© December 1992
Whole Foods Magazine
Tuning Up Metabolism: An Interview with Dr. Bruce N. Ames
Part 2: Treating many genetic diseases with megavitamins.
By Richard A. Passwater, Ph.D.
We chatted with Professor Bruce N. Ames of the University of California, Berkeley in the previous column (October 2002) about the famous "Ames Test for Mutagenicity," as well as the largely unrecognized benefits of the gamma form of natural vitamin E, gamma-tocopherol, and an interesting study showing that a combination of acetyl-l-carnitine and lipoic acid rejuvenated the brains of aged laboratory animals. In the latter study, the animals had more energy and better memory. This month we will discuss a very important report published by Dr. Ames and his colleagues regarding how—to quote the headline in the Berkeley Campus News—"megavitamins may be useful treatment for many genetic diseases, or just good insurance to tune up body metabolism."
Passwater: Dr. Ames, let’s begin with a just a touch of basic biochemistry for those of our readers who are not biochemists. Why are enzymes important to health?
Ames: Enzymes are the protein macromolecules that catalyze chemical reactions in cells (cell metabolism), such as burning fat and carbohydrate fuel to generate energy, and no living creature could function without them.
Passwater: When we speak of enzymes catalyzing reactions, we are saying that these proteins physically interact with other compounds in such a way as to facilitate certain reactions and speed the reactions without the catalyst directly entering into the reaction. The large protein enzymes fold in various ways producing relatively small areas that have shapes and electrical charges called "active sites" to hold or "bind" specific compounds together because their shape matches the active site in a manner that facilitates their joining or breaking apart. This is often described as being similar to how a lock and key fit together. Once the reaction occurs, the reaction products drift away from the active site as they no longer fit and new compounds are attracted to the site and the process repeats over and over. Without enzymes, the chemical reactions that occur in the body would proceed too slowly to sustain life; enzymes speed these reactions and control their rate. Enzymes have two major portions, the coenzyme and the apoenzyme; the apoenzyme is the protein portion, and the coenzyme is the nonprotein portion. Do enzymes critical to health decline in efficiency as we age?
Ames: Yes, particularly in the mitochondria. These are the power plants within the cell. The mitochondria oxidize fat and carbohydrate to generate energy. This is a process that removes electrons from the fats and carbohydrates and can even be considered somewhat like a slow "burning" without producing a flame. An inevitable consequence of this is the leakage of electrons (oxidants) from the electron transport chain. Thus, protein in the mitochondria is being oxidized. Though oxidized proteins are degraded, the system does not quite keep up, and oxidized proteins accumulate with age. In addition, lipid oxidation produces aldehydes that accumulate with age and react with proteins.
Passwater: Are there genetic causes of defective enzymes as well?
Ames: Yes many genetic diseases are known that are caused by defective genes that that produce defective enzymes, including mitochondrial enzymes.
Passwater: So, aging and defective genes both can result in less than optimally functioning enzymes for optimal health. Let’s look closer at how nutrition may influence enzyme production and efficiency. Please explain for our readers what a coenzyme is and what are the roles of coenzymes?
Ames: Coenzymes are small molecules that bind to enzymes and help them perform their catalytic function. There are about a dozen different kinds. A coenzyme may be involved with about 1,000 different enzymes.
Passwater: Do some nutrients serve as coenzymes, or can some nutrients be easily converted into coenzymes in the body?
Ames: Essentially each B vitamin is either a coenzyme or can be converted into a coenzyme. That is why they are required in metabolism, even though the body cannot make them.
Passwater: The B-complex vitamins appear together in nature as a family and have similar chemical properties. They are water-soluble and act as catalysts. With the exception of choline, all function as coenzymes. Without enough B-complex vitamins, sufficient enzymes cannot be formed to carry out many vital body reactions. The vitamin B-3 vitamers, niacin and niacinamide (formerly also called nicotinic acid and nicotinamide), form two important coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). More than 50 enzymes have NAD or NADP coenzymes in them. Most of the NAD- or NADP-containing enzymes are involved in metabolizing carbohydrates (especially sugars), fats and proteins. As one example, without adequate amounts of these enzymes, not only will desired reactions proceed at reduced efficiencies, but also unwanted by-products can accumulate in cells to produce deleterious effects.
