Vitamin E Can Get into Your Genes
Vitamin E Combats Alzheimer’s Disease
The fantastic power of gene-chip technology provides
evidence that this vitamin helps inhibit senile plaque
By Will Block
et’s say you’re a master chef whose repertoire includes a hundred recipes that incorporate the herb thyme. Along comes a modern-day Luther Burbank who develops a new type of thyme that tastes rather different—even better, supposedly—than the traditional variety. Naturally, you’re intrigued, so you try it in a favorite recipe, and like it. Then you try it in another recipe, and—oops!—the dish tastes “off,” because here the new thyme just doesn’t blend well with the other ingredients.
Now what? With a reputation to uphold, you can’t take chances by guessing whether the new, improved thyme will work well in any given dish, and the prospect of preparing a hundred different dishes in your spare time just to test the thyme is daunting. If only there were a way in which you could accelerate and automate the process by, say, combining just a pinch of all the ingredients of a given dish, without the need for cooking, then adding a pinch of thyme, and using a magic machine to determine whether the results would be good or bad. (In your dreams, Chef. Now get busy in the kitchen!)
What’s the Recipe for a Long Life?
But what if you’re a different kind of “chef,” the kind we call a molecular biologist? They “cook” things up too, in the laboratory, trying to unlock the secrets of health and disease, of life and death. Sometimes this means testing innumerable different chemical interactions involving human DNA, which incorporates our roughly 20,000–25,000 genes in its nearly endless sequences of nucleotides, the basic unit of DNA structure. And with each gene consisting of anywhere from several dozen to several tens of thousands of nucleotides, you can see how the molecular biologists’ problem is rather more daunting than that of the chef, whose measly 100 recipes pales by comparison.
Wouldn’t it be great if molecular biologists (who can dream too) were somehow able to combine the sophisticated technology of semiconductor chip fabrication with advanced methods of solid-state biochemistry to create a “gene chip” in which, instead of microelectronic circuitry etched into a silicon wafer, there would be a microarray of human DNA snippets—perhaps a hundred million of them—attached to a quartz wafer in neat rows and columns? Every snippet in this immense, but tiny, array would be of known length and nucleotide composition, and together they would embody “signature” sequences from all the genes in the human genome.
Then, by allowing specially prepared DNA snippets from an external source (such as a cancer patient) to attach themselves selectively to the DNA snippets on the gene chip and analyzing the results with an analytical instrument, the scientists could simultaneously test the entire collection of human genes (the genome) for some aspect of the cancer patient’s gene activity.
From Dream to Reality—and a Nobel Prize?
Sounds impossible, doesn’t it? But it’s real—believe it or not. The gene chip just described is the centerpiece of a new branch of science called combinatorial chemistry, in which enormous numbers of related compounds are formed in infinitesimal quantities in densely packed arrays on a tiny chip so that their chemical interactions with outside agents can be investigated by automated techniques, using powerful computers to analyze the torrents of data generated. (The gene chips are also called DNA chips or biochips or microarrays.)
The potential value of this amazing technology (which will probably win a Nobel Prize for Stephen Fodor, the chemist who invented it) is incalculable. Gene chips allow researchers to scan the entire genomes of humans or other organisms in a single experiment! Talk about saving thyme … er, time. Commercially available gene chips are now being used by molecular biologists, biochemists, pharmacologists, physiologists, agricultural scientists, forensic pathologists, and others to investigate a great variety of questions, such as the biological effects of drugs or nutrients or pesticides or poisons on humans, animals, and plants.
Vitamin E Has Strong Antioxidant Action …
Just such a study was conducted recently by a team of nutritional scientists from England, Germany, and Switzerland. Their objective was to shed some light on the molecular mechanisms by which vitamin E confers protection against neurodegenerative diseases, especially Alzheimer’s disease, in the human brain, using the rat brain as a model.*
In their paper, the researchers cite some of the voluminous scientific literature on the benefits of vitamin E. It includes epidemiological studies relating low levels of vitamin E consumption to an increased risk for Alzheimer’s, as well as a few clinical trials.† In addition, laboratory cell-culture studies and animal studies have demonstrated the neuroprotective effects of vitamin E. Cumulatively, these results have been so persuasive that the American Psychiatric Association now recommends the use of 2000 IU (international units) of vitamin E daily for patients with moderate Alzheimer’s disease.
These preventive and therapeutic effects of vitamin E are believed to occur primarily through the vitamin’s strong antioxidant action against free radicals and other reactive oxygen species, to which the brain is especially vulnerable. Oxidative damage to neurons is believed to play a central role in the development of Alzheimer’s disease—indeed, it has been suggested that such damage is one of the earliest pathophysiological events in this disease.
