Pyridoxamine prevents complications of aging and diabetes

(Note that I originally wrote this article in 2009)

Pyridoxamine: a natural form of vitamin B6 with unique benefits

Vitamin B6 exists in three forms (vitamers) - pyridoxine, pyridoxal, pyridoxamine - as well as each of these with a phosphate group attached. They are all found naturally in foods. Human cells can convert one form to another, with the exception that the pyridoxal and pyridoxamine forms cannot be converted into the pyridoxine forms. This interconvertibility means that humans do not need to ingest all forms, because any one is fully capable of meeting the body's biological need for vitamin B6. Considering this fact it is not surprising to find that supplements containing vitamin B6 usually contain only one vitamer form.

Pyridoxine was the first form found when it was isolated (from plants) and discovered to have a necessary vitamin function in humans. It was named B6 and has become the B6 vitamer in supplements, also partly because its is more stable under processing conditions. Recent research however indicates that while pyridoxine is currently the least expensive to supply in supplements, it is not the most beneficial form for all health purposes. Research is now strongly pointing towards pyridoxamine as the most beneficial B6 vitamer for preventing chronic diseases and inhibiting their progression, as well as slowing aging processes. This is because, even though in its B6 properties pyridoxamine is no better than any other B6 vitamer, its different chemical structure enables it to more strongly inhibit the formation of advanced glycation end products (AGEs) than its other family members.

Advanced glycation end products: their role in age related pathologies

Glycation is a process that occurs when a sugar, such as glucose, binds to a free amino group on a protein, peptide or other molecule (such as some lipids) that contains an amino acid part. It is important to note that the number of such free amino groups is not something that can be altered because it is genetically controlled. While glycation is an important healthy biochemical process when it occurs under the control of one of the body's enzymes, when it occurs randomly without the catalytic help of an enzyme it is almost always harmful. Recently the term "glycation" has also been applied to the random binding of certain kinds of sugar molecules to nucleotides, but that is not something considered in this article. This continuous randomly occurring process leads to the formation of adducts on proteins which distorts their shape and inhibits their optimal functioning. Some of these adducts then connect to other amino groups either on the same protein or between proteins, forming cross-links. Advanced glycation end products (AGEs) are the end products of the non-enzymatic glycation process and their random processes of formation produce many chemical forms in addition to protein cross-links. The process of non-enzymatic glycation and AGE formation progresses slowly with age leading to gradual accumulation of AGEs in all body tissues (1).

Some forms of AGEs remain attached to the molecules that were initially glycated reducing their function because of changed shape and chemical properties. Evidence suggests that accumulation of AGEs contributes to various age related diseases such as atherosclerosis and cardiovascular disease (2). Formation of AGEs also contributes to loss of elasticity of various tissues with age (3, 4) . Such stiffening of tissues is characteristic of aging - one obvious example being the formation of wrinkles in the skin (5). Albeit not externally visible like wrinkle formation, even more important is the damage AGE formation causes to the tissues of internal organs.

Other forms of AGEs cause damage by binding to molecules found on the surface of many types of cells called receptors for advanced glycation end products or RAGE (6). The binding of AGEs to RAGE initiates a signaling cascade in cells causing harmful generation of free radicals (7, 1). It also increases inflammation by causing activation of the pro-inflammatory transcription factor NF-kappaB the sustained activation of which may contribute to various chronic diseases as well as to aging dysfunction (8). Consequently inhibition of AGE formation may prove beneficial in preventing the various diseases in which oxidation and inflammation play a role (9). In support of this the activation of RAGE has been associated with several diseases including diabetes, Alzheimer's disease, atherosclerosis, cardiovascular diseases, age-related macular degeneration, cataract formation, rheumatoid arthritis, kidney diseases and various cancers (10).

