For people who are older now than they were last year…PrimAGE…

zarkovPrimAGE contains two forms of vitamin B-6: pyridoxamine and pyridoxal-5-phosphate (P5P). (Ordinary vitamin B-6 supplements contain a different form called ‘pyridoxine’.) Pyridoxamine is the active principle in PrimAGE and the P5P serves to prolong and enhance its activity.

Protein damage in aging and diabetes. It has been known since the 1940s that pyridoxamine is a form of vitamin B-6, but its unique and exciting properties only came to light in 1996 when it was announced that pyridoxamine inhibits the formation of ‘Advanced Glycation End-products’ (AGEs).

AGEs are damaged proteins – mainly structural proteins and enzymes – that have been fused together by certain sugars in such a way as to impair their normal functions. AGEs accumulate in the body as one ages, causing tissues to lose their elasticity and causing enzymes to malfunction. In fact, this accumulation of AGEs is considered to be one of the principal causes of aging.

Aging is not the only condition in which AGEs play a major role. Diabetes is another. Periods of high blood sugar (‘hyperglycemia’) are a hallmark of diabetes, and the resulting exposure of tissues to certain sugars (especially glucose) greatly increases the rate at which AGEs are formed. The accumulation of AGEs may account for much of the tissue damage that is seen in the diabetic state – including damage to kidneys (nephropathy), nerves (neuropathy), vasculature (atherosclerosis), and eyes (retinopathy, cataracts).

Pyridoxamine and aging. Pyridoxamine looks like an excellent agent for suppressing a major cause of aging. Here’s why:

  • The accumulation of AGEs correlates with aging.
  • AGEs cause some of the symptoms of aging, such as tissue stiffness and loss of function.
  • Pyridoxamine inhibits the formation of AGEs.
  • Therefore, pyridoxamine is likely to suppress some aspects of aging. Only a decades-long clinical study
    can prove this conclusion beyond a shadow of a doubt, but few would be so foolish as to wait for such a
    study to be completed before going ahead and using pyridoxamine as an anti-aging supplement.

Pyridoxamine and diabetic symptoms. The connection between AGEs, diabetes, and pyridoxamine was established by recent research which showed that:

  • AGEs play a key role in the damage of tissues by sugars, such as glucose.
  • The presence of diabetic complications correlates with elevated AGEs in the blood.
  • Pyridoxamine inhibits the formation of AGEs.
  • In animal models of diabetes, pyridoxamine prevents damage to kidneys, retina, and nerves.
  • Pyridoxamine prevents diabetic kidney damage in humans. (Its ability to prevent damage to retina,
    nerves, and cardiovascular system in humans is expected, but has not yet been formally tested.)

For a more detailed discussion of PrimAGE and its medical applications, see the article at:

http://www.ilifelink.com/primage_200_mg_x_50_capsules.html

Will diabetes research lead to a cure for aging?

zarkovThe body’s aging process might seem, at first glance, to be unrelated to the disease we call ‘diabetes’. After all, the root causes of diabetes have to do with how the hormone ‘insulin’ is produced or used in the body, whereas the root causes of aging appear to be free radicals, malfunctioning genes, and damaged proteins.

Nevertheless, there is a connection between diabetes and aging – if not in their ultimate causes, then at least in the biochemical disruptions resulting from these causes, and in the symptoms that are produced by them. Because of these similarities, both diabetes and aging respond to some of the same treatments. This means that diabetes research is giving rise to anti-aging techniques, even though not a great deal of effort is going directly into anti-aging research itself. And it means that some of the supplements that are normally targeted at diabetic complications should also be used to fight aging in non-diabetics.

Let’s look briefly at what is known about the causes and symptoms of diabetes and of aging, and then at the treatments that they have in common.

Diabetes overview

There are two major types of diabetes: type 1 (‘juvenile onset diabetes’), and type 2 (‘adult onset diabetes’ or ‘non-insulin-dependent diabetes mellitus’). They are really two different diseases, although they share the property that sugar metabolism is impaired. Both type 1 and type 2 diabetes involve the hormone insulin, but in different ways.

Insulin is a hormone produced by the pancreas gland in response to rises in blood sugar levels; it tells the body’s cells to absorb and utilize glucose (the main blood sugar). Glucose, it so happens, is a two-faced substance: on the one hand, it is an important source of energy for cells; on the other hand, it is a destructive chemical – it damages the tissues that it comes into contact with. When glucose concentrations increase, the tissue damage happens faster.