… But What About the Gene Connection?
Other aspects of vitamin E chemistry are also involved in neuroprotection, however, and it could turn out that antioxidant action is not the dominant factor after all. The problem is that very little is known about the molecular mechanisms of vitamin E’s role in brain chemistry. Of particular interest is the vitamin’s impact on the expression of genes that are related in some way to the pathophysiology of neurodegenerative diseases. (Gene expression refers to the manner in which a gene’s coded information is converted into a tangible aspect of cellular function; for the great majority of genes, this occurs through the synthesis of one or more proteins whose structure is encoded by the gene.)
So the European researchers decided to investigate this question, using gene-chip technology. For 9 months, they fed two groups of healthy male rats a standard rat chow that, in terms of vitamin E content, was either normal (control rats) or severely deficient (test rats). Then all the rats were killed and their brains were dissected to remove the hippocampus, the brain structure most closely associated with memory and other cognitive functions, and the one most severely affected by Alzheimer’s disease.
The Gene Chip in Action
A portion of a gene-chip laser scan
After measuring the alpha-tocopherol (vitamin E) content of the hippocampi from the two groups of rats, the researchers homogenized the tissue from each rat. They then used chemical techniques to extract the DNA, break it down into snippets of known length, and label it with groups of atoms that fluoresce when irradiated with light at certain wavelengths. The hippocampal DNA snippets were then allowed to interact with a gene chip containing DNA snippets representing about 7000 rat genes.
Following the laws of chemistry, a rat-hippocampal DNA snippet from any given gene would pair up only with a gene-chip snippet representing the same gene. The level of activity of that gene in any given rat (the test was done using one gene chip for each rat) could then be determined quantitatively by measuring the intensity of the laser-induced fluorescence at the sites on the microarray where such DNA pairings had occurred.
When the experiment was complete, it turned out that 1044 genes contained in the DNA of rat-hippocampal tissue displayed a greater than 3-fold change in expression in response to vitamin E deficiency. Of these genes, 948 had been downregulated (meaning that their expression had been suppressed at least 3-fold by chronic vitamin E deficiency) and 96 had been upregulated (meaning that their expression had been stimulated at least 3-fold by chronic vitamin E deficiency).
Vitamin E Deficiency Promotes Senile Plaque
Here, for the first time, was direct molecular evidence for the effects of chronic vitamin E deficiency on genes in the rat hippocampus, including genes whose expression is involved in one way or another with the development of Alzheimer’s disease. The processes regulated by the genes in question fell into four main categories, one of which was the clearance of two forms of harmful gunk from the brain:
- Amyloid-beta – This is the “senile plaque” that forms in certain regions (including the hippocampus) of the brains of Alzheimer’s victims, causing deterioration of cognitive function and the death of countless neurons. It’s the principal anatomical feature of the neurodegeneration associated with Alzheimer’s.
- Advanced glycation end products (AGEs) – These tissue-fouling substances are the result of the degradation of proteins by undesirable chemical reactions with sugars. The aptly named AGEs are seen throughout the body in a wide variety of diseases and are thought to be important contributors to the aging process.
The researchers discovered that chronic vitamin E deficiency in the rats downregulated the expression of a variety of genes whose proteins either help protect against the formation of amyloid-beta and AGEs or help break them down and get rid of them. The result of such downregulation, unfortunately, is to facilitate the production and survival of these extremely destructive substances.
Further Damage Caused by Vitamin E Deficiency
Dr. Stephen Fodor, inventor of the gene chip
Via similar mechanisms involving the downregulation of beneficial genes or, in some cases, the upregulation of deleterious genes, chronic vitamin E deficiency contributed to a variety of other harmful effects in the rats’ brains:
- Hormones and hormone metabolism – The hormones whose function was impaired included a number of extremely important ones, such as growth hormone, insulinlike growth factor-I (IGF-I), the thyroid hormones, and melatonin. These hormones affect many aspects of brain development; they function through their effects not only on various brain systems but also on each other.
- Apoptosis – This is a natural process of cell disintegration, sometimes called “programmed cell suicide,” that rids the body of aging cells that are no longer viable. Many things can accelerate apoptosis, however, and chronic vitamin E deficiency appears to be one of them, by downregulating genes that inhibit this process and by upregulating genes that promote it.
- Neurotransmission – The dopaminergic system, which depends on the neurotransmitter dopamine, plays a major role in many different brain functions, and the degeneration of dopaminergic neurons is a hallmark of Parkinson’s disease. Downregulation of genes that are vital to the dopaminergic system is yet another consequence of chronic vitamin E deficiency in rats.
Welcome to the Revolution!
