric oxide deficiency; and above all else, AGEs from sugars fusing with fats or protein – especially fructose.  “It appears that fructose and galactose have approximately ten times the glycation activity of glucose, the primary body fuel. Glycation is the first step in evolution of these molecules through a complex series of very slow reactions in the body known as Amadori reactions, Schiff base reactions, and Maillard reactions; all lead to AGEs.  Some AGEs are benign, but others are more reactive than the sugars they are derived from, and are implicated in many age-related chronic diseases such as: type I and II diabetes mellitus (beta cell damage), cardiovascular diseases (endothelium, fibrinogen, and collagen are damaged), Alzheimer’s disease Vitek ea 1994 (amyloid proteins are side-products of the reactions progressing to AGEs), cancer (acrylamide and other side-products are released), peripheral neuropathy (myelin is attacked), and other sensory losses -deafness ( demyelination) and blindness (mostly  microvascular damage in the retina).”

“This range of diseases is the result of the very basic level at which glycations interfere with molecular and cellular functioning throughout the body. Glycated substances are eliminated from the body slowly, since the renal clearance factor is only about 30% ie half-life about double the average cell life. As a consequence, long-lived cells (such as nerves, brain cells), long-lasting proteins (such as eye crystalline and collagen), HBA1c and DNA may accumulate substantial damage over time. Metabolically-active cells such as the glomeruli in the kidneys, retina cells in the eyes, and beta cells (insulin-producing) in the pancreas are also at high risk of damage. The endothelial cells of the blood vessels are damaged directly by glycations, implicated in atherosclerosis. Atherosclerotic plaque tends to accumulate at areas of high blood flow (such as the entrance to the coronary arteries) due to  increased presentation of sugar molecules, glycations and AGEs at these points. Damage by glycation results in stiffening of the collagen in the blood vessel walls, leading to high blood pressure. Glycations also cause weakening of the collagen in the blood vessel walls, which may lead to micro- or macro-aneurysms; causing strokes if in the brain.”.

As Desai & Wu from University  Saskatchewan  sum up  2007,” AGEs are unavoidable byproducts of various metabolic pathways formed by reactive metabolic intermediates such as methylglyoxal (MG), glyoxal, and 3-deoxyglucosone. These reactive intermediates bind to proteins, DNA, and other molecules and disrupt their structures and functions, leading to aging – vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer’s disease. In recent years, compounds that prevent the formation of AGEs or degrade the existing AGEs have been recognized or patented including 1. galega-metformin -guanidine; 2. pioglitazone (patented), 3 angiotensin blockers , 4) pentoxyfylline (patented), 5) metal ion chelators desferoxamine and penicillamine, 6) antioxidants such as vitamin C or E, etc.. ”

CROSS-LINKAGE AND AGING: Ward Dean 2009 spells out “the Crosslinkage Theory of Aging: AGEs and Crosslinkages – New Respect for Crosslinkage Theory.  Dr Johan Bjorksten in 1941 first proposed The Cross-linkage Theory of Aging   that aging was caused by inter- and intramolecular crosslinks in proteins, nucleic acids, and other vital macromolecules that caused them to gradually stiffen and lose their function”.

OTHER ANTI-AGEs BLOCKERS: Cataract formation is associated with low vitamin C (Tessier 1998); while Quian ea in 2000 showed that both vits C & E lowered AEGs in diabetic rats. Other natural AGEs blockers include taurine; L-Carnosine, L-Arginine, DMAE dimethylaminoethanol ;   PABA (para aminobenzoic acid); Thiamine HCl ; Alpha R Lipoic acid; Pyridoxal 5’ phosphate;  and to inhibit Amadori products: EDTA,  vits B1,B6, C & E , coQ10, Green Tea, Hawthorn, Grape Seed, Milk Thistle, Ginger Root, Ginkgo, bioflavinoids (Morimitsu 1995 ); curcumin ; and melatonin (Sailaja 2000);  to which one can add for antiaging:  huperzine A and DMAE.