Another example is pantothenic acid (vitamin B-5), a constituent of coenzyme A, which is involved in a great many reactions including energy production, sugar metabolism and hormone production. Thiamine (B-1) forms the coenzyme thiamine pyrophosphate which also forms many different enzymes.
On Page 59 of my 1975 book, Supernutrition: Megavitamin Revolution, I wrote the following: "If you were born deficient in genes that produce a critical enzyme, how can taking extra vitamins overcome your enzyme deficiency? A similar question applies to reduced enzyme production due to aging. The answer is in two parts; the first deals with the nature of the B-complex vitamins, and the second involves basic chemistry.
Some vitamins can correct many enzyme deficiencies. According to a basic chemistry principle called "LeChatelier’s principle" or the "law of mass action," more of the components of a reaction (in this instance, the apoenzyme and coenzyme) can be forced to combine (in this instance, produce an enzyme) by increasing the concentration of just one of the reactants (in this instance, the coenzyme). A person producing a reduced amount of the protein apoenzymes that he needs can still have a normal level of active enzymes by increasing his coenzyme production. The same equilibrium principle holds true in coenzyme production. Taking more B-complex vitamins shifts the equilibrium towards the production of more coenzyme, which, in turn, results in the production of more active enzyme. Therefore, taking larger amounts of B-complex vitamins can restore proper enzyme activity and health—both mental and physical.
That was in 1975. Today, it’s hard to realize that 25 years ago, the medical profession was advising people not to take simple multivitamin pills because they believed that vitamins pills either at best "did no good" or most likely were "harmful." Then, when Drs. Abram Hoffer, Linus Pauling, Emanuel Cheraskin and myself began advocating "megavitamins," quantities at multiples of the recommended dietary allowance (RDA) of the times, based upon our individual research, we created a maelstrom. Finally, in 2002, editorials in the Journal of the American Medical Association recommended that all adults take vitamin and mineral supplements. But, today, still most of the medical profession does not understand how quantities above the RDA can be of benefit.
I know this subject of coenzyme vitamin concentration and enzyme efficiency has been of interest to you for decades as well. With what we know today, can we increase the efficiency of enzymes or increase the concentration of coenzymes to improve enzyme production?
Ames: The efficiency of enzymes cannot usually be changed, except if the binding of the coenzyme to the enzyme is not optimal. But, as you stated in 1975, and as I have suspected for more than 30 years, indeed coenzyme concentrations can be increased by feeding high levels of particular B vitamins. When I was teaching an undergraduate laboratory course in biochemistry, my students kept finding defective genes and found that many coded for enzymes with a problem binding to a cofactor. And, as we discussed previously, the extra acetyl-l-carnitine in the study with aged rats, compensates for the defective binding of the enzyme carnitine acetyltransferase. This opens up the possibility of increasing the activity of some enzymes in certain cases as I discussed in a major review earlier this year.
Passwater: Yes, that was an exciting and extensive review that caught the attention of many. It’s 43 pages—including 377 references—of biochemical dynamite. Please tell our readers what your message was in this April American Journal of Clinical Nutrition [Am J Clin Nutr 2002; 75:] article? I am hoping that this is the seminal paper that will finally convince those remaining skeptics in the medical profession that megavitamin therapy is important for many people. Has it attracted their interest?
Ames: The review was by Drs. Han Elson-Schwab, Eli Silver and myself. We reviewed the literature on genetic diseases due to mutant enzymes and showed that in about 50 cases that involved a disease due to an altered enzyme with a coenzyme the disease could be ameliorated in some of the patients. The therapy was feeding high doses of a particular B vitamin precursor of the coenzyme, which raised the level of the coenzyme sufficiently to enable the defective enzyme to work.