Type 1 diabetes is caused by a genetic defect that allows the immune system to destroy insulin-producing cells in the pancreas. Without adequate insulin to tell cells to absorb and metabolize glucose, blood glucose can rise to very high levels after meals that contain sugar or other carbohydrates.

Type 2 diabetes appears to be caused by malfunctions in the molecular structures that carry signals from the outer walls of cells to the biological nano-machinery inside the cells – signals such as those sent by insulin. The details are not yet understood, but the result is that cells in muscles, liver, and other tissues are unable to utilize the glucose that they absorb, and so glucose accumulates in the body tissues and blood.

While type 1 and type 2 diabetes have different causes, both involve elevated glucose levels in blood and tissues. How do elevated glucose levels give rise to diabetic symptoms? Recent research suggests that the connection lies in the way cells produce energy from glucose. Under normal conditions, cells dissassemble glucose molecules, extract their internal energy and store it in the form of energy-rich molecules called ‘ATP’. Unfortunately cells perform this task sloppily and, as a side effect, produce destructive free radicals called ‘superoxide’. The body has an antioxidant enzyme, ‘superoxide dismutase’, that deactivates superoxide molecules before they can do much damage; but when glucose concentrations are too high, superoxide is produced faster than the dismutase enzyme can deal it. Superoxide molecules then escape in large numbers and wander around in cells doing more damage than usual. Among the structures that are damaged are the enzymes responsible for minimizing superoxide production, as well as the antioxidant enzymes themselves. This leads to even more superoxide production, which in turn promotes other destructive processes inside and outside of cells.

The direct and indirect harm that stems from high glucose levels and superoxide production includes:

  • formation of cross-links between proteins in the tissues;
  • energy starvation by cells that cannot properly utilize the available glucose;
  • inadequate production of needed biological substances, such as antioxidants, enzymes, and growth factors;
  • increased production of free radicals;
  • damage to DNA, inactivation of needed genes;
  • impaired physiological processes, such as the growth and maintenance of body tissues.

Diabetic symptoms follow from these harmful effects, including:

  • stiffening and loss of function of tissues, due to cross-linked proteins and free radical damage;
  • damage to nerves, eyes, skin, kidneys, immune system, and all other organs;
  • fatigue;
  • cardiovascular ailments, including atherosclerosis, heart attack, stroke, poor circulation;
  • impaired wound-healing;
  • susceptibility to infection, due to impaired immune system;
  • an acceleration of the apparent aging of the whole body.

Aging overview

Until recently the aging process was thought of as a proper and inevitable part of life. Today it is widely considered to be a disease or ailment — a process that can be treated and perhaps someday completely cured.

While aging is not well understood at the molecular level, it is partially understood. It appears to have at least five basic causes:

  • damaged genes (i.e., damage to DNA caused by high-energy particles such as UV light and x-rays, viruses, free radicals, sugar aldehydes, or other chemicals in the body);
  • inappropriate activation or deactivation of genes;
  • faulty duplication of the genetic material, DNA, during cell division;
  • accumulation of bulky molecular debris, such as amyloid protein and lipofuscin;
  • damaged structural molecules, especially proteins, inside and between the cells of body tissues.

Three of the above causes of aging directly involve the genes – the DNA molecules that regulate the development and maintenance of body tissues. The fourth involves deposits of material that damage and kill cells either by their bulkiness or by harboring toxic substances.

The fifth cause of aging involves damage to the body’s large molecules, such as structural proteins, many of which are not routinely recycled and replaced by the body’s normal maintenance processes. This molecular damage has two known causes: the cross-linking of proteins by glucose or other biochemicals, and damage by free radicals. Let us examine these two damaging processes in more detail.

Free radicals and antioxidants

Free radicals are chemically reactive molecules (such as hydrogen peroxide) generated mainly as a side-effect of energy production in cells. Free radicals damage proteins, fats, and other molecules both inside and outside of cells. While some of the damaged molecules (such as fats and polysaccharides) are routinely replaced as part of the body’s normal maintenance routines, others are not. For example, structural proteins in connective tissue are not necessarily replaced at all. Molecular fibers such as collagen and elastin reside for years in the tissues, where they become increasingly damaged by cross-linkers and free radicals. This kind of damage is responsible for age-related tissue stiffness, loss of elasticity, and loss of the normal functions of the tissues.

Prevention of free-radical damage is the task of antioxidants. Antioxidant molecules sweep up free radicals and either neutralize them or carry them out of the body. The human body produces many of its own antioxidants (such as superoxide dismutase, alpha-lipoic acid, and glutathione peroxidase), and relies upon external sources for many others (such as vitamins C and E, and bioflavonoids).