Pyridoxamine inhibits AGE formation

When it comes to improving health what sets pyridoxamine apart from the other B6 vitamers is its superior ability to inhibit the formation of AGEs. All B6 vitamers can inhibit AGE formation to some extent but pyridoxamine is far more potent than the others. In an in vitro study of AGE formation, pyridoxamine was found to be the most potent AGE inhibitor (11). Among the B6 vitamers pyridoxal came in second while, ironically, pyridoxine, the form most commonly found in supplements, was least effective.

Pyridoxamine acts through several mechanisms to prevent the formation of AGEs in the body. The initial attachment of a sugar molecule to an amino group involves oxidation and is generally promoted by oxidative stress. For this reason all agents that reduce oxidative stress generally inhibit glycation and consequent AGE formation. Pyridoxamine inhibits this initial glycation step in two ways. First, it competes with the sugars for binding with amino groups (12) and second, it inhibits oxidation by trapping reactive oxygen species (13).

The next stage of glycation is the irreversible formation of an Amadori product. Some metal ions catalyze the oxidation of Amadori products and by doing so contribute to their further transformation to AGEs. Pyridoxamine reduces AGE formation by chelating metal ions with catalytic oxidation capacity (14).

Pyridoxamine also inhibits unhealthy biochemical processes unrelated to glycation. Reactive carbonyl compounds are compounds formed naturally in the body during oxidation of carbohydrates and lipids. These compounds are intermediates in the formation of AGEs and ALEs (advanced lipoxidation end products). Pyridoxamine traps a wide variety of reactive carbonyl compounds. It is particularly potent at trapping specific types of carbonyl compounds called 1,4-dicarbonyls (15). Among these are the highly reactive and toxic levuglandins and isoketals (16, 17).

Pyridoxamine has been shown to reduce the level of AGEs and ALEs in the skin of diabetic rats (18), of AGEs in the plasma, red blood cells and kidneys of diabetic rats (19, 20) and of AGEs in the kidneys of diabetic mice (21). In addition it has been shown to reduce glycated hemoglobin (measured by HbA1c) in human patients with type 2 diabetes (22). Pyridoxamine's effectiveness at inhibiting AGE formation is reflected in numerous in vivo studies supporting its efficacy against various disorders in which AGE formation plays a contributory role.

Pyridoxamine protects against the complications of diabetes

The rate of glycation is a function of both time and concentration. The longer a sugar is exposed to an amino group the more chance it will bind to it. Since free sugars must be continuously present in all body tissues to fuel the generation of ATP, the cell's energy currency, the tissues of older people will have been exposed to sugars for far longer than younger people and consequently contain far more AGEs.

Concentration is also of major importance because the higher the concentration of a sugar the more chance that it will come sufficiently near an amino group to attach to it. Glucose, being the most abundant sugar in the human body, is the major culprit here. The higher its concentration, the more glucose there is around to bind to the ubiquitous amino groups. This is why glycation and AGE formation is accelerated in cases where blood glucose levels are high. High blood glucose levels are generally experienced in humans with diabetes, particularly those with type 2 diabetes. Diabetes thus generally represents a case of accelerated glycation and AGE formation. Given the role of AGEs in chronic diseases and aging itself, diabetes also represents a form of accelerated aging (23, 24) .

Evidence suggests that the formation of AGEs plays a key role in the complications of diabetes (25, 26). Being an inhibitor of AGE formation pyridoxamine is therefore an ideal candidate for prevention of diabetic complications.

Pyridoxamine was tested in human patients with type 2 diabetes at a dose of 150mg per day for 6 weeks. At this dose pyridoxamine treatment resulted in a significant reduction in glycated hemoglobin (22). Importantly, these effects could not be explained by changes in fasting blood glucose, which strongly suggests that pyridoxamine was acting by inhibiting glycation.

Reactive aldehydes are toxic compounds that serve as precursors for AGEs in the body. Glyoxalase I is an enzyme involved in the detoxification of reactive aldehydes. In a study on diabetic rats pyridoxamine administration reduced levels of AGEs in their blood plasma (19). Interestingly it was found to increase levels of Glyoxalase I in the erythrocytes of the rats. This may present yet another mechanism by which pyridoxamine confers benefit for diabetic complications.