We also showed that some polymorphisms (an alternate form of a gene found in greater than 1% of the population) are likely to benefit from high doses of particular B vitamins. Of the 50 diseases that we tracked down, 11 respond to vitamin B-6. These include enzyme diseases that lead to blindness, mental retardation, kidney failure and developmental problems. In all of these, the disease is pinned to a problem in how an enzyme binds to a cofactor derived from vitamin B-6. Of 3,870 known enzymes, 22% use cofactors and 112 of those utilize vitamin B-6. Perhaps there are diseases associated with every one of these enzyme problems and maybe they are treatable, to some degree, by megadoses of vitamin B-6 or another nutrient.
We also found 22 other diseases caused by defective binding to a cofactor derived from thiamine (B-1), riboflavin (B-2), niacin (B-3), cobalamin (B-12) or biotin (B-7).
The nutrition community knows about our paper, because we published it in a nutrition journal. The alternative medicine community also mostly knows about it. The human genetics community does not, in general, but will in time. I think it is a landmark paper, but I may be prejudiced.
Passwater: Is there good clinical or biochemical evidence that increasing vitamin intake is beneficial in many diseases?
Ames: I do not recommend taking more than the RDA of vitamins and minerals, except when there is a clear reason for thinking that the increased level is both non-toxic and efficacious. It may be, as I told the Berkeley Campus News in April, that these 50 diseases might be just the tip of the iceberg. Individual doctors have noticed this, but nobody put it all together. Now doctors are going to try high-dose vitamin therapy the minute they know a coenzyme is involved in a disease or there is a problem with the substrate. It makes sense, since many of the vitamins are generally recognized as safe in large doses. I think this kind of thing will turn up all over once people start looking.
Since anything can be toxic in excess, including vitamins and minerals, I think we must proceed with caution, even though I am optimistic that high doses of the B vitamins and some other biochemicals will turn out to be quite useful in some people. In our paper, we estimate that up to one-third of all mutations in a gene may effect binding to a vitamin-derived coenzyme, which means that high-dose vitamin therapy might reverse the effects of these mutations.
This approach has broader implications as the human genome is rife with genetic variation that probably affects enzyme-coenzyme interactions, and thus vitamin requirements.
Passwater: Just what I wanted to hear. This is a sophisticated elucidation similar to Dr. Roger Williams’ principle of "Biochemical Individuality" of the 1960s. There is no "average person." When it comes to optimal nutrient requirements, one size does not fit all, as there are so many genetic variations. Dr. Williams, the discoverer of the B vitamin pantothenic acid and pioneer of folic acid, headed the University of Texas’ Clayton Foundation Biochemical Institute where more vitamins and their variants have been discovered than in any other laboratory in the world. He made his case for Biochemical Individuality to the general public in his 1967 book, You Are Extraordinary.
Ames: High-dose vitamins might tweak enzyme functioning enough to improve the health of many segments of society. Eliminating vitamin and mineral deficiencies will restore what I call "metabolic harmony."
Passwater: Now we have a new principle—the "Ames’ Principle of Metabolic Harmony." Would you expect that intakes of nutrients above the RDA levels would be especially beneficial as we age?
Ames: Yes. We are actively trying to show in our experimental work that high doses of certain B vitamins might be useful for improving mitochondrial function in old animals. I suspect that the big impact is going to be in aging, though younger people, too, might benefit from supplementary B vitamins to "tune up" their metabolism.
Passwater: Is there a reliable body of evidence to suggest that antioxidant supplements produce health benefits?
Ames: Yes, if the subjects are ingesting too little of antioxidants such as vitamins C or E. No, if their system is already saturated and don't have any major oxidative stresses such as smoking. How much vitamin C old people require, however, is unknown and has not been examined seriously. It may be different.
Passwater: Well, we have learned about the "Ames Test for Mutagenicity," the "Ames Principle of Metabolic Harmony," that many genetic diseases may be treated with nutrients, that we need to pay more attention to the amount of gamma-tocopherol in our diets, and that your laboratory studies with acetyl-l-carnitine and lipoic acid are very encouraging. Thank you, Dr. Ames. WF
© 2002 Whole Foods Magazine and Richard A. Passwater, Ph.D.
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