The aging process, however, reduces the body’s ability to produce and utilize its own antioxidant enzymes — because the genes required to control the production of these enzymes become damaged, and the antioxidant enzymes themselves become damaged. It’s a ‘vicious circle’: free radicals damage the antioxidant enzymes and their genes, resulting in lower antioxidant production and the escape of more free radicals which further damage the genes and enzymes. Aging thus feeds on itself, eventually spiraling quickly into decrepitude unless preventive measures are taken.

Diabetes, like aging, also causes an increase in free radical production and a decrease in the body’s antioxidant defenses. The mechanisms are not fully understood, but the consequences are clear: damage to DNA, to structural proteins, and to the enzymes needed for metabolism and tissue maintenance.

Cross-linked proteins

Some chemicals, including sugars like glucose, are able to react chemically with certain amino acids in proteins, thereby bonding the proteins together. This cross-linking process is called ‘glycation’ if the cross-linker happens to be a sugar. Since the linked proteins have a restricted ability to move, cross-linking produces a stiff, inactive material called an ‘AGE’ (Advanced Glycation End-product). Drugs are being developed for preventing and even reversing this kind of damage in the body, and there are nutritional supplements that are thought to have similar actions.

As proteins get converted into AGEs by cross-linking, they lose their original functions. For example, elastin is a protein responsible for the elasticity of the skin and other tissues. Elastin molecules are nano-springs – when they are stretched, they try to pull back to their original length. But when extensively cross-linked, elastin fibers become fixed in length and can no longer be stretched. The skin loses its tension and it sags and wrinkles; tendons become stiff and easy to tear; blood vessels lose their flexibility and are prone to rupture.

Aging and diabetes: shared causes and symptoms

With regard to the mechanisms by which they damage the body, aging and diabetes have much in common. Both of them involve:

  • increased free radical activity due to loss of antioxidants;
  • damage to structural proteins caused by cross-linking;
  • damage to genes by free radicals and by sugar aldehydes;
  • accumulation of bulky molecular debris, including amyloid and lipofuscin.

Diabetes and aging also have symptoms in common, including:

  • Loss of elasticity and flexibility of skin and other tissues;
  • Skin ailments – such as infections, discolored spots, thin skin, rashes;
  • Cardiovascular disorders – poor circulation, atheroscerosis, blood clots, strokes, heart attacks;
  • Increased cancer prevalence;
  • Eye disorders – cataracts, glaucoma, retinal degeneration;
  • Hearing loss;
  • Cognitive impairment, memory loss, dementia;
  • Impotence.

Let’s look now at some dietary supplements that are being studied as diabetic treatments and that also look promising as anti-aging supplements.

Anti-aging supplements from the diabetes arena

Many different dietary supplements have anti-diabetic properties. They fall into at least five categories:

  • Antioxidants – to counteract free radical damage to body tissues;
  • Insulin activity enhancers – to increase the production of insulin or of insulin receptors;
  • Glycation inhibitors – to prevent the cross-linking of proteins by sugars;
  • Vascular function enhancers – to improve blood circulation;
  • Nerve cell protectors – to prevent or repair damage to nerve cells.

Substances in all five of these categories have anti-aging properties, even when used by non-diabetics. Even the ‘insulin activity enhancers’ may benefit non-diabetics since evolution did not provide the human body with an insulin production apparatus capable of dealing with high blood sugar levels – such as those that occur, even in non-diabetics, after a sugary meal. Non-diabetics can therefore suffer glucose-induced tissue damage just as diabetics do, unless they take special measures to regulate insulin levels.

Antioxidants regarded as having value in treating diabetes include: alpha-lipoic acid, N-acetyl cysteine, ferulic acid, genistein, quercetin, vitamins C and E, coenzyme Q10, L-carnitine, manganese, zinc, glutathione, inositol, selenium, melatonin, and glucomannan. Most herbal supplements also have significant antioxidant properites and are used as diabetes remedies. Many of these antioxidants are quite familiar to anti-aging activists, but some are under-appreciated – ferulic acid, genistein, quercetin, and manganese, for example.

Insulin activity enhancers that may be of interest as aging inhibitors include: chromium picolinate, omega-3 fatty acids, genistein, conjugated linoleic acid, vanadium, vitamins C and E, magnesium, ginseng, Gymnema montanum, Aloe vera, bitter melon, onion, mistletoe extract, and olive leaf.

Glycation inhibitors: quercetin, rutin, L-arginine, and pyridoxamine.

Vascular function enhancers: benfotiamine and vinpocetine.