Only about 15 years old, gene-chip technology is still in its infancy as a tool for scientific research and industrial applications. Yet we have now seen its stunning ability to provide a wealth of useful information about gene expression in relation to vitamin E that will better enable molecular biologists, physicians, nutritional scientists, and others to understand how this versatile vitamin works in our brains and throughout our bodies. More studies of a similar kind, on a great variety of nutrients, are sure to follow. Welcome to the gene-chip revolution!
- Rota C, Rimbach G, Minihane AM, Stoecklin E, Barella L. Dietary vitamin E modulates differential gene expression in the rat hippocampus: potential implications for its neuroprotective properties. Nutr Neurosci 2005;
- Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ, for the Members of the Alzheimer’s Disease Cooperative Study. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 1997;336:1216-22.
- Kontush A, Mann U, Arlt S, Ujeyl A, Lührs C, Müller-Thomsen T, Beisiegel U. Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer’s disease. Free Rad Biol Med 2001;
- Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer’s disease. J Neuropathol Exp Neurol 2001;60(8):759-67.
How Safe Are Vitamins E and C?
When confronted with conflicting claims regarding anything technical, it’s a good idea to take a hard look at the totality of credible evidence on the subject. To do that, of course, requires a thorough knowledge of all the relevant literature, as well as the professional expertise to evaluate it authoritatively.
Such an analysis of the safety of vitamins E and C was published early in 2005. The 14 authors represented nine universities in the United States, England, Germany, and Switzerland, as well as a manufacturer of vitamins (BASF, Germany) and a dietary supplement industry trade association (the Council for Responsible Nutrition, Washington, DC).
The authors were not concerned with the RDA (Recommended Daily Allowance) values, which represent minimal nutritional requirements for preventing deficiency diseases. Instead, they sought to ascertain appropriate values for the much more meaningful UL (Upper Limit), which is defined by the Food and Nutrition Board of the IOM (Institute of Medicine, a part of the U.S. National Academies) as the highest daily nutrient intake that is likely to pose no risk of adverse health effects to almost all persons in the general population. In other words, it’s the tolerable upper intake level.
After evaluating the literature on vitamin E [and noting that the IOM’s recommended UL is 1000 mg/day of natural vitamin E (alpha-tocopherol), which is equivalent to 1500 IU (international units)], the authors concluded:
Several frequently cited literature reviews meticulously document the very consistent absence of adverse effects of vitamin E at intakes well above the RDA. … At present, the evidence is not convincing that vitamin E supplementation up to the UL increases the risk of death due to CVD [cardiovascular disease] or other causes. … On the basis of the totality of human evidence, we identified a vitamin E UL of 1600 IU/day … thus 1600 IU/day represents a supplemental intake that is safe for the general population.
Regarding vitamin C (and noting that the IOM’s recommended UL is 2000 mg/day), the authors concluded:
The preponderance of scientific evidence, which has been thoroughly reviewed by several authors, shows consistently that vitamin C is safe at intakes of 2000 mg/day or less. Several hypothesized adverse effects—including the hypotheses of adverse effects of increased oxalate and kidney stone formation, increased uric acid concentrations, excess iron absorption, reduced vitamin B12 concentrations, systemic conditioning (induced scurvy), and pro-oxidant effects—were examined in detail and were found to have no substantive basis. … On the basis of human studies of the osmotic diarrhea that can result from large bolus [a single slug] ingestions of vitamin C, we recommend a UL of 2000 mg/day for supplemental vitamin C.
Thus, the recommendations of these authors and those of the IOM agree exactly on vitamin C, and almost exactly on vitamin E.
The authors commented on the recent study that cited a 6% increased risk of death from any cause in people who were taking vitamin E supplements at 400 IU/day or more. They noted that this study (which was a meta-analysis covering 19 clinical trials) pertained not to healthy individuals but to those who were at serious risk for various chronic degenerative diseases, such as heart disease, end-stage renal failure, and Alzheimer’s disease. They stated that further analysis of the data indicated that the increased risk of death was significant only at doses of 2000 IU/day, which is higher than the recommended UL for adults.
Finally, the authors asserted that vitamins E and C are safe when taken in combination, as evidenced by the history of their use at high levels without adverse interactions. In other words, neither vitamin appears to affect the UL of the other. (For more on this vitamin combination, see
“Antioxidant Vitamin Combo Cuts Alzheimer’s Risk” in the March 2004 issue.)
- Hathcock JN, Azzi A, Blumberg J, Bray T, Dickinson A, Frei B, Jialal I, Johnston CS, Kelly FJ, Kraemer K, Packer L, Parthasarathy S, Sies H, Traber MG. Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr 2005;81:736-45.
- Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
Will Block is the publisher and editorial director of Life Enhancement magazine.