Many companies are racing to market new ie patentable synthetic anti-AGEs agents like peptides ; benfotiamine and pyridoxamine . But as with some 1000 available natural insulin sensitizers, there are plenty of natural anti-AGEs supplements, starting with : galega officinalis (50% guanidine with negligible content of galegine) and it’s extracts aminoguanidine, galegine and dimethylguanidine-metformin. Already in 1999 Tanaka ea showed in rats that metformin treatment may be effective in the prevention of diabetic complications through not only lowering plasma glucose, but also directly inhibiting AGEs formation.   Sowers 2002 theorizes that the reason that statins “do not reverse endothelium-dependent and -independent vascular dysfunction in DM2 (in contrast to in non-diabetics) is precisely because of AGEs.  But Jinnouchi 2006 shows that atorvastatin also reduces AGES.

These studies affirm that  METFORMIN is the Gold Standard (Bailey ea 2007: Merck Sante), arguably both the safest and the most pluripotential therapeutic agent ever discovered, being an age-old medicinal plant extract (Werner and Bell 1922).

So we do not need patent designer inhibitors (of AEGs  or reactive oxygen species or insulin resistance or lipidemia or inflammation or appetite-weight gain) – there are dozens available from nature, with galega- metformin the longest and  broadest potential proven and used, that when simply and safely titrated slowly upwards to good tolerance, at least halves the incidence of new diabetes and thus adds at least a decade to health and longevity.

THE GODDESS PANACEA: A panacea is defined as a “cure all”, to “retard the aging process”, and to increase the “quality of life”. Today a balanced diet and lifestyle is far from a guarantee of healthspan.  Despite  denial by  the food and drug industry (aka the FDA, the Disease Industry  who want to suppress the old so as to sell  their   new  designer patents) metformin fulfills all the criteria for a panacea in a stressed fattening population, from promoting copulation, conception and pregnancy to healthy  old age.

An old study from Germany (Hammes 1996)  shows again a potential trap of testing one substance in isolation and in rodents – in this case, EPA + DHA (as Maxepa) about 130mg/day for 6 months if anything harmed the retina in diabetic rats. Does this have any bearing on the global benefits of natural EPA+DHA and brod supplements  in  humans?

By contrast, El-seweidy ea in Egypt in 2002  showed also in diabetic rats that “combined treatment with galega (aminoguanidine) and omega3  markedly reduced all the adverse blood markers and nearly restored the atrophy of islets of Langerhans and the peripheral lymphocytic infiltration compared to untreated diabetic rats and those treated only with guanidine.”

The cardinal principle of nutrition and medicine is synergy- that we do not or should not eat single foods in isolation, nor expect disease to respond to a single extract/medicine;   nutrients and nutriceuticals complement each other. This is obviously contrary to the imperative of the Disease Industry to sell a profiteering rainmaker snake-oil per disease..

GALEGA/METFORMIN AS MANDATORY PREVENTION AND THERAPY: The common lethal poisons that humans consume – sugar, salt, alcohol, aspirin, paracetamol, ibrufen and cigarettes – are freely sold over the counter.

Metformin must thus similarly be released for over the counter sale as the only proven panacea (aside perhaps from fish oil) and the only drug ever in RCT for 20year AND  proven to be without any major adverse effect – including for halving deaths in diabetes, and (in four major trials on four different continents) halving the incidence of new diabetes in the overweight, and reversing progressive weight gain. And it can be simply and cheaply manufactured from basic chemicals in 5 minutes.

It  must thus be made mandatory prescription to tolerance for prevention obesity and diabetes in the overweight (ie those whose BMI persists despite attempted correction above about 25kg/sqm),  let alone in all diabetics.

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4 responses to “Fighting the 8th AGE: the mandatory panacea metformin and other natural supplements.

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