Nerve cell protectors: acetyl-L-carnitine, omega-3 fatty acids, quercetin, vitamin B12, inositol, and vinpocetine.

It is a fair guess that all of the above substances have some benefit as anti-aging supplements. To whittle the list down to a more convenient and affordable length one needs to consider not only the kind of action each substance has, but also where it exerts its effects in the body and in cells. The following shorter list is based on those considerations:

  • Pyridoxamine inhibiting diabetes-related damage to the body
  • benfotiamine protects blood vessels from damage by glucose.
  • Resveratrol antioxidant and also has direct effects on the activities of certain genes and proteins.
  • vitamin B12 improves nerve function; deficiencies are common.
  • alpha-lipoic acid antioxidant; acts in mitochondria (where superoxide is produced); acts in solution and in membranes.
  • vitamins C and E antioxidants that act in solution and membranes.
  • selenium antioxidant; needed for making glutathione peroxidase.
  • N-acetyl cysteine (NAC) precursor for the antioxidant glutathione, an essential cofactor of glutathione peroxidase.
  • manganese antioxidant; needed for making superoxide dismutase.
  • ferulic acid antioxidant; acts against superoxide; enhances other antioxidants; suppresses blood glucose; improves cholesterol profile; may prevent UV damage to skin.
  • genistein antioxidant; insulin activity enhancer; protects brain cells; inhibits LDL oxidation (a cause of atherosclerosis).
  • quercetin glycation inhibitor; glucose and sorbitol suppressor; acts in membranes.
  • vinpocetine improves circulation, especially in the brain and retina.
  • acetyl-L-carnitine improves nerve function; increases efficiency of glucose and fat metabolism; acts in mitochondria.

Conclusion

Is diabetes research leading to a cure for aging? A great deal of funding and scientific effort is going into the study of diabetes – a lot more than is going into anti-aging research – and we are fortunate that the two diseases have at least some elements in common: damage from free radicals, glucose cross-linking, and arterial plaques. Diabetes research is helping to provide techniques for preventing and reversing these causes of aging.

But what about the other causes of aging – damaged and inactivated genes, and faulty duplication of DNA? Are diabetes researchers developing techniques for dealing with these, also? At the moment, the answer is ‘no’ – genetic therapy is receiving very little attention. However, type 1 diabetes does involve defective genes, and type 2 diabetes involves damaged genes. It is therefore likely that these aspects of the disease will become important research topics. Considering the fact that diabetes research attracts huge amounts of money and expertise, it is reasonable to think that the study of this disease could indeed lead to a general cure for aging.

Which Crosslinking Inhibitors and Breakers Are Right for You?

zarkov

Acarbose

AcarboseAcarbose (precose or glucobay) interferes with alpha-glucosidase, an enzyme key in breaking down complex carbohydrates into simple sugars. This reduces blood-sugar levels,  inhibiting crosslinking and AGE formation. It does not, however, interfere with the actual binding of sugars to proteins.

Lowering blood-sugar levels protects organs with many delicate blood vessels such as the retina, kidney, brain, etc. from damage. The problem with acarbose is twofold: The long-term effects of suppressing carbohydrate breakdown are unknown, and it leaves high levels of unabsorbed carbohydrates in the intestines, causing pain, cramps, bloating, and diarrhea. Given the risks and problems, it is unsuitable as an anti-aging compound.

Acetyl-L-Carnitine

ALCAcetyl-L-carnitine protects the eye’s lens from cataracts. (Its numerous antiaging properties will be covered in the future.)
The protective effect comes from the acetyl group potential binding sites; aspirin and n-acetyl-cysteine contain an acetyl group and have a similar effect. While taurine also protects the lens of the eye, the underlying mechanism is different, suggesting benefits from using multiple inhibitors.   No such protection was seen for the unacetylated L-carnitine, since it cannot preempt the binding sites.

Aminoguanidine

AminoguanidineAminoguanidine (pimagidine) targets molecules created in the later stages of AGE formation. This prescription drug is based on the guanidine found in French Lilac (aka Goat’s Rue), a bushy perennial.

Diabetics have used French Lilac since medieval times, but were limited to small amounts because the plant contains the toxic molecule galegine.

Protecting collagen against crosslinking, aminoguanidine shields the skin and connective tissue from stiffening and wrinkling, and muscle, like the heart, from hardening. Typical  dosages do not inhibit the routine collagen crosslinking required for strength.

Preventing crosslinking between proteins and fats, aminoguanidine spares the arteries from clogging. By protecting small arteries feeding the peripheral nervous system, it reduces age- and diabetes-associated nerve damage. It also prevents lipofuscin (age spots), a signature sign of aging and crosslinking.

