Life Extension Magazine July 2009
By Julius Goepp, MD
As you read this sentence, a destructive biochemical process known as glycation is occurring in your body.
Glycation arises when simple sugars react with proteins to generate protein “cross-links.” These cross-linked proteins are called advanced glycation end products (AGEs). Cataract development in the lens of the eye, the drop in kidney function,damage to the delicate endothelial cell layer of our blood vessels, and the unsightly sagging and wrinkling of our skin are all examples of glycation.
In addition to protein glycation, many health-conscious people do not realize that lipid glycation plays an important role in the development of age-associated complications. In fact, a high rate of lipid glycation occurs in the plasma of patients with type 2 diabetes. Since accelerated aging is a hallmark of type 2 diabetes, the cellular toxicity caused by lipid glycation must be minimized to reduce the risk of complications of aging as well as diabetes.
Late last year, Life Extension was able to offer members access to pyridoxamine, a form of vitamin B6 well-validated to reduce glycation. Regrettably, a pharmaceutical company’s petition to have the regulatory status of pyridoxamine changed from a dietary supplement to an investigational new drug was very recently published by the FDA.
However, the good news is that another form of vitamin B6, pyridoxal-5’-phosphate (a different B6 vitamer), offers anti-glycation benefits that scientific studies suggest may have similar properties as pyridoxamine plus better inhibitory effects against lipid glycation.
Links and Cross-Links: The Processes of Glycation
Life Extension members understand that glycation is a crucial aspect of the aging process. In patients with type 2 diabetes, aging occurs at an accelerated rate, and one of the most important factors responsible for this enhanced rate of aging is glycation. There is a striking similarity between the complications of diabetes and the negative changes that are commonly recognized as aging. These include the gradual loss of youthful elasticity of our blood vessels, the unsightly sagging and wrinkling of our skin, the degradation of the lens in the eye, the delay in wound healing and increased susceptibility to infection associated with aging, and the progressive, age-induced decline in kidney function. All of these problems include a common factor—glycation.
B6 Reduces Glycation
One of the best known anti-glycating agents is vitamin B6, which actually occurs in nature in several different chemical forms, or vitamers.22 The main dietary form of B6 is called pyridoxine, which is subsequently converted into pyridoxal-5’-phosphate. In fact, each of the major B6 vitamers are ultimately converted into pyridoxal-5’-phosphate in the body (see Figure 1 below). Although the different B6 vitamers possess slightly different biochemical properties, the most active forms in terms of anti-glycation capability are pyridoxamine and pyridoxal-5’-phosphate.23
Scientists first became interested in pyridoxamine because of its tremendous glycation-fighting activity. They began to research the benefits of both pyridoxamine and pyridoxal-5’-phosphate23 in reducing the age-accelerating aspects of glycation. As these data came to the attention of the pharmaceutical companies, they realized that there were important medical benefits to pyridoxamine that were unmatched by their current roster of pharmaceuticals in development. Unfortunately, a recent ruling by the FDA may remove pyridoxamine from consumers and place it in the hands of the pharmaceutical industry.
In January 2009, responding to a petition by a pharmaceutical company, the FDA determined that pyridoxamine would not be considered a “dietary supplement,” paving the way for declaring pyridoxamine an “investigational new drug” for eventual sale as a prescription-only pharmaceutical.24
However, aging individuals cannot afford to wait as long as perhaps 10 years for the B6 vitamer pyridoxamine’s availability due to pharmaceutical greed and the inefficient quagmire that characterizes the FDA drug approval process.
Pyridoxal-5’-phosphate offers an alternative. In addition to preventing formation of AGEs and ALEs, pyridoxal-5’-phosphate actually engages in “trapping” already formed AGEs and chaperoning them out of cells.25,26 Furthermore, there is striking scientific evidence that pyridoxal-5’-phosphate offers anti-glycation benefit that is the equal of several strong, natural inhibitors of glycation and comparable to some pharmaceutical agents.
Kidney Disease and B6 Vitamers
The loss of kidney function under the influence of chronic blood sugar elevation is one of the leading causes of disability among diabetic patients. Kidney damage leads to hypertension and exacerbates cardiovascular disease, both of which in turn produce additional kidney injury, so prevention of kidney disease is of utmost importance for diabetics.
Scientists have evaluated various anti-glycation B6 vitamers in preventing diabetic complications.4,27 For example, scientists have shown that chemically combining pyridoxal, a B6 vitamer, with an AGE-fighting drug, aminoguanidine, enhanced the kidney protection conferred by the drug alone, and provided additional antioxidant effects as well.28 Basing their work on evidence that pyridoxamine could prevent development of kidney damage in experimental models of diabetes, scientists at the University of South Carolina hypothesized in 2003 that this B6 vitamer would provide similar benefits in experimental subjects that, while not diabetic, were obese.29 The researchers were also interested in identifying the impact of glycated lipids on cardiovascular damage and kidney disease. They divided the experimental cohort into three groups: a healthy lean group, an obese group without B6 vitamer treatment, and an obese group given pyridoxamine daily in their drinking water. The results were compelling: the obese untreated group had formation of glycated proteins and lipids at rates two to three times greater than those of the healthy lean group. Pyridoxamine supplementation, however, blocked those increases, while simultaneously decreasing plasma triglycerides, cholesterol, and the waste-product creatinine (a marker of kidney function). Physiologically, the supplemented obese group experienced reductions in both their previously elevated blood pressure and thickened blood vessel walls. Urinary protein excretion, a sign of kidney disease, was restored to near normal levels as well. The authors concluded that “Lipids are an important source of chemical modification of tissue proteins, even in the absence of hyperglycemia,” and that B6 vitamer treatment with pyridoxamine reduced protein and lipid glycation and “…protected against renal and vascular pathology in a nondiabetic model” (of obesity).