Pyridoxamine may also complement lipoic acid in preventing diabetic complications. Lipoic acid is a supplement that has been shown to have beneficial effects for diabetes (27). In a study of obese Zucker rats the effectiveness of pyridoxamine alone and in combination with R-lipoic acid was tested. When injected intraperitoneally into the rats, either individually or in combination, the compounds reduced markers of oxidative stress. Both compounds also demonstrated very favorable effects by reducing fasting plasma glucose, insulin, free fatty acids and muscle triglycerides while increasing insulin sensitivity. In all these cases the combination of R-lipoic acid and pyridoxamine was more effective than either compound alone (28).

Benefits for kidney function

Kidney damage from diabetes is called diabetic nephropathy. As a common complication of diabetes it is a major cause of morbidity and mortality in diabetics and is currently the leading cause of end stage renal failure in most Western countries (29).

AGEs contribute to the progression of nephropathy. AGEs in the blood are eliminated from the body by filtration through the kidneys. In nephropathy this results in a vicious cycle where reduced kidney function results in accumulation of AGEs, which in turn results in further impairment of kidney function (30). By reducing AGE formation pyridoxamine is therefore an ideal candidate to prevent nephropathy.

In a study of streptozotocin-induced diabetic rats, the effect of pyridoxamine on formation of AGEs and the development of nephropathy was compared to that of alpha tocopherol, alpha lipoic acid and the ACE inhibitor enalapril. All interventions reduced the progression of nephropathy without affecting blood glucose levels (20). Pyridoxamine however was the most effective of these. It was the only compound that reduced AGEs in the skin and kidneys of the rats. In addition, except for alpha tocopherol, which had minor effects on cholesterol, pyridoxamine was the only compound that reduced triglycerides and cholesterol.

An important marker of renal impairment is the appearance of albumin in the urine, also referred to as albuminuria. This is caused by impaired glomerular filtration and is generally reflected in a raised albumin/creatinine ratio in the urine. In type 2 diabetic KK-A(y)/Ta mice, pyridoxamine, administrated through drinking water, reduced the urinary albumin/creatinine ratio indicating improved kidney function (1) . It also reduced fasting serum triglycerides and 3-deoxyglucosone (an early product of AGE formation). Levels of the AGE carboxymethyllysine in the kidneys were also reduced, as were glucose and glycated hemoglobin levels in the blood. In addition, pyridoxamine reduced levels of TGF-beta in the kidneys. This may contribute to the benefits of pyridoxamine since TGF-beta has been shown to play a contributory role in nephropathy (31).

A more recent study done by the same research group reported similar results (32) . In that study, using the same mouse model, pyridoxamine again reduced the albumin/creatinine ratio. It also reduced triglyceride levels, particularly the harmful VLDL cholesterol fraction.

Two characteristics of nephropathy are glomerular hypertrophy and mesangial matrix expansion, both of which are enlargement of a particular type of kidney tissue with accompanying decrease in function. In CD1 mice, as a model of diabetic nephropathy, pyridoxamine and the AGE inhibitor aminoguanidine inhibited glomerular hypertrophy and mesangial matrix expansion (33). These results confirm the role of AGEs in the progression of diabetic nephropathy.

In one study on pyridoxamine, obese Zucker fa/fa rats were used. Rats of this strain are not diabetic, but are hyperlipidemic and insulin resistant and serve as a model of diabetic nephropathy. Lipids can contribute to AGE and ALE formation. Pyridoxamine given to these rats reduced AGEs and ALEs in skin collagen. It also decreased the rise in plasma triglycerides and cholesterol, suggesting that lipids may be an important contributor to AGEs and ALEs (34).