Aminoguanidine is among the most effective crosslinking inhibitors, with vitamin B-6 comparable. But don’t rush out to get a prescription quite yet!

The drug has numerous side effects, including anemia and autoimmune disorders. While a potent inhibitor of diabetic complications, aminoguanidine is not safe enough to justify its use by nondiabetics.

Aspirin (Acetylsalicylic Acid)

AspirinOriginally isolated in tree bark, salicylic acid has been used for millennia for fever and inflammation; the famed physician Hippocrates praised its benefits.
The addition of an acetyl group – done twice in the 1800s by two different chemists – finally eliminated much of the harsh side effects on the stomach, increasing its popularity and therapeutic potential. Aspirin is now the most commonly prescribed drug.

More recently, aspirin has been discovered to interfere with post-Amadori reaction because the phenol ring provides antioxidant properties and the physical structure chelates iron and copper.

Both of these metal ions have been implicated in crosslinking; the betaamyloid plaques found in Alzheimer’s disease, for example, contain both AGEs and complexes with copper and iron.

Aspirin, like acetyl-L-carnitine and taurine, also protects the lens of the eye from cataracts. Experiments using eye lenses submersed in sugar solutions show a profound reduction in cataract formation when aspirin is added.

Benfotiamine

BenfotiamineBenfotiamine (S-benzoylthiamine-O-monophosphate) is a fat-soluble vitamin B-1 (thiamine) derivative that prevents crosslinking and inhibits AGE formation. The body metabolizes it into thiamine pyrophosphate (TPP), vitamin B-1’s active form.

An allithiamine – it is found in the allium family of vegetables, including garlic, onions, and leeks – benfotiamine is a fairly old compound, having been discovered in 1951. (Alteon Pharmaceutical’s alagebrium is derived from B-1.)

Its original application was in the treatment and prevention of a variety of conditions in both diabetics and nondiabetics: nerve damage, including neuropathy, sciatica, and shingles; cardiovascular damage, including heart, kidneys, and eyes, and high blood pressure; and general aging related disorders.

Diabetes damages blood vessels through four chemical pathways, and benfotiamine completely blocks three of them. It also converts the toxic triosephosphates to the more benign pentosephosphates.

Absorption of B-1 is so poor that supplements often contain far more than is usable. Benfotiamine uptake, however, can exceed one hundred times that for B-1.

Reducing AGE levels – preventing retinopathy, renal damage, etc., even in the healthy – benfotiamine can undo damage, substantially improving nerve function while profoundly reducing pain.

Benfotiamine is widely regarded as safer than the already-safe vitamin B-1 it is derived from.

Bioflavonoids

A family of more than four thousand compounds with antioxidant properties, bioflavonoids are found in citrus, grape seeds and skins, green tea, cranberries, pine bark, and fruits. Common bioflavonoids are oxerutin, green-tea polyphenols, proanthocyanidin, and quercetin.

Bioflavonoids inhibit oxidation and aldose reductase, reducing conversion of glucose into the more damaging sorbitol. Pairing with taurine and n-acetyl-cysteine reduces crosslinking far more than these compound do alone.

Biotin

BiotinBiotin has a crucial role in the metabolism of sugar, moving glucose into cells, stimulating the release of insulin, and increasing the conversion of glucose into fatty acids burned for energy and glycogen for stored energy.

Diabetics taking 10 -15mg. of biotin daily have significantly lower fasting blood-sugar levels -‘nearly fifty percent lower – and can reduce the size and frequency of their insulin  injections. Lowering levels of sugar in the blood also reduces AGE formation. Results suggest biotin improves or reverses m a n y symptoms of diabetes. It has no known toxicity even in very high dosages.

BHT

BHTWidely used as a food preservative, butylated hydroxytoluene (BHT) is also a potent antioxidant. Like other antioxidants – vitamins C and E, lipoic acid, and rosmarinic acid – it inhibits oxidation of glucose and thus prevents the formation of the Schiff bases, which start the AGE creation cycle.

BHT is technically approved for use only as a food preservative, so supplement sellers market it only for that purpose.

Chromium

The body uses the element chromium (chromium picolinate, glucose tolerance factor, GTF) in combination with insulin to regulate blood-sugar levels. Chromium deficiencies are common, and supplementing reduces blood sugar levels and AGE formation.

Coenzyme Q10 & Idebenone

Ubiquinone

As potent antioxidants and metabolic enhancers, coenzyme Q10 (CoQ10) and idebenone reduce AGE formation and lower blood-sugar levels by stimulating insulin, improving the metabolism and preventing the oxidation of glucose.

