Life Extension Magazine July 2009
By Julius Goepp, MD
Brain and nerve tissue are also highly vulnerable to the effects of glycation, and neurologists and gerontologists are beginning to suspect that glycation plays a significant, and perhaps central role in the development of age-related dementias such as Alzheimer’s disease. German neuroscientists reviewed the state of knowledge in 2001, pointing out that products of glycation accumulate within brain cells, causing them to clump and impairing their ability to perform vital transport processes, and ultimately leading to cell death.11 They also recognized that extracellular glycation exerts chronic oxidative stress on neurons, triggering toxic inflammatory cytokine release. The reviewers went on to speculate that, as a result, “Glycation inhibitors might also become interesting novel therapeutic drugs for treatment of Alzheimer’s disease.”
A 2002 study from the University of California, Davis, for example, examined vitamin B status, including pyridoxal-5-phosphate, in 43 Alzheimer’s disease patients, comparing them with 37 control subjects.41 Alzheimer’s disease patients were more than 12 times more likely to have low pyridoxal-5’phosphate levels than were control patients. An even more comprehensive study by Norwegian geriatricians demonstrated lower levels of a number of nutrients in apparently well-nourished Alzheimer’s disease patients, compared with controls.42 In particular, pyridoxal-5’-phosphate levels were found to be 90.2 nmol/L in healthy control patients, and just 24.8 in Alzheimer’s disease subjects. Most remarkably, all of the analyses conducted by these researchers identified pyridoxal-5’-phosphate as the common factor capable of identifying Alzheimer’s disease patients with 100% reliability!
Pyridoxal-5’-Phosphate: A B6 Vitamer with Anti-Glycation Benefits
The scientific literature clearly shows that B6 vitamers can play an important role in reducing the damaging impact of glycation upon aging.
The recent decision by the FDA charged with protecting and promoting the health of the public by maintaining safe access to our supply of food and drugs now paradoxically places access to the B6 vitamer pyridoxamine out of the reach of private citizens.
The B6 vitamer pyridoxal-5’-phosphate has been shown in several studies to possess potent anti-glycation benefits.43-45 In addition, the fact that pyridoxal-5’-phosphate levels are especially low in Alzheimer’s patients raised scientific interest in this B6 vitamer’s role in supporting cognitive health beginning in 2004.42
B6 vitamers possess subtle biochemical differences that help account for their specific biochemical and metabolic properties. Pyridoxamine is converted to pyridoxamine-5’-phosphate and pyridoxal-5’-phosphate in the liver and intestine. Therefore, pyridoxamine exerts beneficial effects on inhibition of glycation, at least in part, by pyridoxal-5’-phosphate. Pyridoxal-5’-phosphate is a naturally occurring metabolite of vitamin B6, and inhibits AGE formation, but in a different way than pyridoxamine due to differences in chemical structure (see Figure 2 below).
The difference in structure between pyridoxamine and pyridoxal-5’-phosphate helps explain the differences in their effect on AGE inhibition. The nucleophilic amino group of pyridoxamine binds to reactive carbonyl compounds to inhibit AGE formation. However, pyridoxal-5’-phosphate does not have any amino group, and instead has an aldehyde group and a phosphate group (see Figure 2 below).
For example, in comparison to pyridoxamine, pyridoxal-5’-phosphate traps a major glucose degradation product called 3-deoxyglucosone that contributes to glycation-induced damage, preventing 3-deoxyglucosone from reacting with tissue proteins and lipids.26
In a fascinating study, Japanese researchers evaluated the process of peritoneal dialysis, a common procedure in humans with diabetic kidney failure.26 The researchers showed that pyridoxal-5’-phosphate inhibited AGE formation by trapping 3-deoxyglucosone, a major glucose degradation product in peritoneal dialysis fluid. The fact that pyridoxamine does not trap 3-deoxyglucosone, but pyridoxal-5’-phosphate does, is very likely due to differences in their chemical structure. Because 3-deoxyglucosone is a precursor of imidazolone, a significant glycation end product, trapping of 3-deoxyglucosone by pyridoxal-5’-phosphate directly reduces accumulation of imidazolone, a major glycation end product.
Scientific researchers have directly compared the effect of oral supplementation with either pyridoxamine or pyridoxal-5’-phosphate on prevention of kidney disease in experimental models. In an interesting 2007 study, researchers evaluated the B6 vitamers pyridoxamine and pyridoxal-5’-phosphate in the prevention of kidney disease progression.25 In this experimental model, the scientists provided oral supplementation with either pyridoxal-5’-phosphate or pyridoxamine at a dose of 600 mg/kg body weight per day for 16 weeks, monitoring kidney function, AGE production, and biochemical markers of inflammation. Pyridoxal-5’-phosphate was found to significantly reduce protein loss in the urine as well as the microscopic evidence of damage to kidney structures, compared with the control diabetic group. There was a marked reduction in accumulation of AGEs in kidney tissue, with a concomitant reduction in inflammatory molecules and the aptly named receptor for advanced glycation end products (RAGE). Of interest, this experimental study of kidney disease showed that oral supplementation of the B6 vitamer pyridoxal-5’-phosphate was slightly better than pyridoxamine at preventing the development of diabetic nephropathy in the experimental test group. The scientists concluded, “Pyridoxal-5’-phosphate prevented progression of nephropathy in diabetic animals by inhibiting formation of AGEs. Pyridoxal-5’-phosphate is considered a promising active form of vitamin B6 for the treatment of AGE-linked disorders such as diabetic nephropathy.”
Scientists have recently started to focus on the damage to DNA by glycation and free radical (oxidant) stress. New research suggests that glycation-induced damage to DNA can be a factor in the initiation of cancer as well as cellular aging.46 Using an elegant experimental model of DNA damage, Indian scientists tested various vitamins for their ability to prevent the damage. Of interest, pyridoxal-5’-phosphate showed maximal protection at preventing damage to DNA, and the scientists correlated this protective effect to inhibition of production of hydroxyl and superoxide free radicals.
Recent research has identified lipid glycation, in addition to protein glycation, as an important factor in aging, kidney disease, diabetes, and pre-diabetic (insulin-resistant) states.30,47,48 Scientists have developed experimental models to test the inhibitory effects of different nutrients and drugs on lipid glycation. One such experimental model screened compounds that could prevent formation of so-called Amadori-PE, a product of lipid glycation with LDL cholesterol.49 Pyridoxal-5’-phosphate emerged as not only the best B6 vitamer at inhibiting lipid glycation, but significantly better than the drug aminoguanidine in this experimental model (see Figure 3 to the below).
B6 vitamers offer a variety of interesting and beneficial biochemical properties. Glycation of tissue proteins is a critical factor in the aging process as well as diseases of the cardiovascular system, kidneys, and eyes. New and emerging research strongly suggests that lipid glycation also plays a prominent role in aging as well as other diseases.
B6 vitamers like pyridoxamine and pyridoxal-5’-phosphate provide protection against the ravages of glycation. Recent experimental studies show that oral supplementation with pyridoxal-5’-phosphate offers dramatic anti-glycation benefits in a model of diabetic kidney disease comparable to oral supplementation with pyridoxamine. Over the next decade, new and exciting scientific developments with B6 vitamers will help us in our quest to minimize accelerated aging induced by protein and lipid glycation.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
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