In that same study, pyridoxamine furthermore corrected hypertension and vascular wall thickening; markedly reduced urinary protein and albumin levels, and plasma creatinine levels; and offered protection against renal and vascular pathology (34) .

The effects of pyridoxal phosphate (PLP) and pyridoxamine on nephropathy was studied in streptozotocin-induced diabetic female rats. Pyridoxamine demonstrated very favorable effects, including inhibition of AGEs accumulation, increased creatine clearance, reduced TGF-beta in the kidneys and decreased kidney fibronectin expression. PLP had similar effects and was overall even more effective than pyridoxamine. This result does not, however, imply that PLP is superior to pyridoxamine for humans since the extremely high dose of PLP used in this study clearly enabled much of it to escape hydrolysis in the digestive tract (35). Since such dosages would be toxic to humans if taken chronically, the highest tolerable doses of PLP will largely be converted to and absorbed as pyridoxal, which is a weaker inhibitor of AGE formation than pyridoxamine and PLP.

In two randomized double-blind placebo-controlled clinical trials, pyridoxamine was given to patients with diabetic nephropathy. When the data from these trials was analyzed in combination, pyridoxamine was found to significantly reduce the rise in creatinine levels from baseline, suggesting positive effects on kidney function. Levels of TGF-beta in the urine were also found to be decreased by pyridoxamine compared with placebo (36).

In one of these trials the safety of pyridoxamine at a dose of 250 mg twice daily for 20 weeks was studied. At that dose, not only was pyridoxamine found to be generally safe and well tolerated, it was also found to reverse the increase in plasma AGEs (36).

Pyridoxamine may also benefit kidney function by preventing kidney stone formation. About 5% of American women and 12% of men will develop a kidney stone at some time in their life (37). About 75-80 percent of all kidney stones are composed primarily of calcium oxalate (38, 37). Based on the role of oxalate in kidney stone formation, any treatment that reduces oxalate production could prove to be highly beneficial for kidney stone prevention.

Oxalate is found in the diet but is also produced in the body. Some of the intermediates of oxalate biosynthesis in the body are carbonyl compounds. Pyridoxamine's ability to scavenge carbonyl compounds has lead to research on its ability to scavenge oxalate precursors and reduce oxalate levels in the urine (39).

In a rat study of hyperoxaluria (a rare disorder that results in overproduction of oxalate) pyridoxamine caused a 50 percent reduction in urinary oxalate excretion. This was accompanied by a significant reduction in the formation of calcium oxalate crystals in the kidneys (39).

Pyridoxamine may also benefit chronic allograft nephropathy, a disease characterized by progressive deterioration of renal function following kidney transplant and which is the most prevalent cause of kidney transplant loss (40) . In a rat model of chronic allograft nephropathy, pyridoxamine inhibited AGE accumulation and ameliorated renal function impairment (41).

Pyridoxamine protects the eyes from age-related damage

High blood glucose levels, such as experienced in diabetes, can damage blood vessels. This can impact the viability of the capillaries in the eyes causing retinopathy which is a common complication of diabetes and a leading cause of acquired blindness during the working years (42). Evidence suggests that AGEs play a role in the progression of eye diseases including retinopathy (43).

Not surprisingly, pyridoxamine given to diabetic rats reduced the accumulation of carboxymethyllysine (an AGE) and inhibited a range of pathological changes in their retinas (44). This strongly supports pyridoxamine's potential to prevent retinopathy.

With age, oxidative stress from ultraviolet light exposure and other sources damages the lens of the eye. This ultimately leads to cataract formation, characterized by cloudiness of the lens. Evidence suggests that AGEs play a role in this process, which explains in part why the formation of cataracts is higher in diabetics (45).

Pyridoxamine has been shown to reduce the formation of AGEs in lens protein in vitro (19). In another in vitro study pyridoxamine decreased the protein oxidation of rabbit lens cells and also the oxidation of lens proteins, suggesting that it may prevent the cataract development caused by aging and diabetes (46).