CoQ10 and idebenone are regarded as very safe and well tolerated.

L-Arginine & L-Lysine

L-Arginine

L-Arginine

The amino acids L-arginine and L-lysine inhibit glycation and AGE formation by sacrificially reacting with carbonyls, ketones, aldehydes, and metal ions, saving the body’s proteins from attack.

L-Lysine

L-Lysine

In large doses, L-arginine can lower blood pressure and increase viral replication, particularly for the herpes family. L-lysine, however, suppresses L-arginine’s effect on viral replication. Together, the two slow or prevent AGE formation.

L-Carnosine

L-CarnosineMade by the body and found in muscle and nervous system tissue, L-carnosine (beta alanyl-Lhistidine or n-acetyl-L-carnosine) is composed of two amino acids: alanine and histadine and has several important roles.

By binding to free carbonyl groups, it inhibits sugar binding to proteins and DNA, and reduces protein-protein and protein-DNA crosslinking. As an antioxidant, it preserves the body’s primary antioxidant, glutathione. Finally, by breaking the bonds in crosslinked proteins it undoes damage.

Known to reduce levels of AGEs and free radicals in the body, L-carnosine prevents and even removes age-related cataracts. (It may also benefit age-related eye conditions like glaucoma.)

Combining L-carnosine with AGE breakers like benfotiamine may eliminate newly liberated carbonyls before they can bind to other proteins. L-carnosine is regarded as safe in normal amounts. Large dosages – typically more than one gram per day – have been linked to histamine-type allergies.

Lipoic Acid

Alpha Lipoic AcidA potent sulfur-bearing antioxidant, lipoic acid (thioctic acid) inhibits glucose oxidation, Schiff-base formation, lipid peroxidation, and the binding of fats to proteins.

Complexing excess metal ions, lipoic acid reduces AGE formation. It also recycles oxidized vitamin C, preventing it from producing the reactive carbonyls leading to AGEs. Finally, lipoic acid works like insulin, lowering blood-sugar levels without injections. Like other antioxidants lipoic acid is an earlystage inhibitor. It pairs nicely with mid- and late-stage inhibitors like L-carnosine, PABA, vitamin B-6, and benfotiamine.

Metformin

MetforminMetformin (glucophage) is a prescription drug for diabetes. A slightly modified double guanidine, the drug prevents the liver’s breakdown of carbohydrates into glucose – thereby lowering bloodsugar levels – and inhibits the formation of AGEs, particularly those involving collagen in the heart, connective tissue, and skin.

Like L-carnosine, metformin binds to carbonyl groups, interfering with crosslinking. It also ties up binding sites on the fibrin proteins responsible for coagulation and, like aspirin, reduces the risk of heart attack and stroke.

Metformin, unfortunately, has serious side effects: lactic acidosis, liver and kidney damage, and decreased folate and vitamin B-12 levels. Drops in these vitamins are known to raise the homocysteine levels associated with heart and circulatory system damage.

The chemically similar drug phenformin killed a number of patients before being removed from the market. Given the risks, metformin is too risky to use as an antiaging compound.

N-Acetyl-Cysteine

NACN-acetyl-cysteine is a powerful antioxidant with wide antiaging properties. By preventing the oxidation of glucose, it slows down early-stage AGE formation.

Like aspirin and acetyl-L-carnitine, n-acetyl-cysteine acetylates potential binding sites, preventing AGE formation. It pairs nicely with inhibitors like L-carnosine, PABA, vitamin B-6, and benfotiamine.

Penicillamine

PenicillamineA distinct molecule from the antibiotic, penicillamine (dimethyl cysteine) inhibits crosslinking, but not particularly well. Its primary use is in chelation, like EDTA, since it complexes metals and reactive molecules. It also interferes with routine metabolism.

Known side effects include immune system suppression, impaired collagen synthesis, lupus, aplastic anemia, and myasthenia gravis. Given the serious risks, penicillamine is suitable only for life-threatening illnesses on a short-term basis.

PABA (Para-Amino Benzoic Acid)

PABAA vitamin B cofactor, PABA (para-amino benzoic acid) is an antioxidant and crosslinking inhibitor. It is the active ingredient in many sunscreens.

PABA is generally safe and well tolerated, even up to several grams daily. Some users find it disagrees with them, even in small quantities, so some caution is required. The typical side effects of high dosages are nausea and diarrhea, which vanish upon dosage reduction.