Further evidence for a role of lipid glycation as a cause of human kidney disease came from Japanese scientists in 2005, in a study comparing glycated lipid levels in diabetic and non-diabetic patients with kidney disease.30 They found that levels in diabetic patients on chronic hemodialysis were nearly twice those in diabetic patients not on dialysis, whose levels in turn were slightly higher than those in non-diabetic dialysis patients. Levels of glycated lipids were lowest of all (by a substantial margin), in control patients with neither diabetes nor non-diabetic kidney disease. These findings are of great importance because, as we’ll see, research indicates that the B6 vitamer pyridoxal-5-phosphate compares very favorably with the B6 vitamer pyridoxamine at reducing lipid glycation.
Harvard’s Joslin Diabetes group has published the results of a Phase II (safety and tolerability) study of the B6 vitamer pyridoxamine in diabetic patients with fully developed kidney disease.31 Their work involved two studies in which patients received pyridoxamine 50 or 250 mg twice daily, or placebo, for 24 weeks. B6 vitamer-treated patients experienced significantly slower deterioration of their serum creatinine (a standard biomarker of renal function) compared with placebo recipients. There was also a statistical trend towards lower levels of the inflammatory protein TGF-1 in urine, as well as urinary levels of AGEs, in the treated patients compared with placebo patients.
Data on B6 vitamers’ benefits in renal disease continue to accumulate, with evidence for its effect on improving the health of experimental animals receiving peritoneal dialysis and on those having undergone kidney transplantation.32,33 These and similar studies are generating hopes that we will see similar protective effects in humans whose kidney function has deteriorated to the point of needing these advanced interventions.
Eye Disease: The Impact of B6 Vitamers on Cataracts, Retinopathy, and Ischemia
With its high rate of metabolic activity and precision of function, the human eye is particularly vulnerable to the effects of glycated protein and lipids, as well as the structural and inflammatory effects they produce.34 The lens, which depends for its clarity on precise protein structure, becomes cloudy and eventually opacifies (cataract) when those proteins become cross-linked as the result of glycation.9,10,35
An important demonstration of this effect was provided in a 2002 study, in which scientific researchers studied the impact of high-glucose solutions on cultures of lens cells, with or without the presence of the B6 vitamers pyridoxine and pyridoxamine.36 Cells grown in high-glucose environments without B6 vitamer protection had substantially higher rates of glycation and protein cross-linking than did similar cells grown with the addition of pyridoxine or pyridoxamine.
Ophthalmologists at Case Western Reserve University subsequently demonstrated an anti-cataract effect of a B6 vitamer in an experimental diabetes model with pyridoxamine.37 Treatment increased the activity of a chemical pathway that reacts with, and decreases, glycation before the process can damage the lens.
Japanese scientists showed in 2004 that the B6 vitamer pyridoxal was found to have anti-glycation benefits superior to the drug aminoguanidine in an experimental model of cataract formation. The scientists administered either pyridoxal or aminoguanidine to the study groups in drinking water for seven weeks. Pyridoxal, but not aminoguanidine, significantly improved motor nerve conduction velocity. The time to develop cataract was longer in the pyridoxal-treated group than in the aminoguanidine-treated group. The increase in lens opacification in culture medium containing high glucose levels was more efficiently reduced by pyridoxal than by aminoguanidine. Furthermore, the level of urinary 8-hydroxy-2’-deoxyguanosine, a marker of oxidative DNA damage, and the level of liver malondialdehyde plus 4-hydroxy-2-alkenals, a marker of tissue lipid peroxidation, both of which are elevated in diabetes, were significantly reduced by pyridoxal but not by aminoguanidine.38
Diabetic retinopathy is the term physicians use to describe the progressive destruction of retinal blood vessels under the effects of chronic blood sugar elevations. Ophthalmologists in Northern Ireland suspected this to be the case, and explored the possibility that B6 vitamers could protect against those changes.39 Treatment with the B6 vitamer pyridoxamine protected against the blood vessel changes, and decreased the amount of protein and lipid glycation in retinal tissue.
A 2002 study showed that the B6 vitamers pyridoxal-5’-phosphate and pyridoxal hydrochloride protect the retina of the eye from ischemia (lack of blood flow). Daily administration of the B6 vitamers pyridoxal hydrochloride and pyridoxal-5’-phosphate was performed for 10 consecutive days. On the sixth day, whole brain complete ischemia was produced by clipping the innominate and the left subclavian arteries for 20 minutes. The ischemia induced toxic cellular damage in the retina as shown by the loss of ganglion cells and the reduction of thickness of the ganglion cell, inner plexiform, and inner nuclear layers. Pyridoxal-5’-phosphate significantly prevented the ganglion cell loss and the reduction of thickness of the ganglion cell layer. Pyridoxal hydrochloride significantly prevented the ganglion cell loss as well as the reduction of thickness of ganglion cell, inner plexiform, and inner nuclear layers. These results suggest that the B6 vitamers pyridoxal-5’-phosphate and pyridoxal hydrochloride counteract the ischemic nerve cell death in the retina.40