In one study of diabetes-induced rats, pyridoxamine administration was unable to prevent cataract formation. However there was still a significant decrease in AGEs in the lenses of both the diabetic and the non-diabetic rats (47).

A major cause of vision loss in diabetic patients is diabetic macular edema which commonly results from breakdown of the inner blood-retinal barrier (48). As expected, in a study of mice made diabetic by injection of streptozotocin, such a breakdown occurred. This was prevented by administration of pyridoxamine through the drinking water (49). Pyridoxamine also reduced AGEs in the retinas of the mice and reduced the increase in vascular endothelial growth factor experienced in the control group. Pyridoxamine's ability to directly inhibit AGE formation appears to be responsible for these benefits since the favorable effects were independent of blood glucose levels.

Pyridoxamine may slow down the progression of atherosclerosis

There is abundant evidence supporting the role of AGEs in atherosclerosis. AGEs have been found to accumulate in atherosclerotic plaques in humans (50). LDL that has been modified by glycation appears to contribute to the development of atherosclerotic lesions (51). Some AGEs can also modify LDL, reducing its clearance from the circulation (52). AGEs may thus promote atherosclerosis both by increasing LDL levels and by increasing its atherogenic potential.

HDL, often called the good cholesterol, can also be negatively effected by AGEs. AGE inhibitors, including pyridoxamine, have been shown to preserve the beneficial function of HDL (53).

Evidence for the role of AGEs in atherosclerosis also comes from studies on diabetic mice specifically bred to lack the receptor for AGEs. In these mice the lack of the receptor for AGEs prevented the development of atherosclerosis seen in the control group (54).

These studies and many others strongly favor the involvement of AGEs in atherosclerosis. Although direct research is needed, based on its mechanism of action there is every reason to believe that pyridoxamine, as an AGE inhibitor, will help prevent atherosclerosis (55).

Potential benefits for a wide range of diseases

One serious complication of diabetes is nerve dysfunction or neuropathy. Evidence indicates that AGE formation plays a causal role in diabetic neuropathy (56) . In diabetes-induced rats pyridoxamine has been shown to inhibit the development of neuropathy (57).

Alzheimer's disease is the most common cause of dementia in developed countries. Pyridoxamine may be of benefit for prevention of Alzheimer's disease. Alzheimer's disease risk has been shown to be higher in diabetics compared to the general population (58). The hyperglycemia and resultant increase in AGE formation in diabetics appears to be a major factor contributing to this increased risk (59). While direct research on the benefits of pyridoxamine for prevention of Alzheimer's disease is urgently needed, scientists have already proposed that AGE inhibitors, including pyridoxamine, may provide a novel therapy for Alzheimer's disease (60).

Pyridoxamine may be of benefit in preventing several other diseases in which AGEs play a role. Some scientists have even gone as far as to state that all chronic disease patients may benefit from measures that control formation of AGEs and ALEs (9).

Summary

AGEs are harmful products formed naturally in the body that accumulate with age and at an accelerated rate in diabetes. It is clear that AGEs play a causal role in a host of chronic and age-related diseases as well as in the aging process itself.

Pyridoxamine is a natural form of vitamin B6 that is uniquely able to greatly inhibit the formation of AGEs. Consequently its benefits extend far beyond its ability to fulfill the human need for vitamin B6. Considering the facts that with advancing age almost all people will eventually succumb to one or more diseases in which AGEs play a role, and that human lifespan is ever increasing, it is clear that there is immense potential for pyridoxamine supplementation to reduce morbidity and the rising cost of medical care.

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Disclaimer
Although I have a BS degree in nutrition, have done intensive self-study on life-extension since 2003, and have worked in the field doing literature research since 2011, I am not a medical doctor or a licensed practitioner. Any information provided in this article is based on my personal research, opinions, and experiences. It is up to the reader to make their own decisions about what information to trust and which actions to take. I do not accept responsibility for any actions taken based on the information provided in this article.