Rosmarinic Acid

Rosmarinic AcidA potent antioxidant, rosmarinic acid inhibits the oxidation of glucose, slowing the formation of the Schiff bases created in the early stages of AGE formation. It also is a strong anti-inflammatory, which may prevent autoimmune reactions to AGEs and the tissues containing them.

As an inhibitor of aldose reductase, rosmarinic acid prevents the conversion of glucose into sorbitol. Many cells, like those in the eye, cannot metabolize sorbitol, and suffer damage.
(See taurine for details.)

Selenium

The element selenium (selenomethionine, sodium selenate) is a key ingredient in the antioxidants made by the body that prevent the oxidation of glucose, thereby inhibiting AGE formation.

Taurine

TaurineThe amino acid taurine (2-aminoethane sulfonic acid) is several times better at inhibiting AGE formation than the risky prescription drug aminoguanidine.

Taurine is believed to work by binding to sugar, sparing the proteins in the eye’s lens. This has particular value when it comes to protecting sight.

About the size of a shirt button, the eye’s lens is made of transparent protein that focuses light onto the retina. When crosslinked by the sun’s ultraviolet rays or by sugar, it turns cloudy with cataracts, causing a loss of vision.

The high taurine levels in the eye protect the lens by preferentially bonding to sugars. In addition to taurine, high levels of vitamins C and E are known to halve the risk of cataracts.

Vitamin B-6

Pyridoxamine (PM)

PyridoxaminePyridoxal (PL)

PyridoxalPyridoxine (PN)

PyridoxineVitamin B-6 is crucial for metabolism of proteins, carbohydrates, and fats. It is found in three different forms: pyridoxal (pyridoxal-5-phosphate, P5P, and PL), pyridoxine (PN), and pyridoxamine (PM). The best crosslinking inhibitor is PM.

Trapping carbonyls and acting as an antioxidant, B-6 inhibits AGE formation better than aminoguanidine, but without the risk of injury or death.

Vitamin C

Vitamin CLike other antioxidants, vitamin C inhibits glucose oxidation, reducing chiff-base formation. An early-stage inhibitor, it pairs nicely with mid- and late-stage inhibitors like L-carnosine, PABA, vitamin B-6, and benfotiamine.

Vitamin E

Vitamin E

Vitamin E (tocopherol, tocotrienol) is a family of antioxidants that, among its other benefits, prevents the oxidation of glucose, reducing the formation of Schiff bases. It also slightly inhibitscarbonyl formation. Using a single synthetic supplement like DL-tocopherol will not deliver optimal protection from oxidation and AGEs; evidence suggests synthetics are inferior to natural vitamin E and can cause a variety of problems. Supplementing with a blend of natural tocopherols and tocotrienols is superior to using a single synthetic supplement.

Crosslikig


Everything You Always Wanted to Know about the Maillard reaction… But Were Afraid to Ask!

zarkovEver since Prometheus brought fire to mankind and cooking began, humans have enjoyed the results of the Maillard reaction; without it cooked or fermented foods would lack much color and taste. But the reaction has a dark side, and causes deterioration of the body.

Beer, Food & Chemistry

In 1908, the English chemist A.R. Ling was trying to explain how beer obtained its color. He deduced that the reaction involved sugar and protein, but was unable to determine the precise mechanism. Across the English Channel, the French chemist Louis Camille Maillard was investigating how individual amino acids linked together to form proteins. (Proteins are just long chains of amino acids glued together and then folded into compact shapes.)

Maillard discovered, in 1912, when he combined sugar and amino acids in water and then heated the mixture it turned a yellowish-brown. This was the first time anyone was able to initiate nonenzymatic browning using well-defined materials.

When people talk about the Maillard reaction, they often to use the word “sugar” to mean either sugars or carbohydrates.

In honor of his discovery, the process binding a sugar to an amine, amino acid, peptide, or protein is known as the “Maillard reaction.” Familiar to chefs for centuries, it was not until 1953, however, that the complex web of underlying reactions was finally deciphered.

Why the Maillard Matters

The reaction is of crucial importance, and not just in chemistry. Crosslinking between sugars and amino acids, among others, produces much of the color and taste we associate with cooked or fermented foods. More ominously, crosslinking also forms many mutagenic, carcinogenic, and otherwise toxic compounds.

The very same reaction occurs in the body, as the proteins making up collagen, muscle tissue, bone, organs, eyes, etc. are hardened, distorted, corrupted, and otherwise rendered nonfunctional by sugar. Understanding the Maillard reaction leads not just to safer – and tastier – food, but also to longer, healthier living.

What Happens

A chemist explains the reaction as one of the reactive carbonyl groups in the sugar molecule binding with the amino acid’s nucleophilicamine group, yielding a variety of interesting, and frequently uncategorized, low-molecular weight organic compounds.

This is just a fancy way of saying that sugars and amino acids shuck off their shoes and join together permanently, forming new molecules, in a variety of small sizes, each with different chemical properties. The end products of the reaction, called “melanoidins,” have different colors and tastes, and have such variety that many have never been categorized, let alone studied.

What’s All That Brown Glop?

The brown residue left over after sauteing meats, commonly used to make sauces – aka “deglazing the pan” – is concentrated residue from the Maillard reaction.

So are: the color and taste of roasted coffee and cocoa beans; the crunchy, browned surface of toast; the caramelized tomato and sugar hybrids in barbeque sauce; the sweet, rich taste of roasted vegetables and caramelized onions; the crunchy goodness of creme brulee; the sticky, brown caramel formed when milk proteins and sugar combine; the taste and color of whiskey and beer; and even artificial maple syrup.

Yuck! That Smells & Tastes Bad!

The Maillard reaction, however, isn’t always pleasant. During World War II soldiers complained that powdered eggs were an unappetizing brown and tasted spoiled. This was of great concern to everyone since an army marches on its stomach.

Investigation showed that the eggs were dehydrated and stored at room temperature, which should have made them quite stable. It turned out that the egg’s sugars were reacting with the amino acids in the proteins and creating some most unpalatable results.

Only after a fermentation process was adopted to eliminate glucose from raw eggs did the powdered version finally obtain a shelf life beyond a few weeks.

Smile for the Camera!

A related problem exists with old photographs. More than eighty percent of 19th-century photographs are “albumen prints” using an egg-white fixative. These prints have yellowed, in what is now known to be a Maillard-based process identical to the spoiled powdered eggs during WWII.

For a long time, scientists and food experts focused solely on shutting down the Maillard reaction in food to prevent exactly this sort of spoilage, but quickly realized the potential for improving both food and food safety.

Cooking Up Taste or Trouble

The flavors and aromas used by the food industry; about half depend upon the Maillard reaction.

Literally thousands of different results depend upon the raw ingredients and how they are cooked together: a dozen types of carbohydrates or sugars (ranging from simple to complex, including fructose, glucose, lactose, maltose, maltotriose, pullulan, sorbitol, starch, sucrose, and trehalose); twenty different amino acids; a variety of reaction temperatures, a wide spectrum of pH (acid or base); and variable reaction times.

For example, dry-toasting malt for beer yields a cereal flavor whereas heating wet malt delivers more of a caramel taste. The raw ingredients are identical; the only difference is the amount of water. The flavors we associate with meat, nuts, coffee, and even chocolate originate with pyrazines and guaiacols containing nitrogen,oxygen and sulphur groups. Not very glamorous, perhaps, but chemistry deals with explanations, not poetry.

The melanoidins may have unpleasant flavors or odors – bitter, burnt, or rancid – or pleasing ones like bread, caramel, malt, or roast meat. The same goes for a wide range of colors; from Maillard’s original yellowish-brown to nearly pitch black.

No Oven Needed

The surfaces of roasted meats undergo extensive Maillard reactions because of exposure to high temperatures. The interior is largely unchanged because it is cooler, and the reaction proceeds far too slowly to yield significant results during the short cooking time. Low sugar levels and high water concentrations in the interior also slow down the reactions.

While the Maillard normally occurs above 285°F (140°C) – as in an oven or on a stove – it does occur at room temperature, only slower. This is why beer browns, pasta darkens during drying, and human tissue crosslinks, all at relatively “cool” temperatures. These cooler reactions take weeks or months instead of minutes, but they do occur, just the same.

Other Uses

Artificial tanning solutions, such as dihydroxyacetone (DHA), react with the arginine in the stratum corneum, the outermost layer of skin. The result is a brown “tan” at room temperature, with the darkness determined by exposure. Such tans are purely cosmetic since they have only minimal UV blocking effects.

Soybeans for cattle feed are now treated with a Maillard process to enhance digestibility and nutritional value.

Role in Diabetes & Aging

An article in this issue (“Aging is Just Diabetes, Only Slower”) explains how damage from aging and diabetes is directly attributable to Maillard crosslinking. The basic problem is sugar bonding to proteins and ruining them.

Conclusion

Understanding the Maillard reaction improves food’s taste and color, increases food safety, and provides ways to slow down or undo the effects and damage caused by aging and diabetes. Maillard’s discovery is thus still important and highly relevant more than one hundred years later – even if you don’t cook!