Patent or not, that is the question

November 16, 2023

Is it really necessary to have a patent and billions of kroner before the media takes an interest in sensationally good results?

The other day in the newspaper Politiken, you could read an article (1) about Ozempic and Wegovy /Semaglutide, including an interview with Professor Jens Søndergaard, who stated that a recent study from the Cleveland Clinic had shown a 20% reduction in serious cardiovascular events after 4 years of treatment, which is such a great medical breakthrough that he had never seen anything like it, and compared it to the discovery of penicillin. -This is really great.

Semaglutide costs DKK 2,400 per month and has side effects in the form of upset stomach and nausea.

The result is quite impressive, even if it is a relative risk reduction rather than an absolute risk reduction. But there are now other scientific studies from this year that have shown far more impressive results.

What if there were a treatment that after 4 years showed a reduction in cardiovascular mortality of over 50% at a price of DKK 369. per month and completely without side effects? … What??
Yes, that is precisely the conclusion of the 10-year follow-up of the 2013 study (2) of Selenium and Coenzyme Q10 in combination.

The study (3) was previously described in the Vitality Council’s newsletter of 23 April 2023. However, that is not what I want to focus on here. It is rather the selection of news in the media that I want to discuss.

What really surprises me is that a risk reduction of 20% for cardiac events draws huge headlines and benevolent admiration whereas an equally valid study, which even shows a reduction in cardiovascular mortality of over 50%, is not even mentioned in the same newspapers -and you can’t deny the quality of this study.

Is it because it’s too good to be true that the media don’t want to bother writing about the scientific article, or does it absolutely have to be an expensive prescription drug with side effects before it’s interesting?

Actually, Professor Urban Alehagen also doubted his own results, which is why he analyzed them again and again from different sides but came to the same result.

And he is not the only one, as numerous previous studies have shown consistent increased survival with selenium and/or Q10.

Senior physician Svend Aage Mortensen at Rigshospitalet published several fine studies (4) of Q10 against heart failure but without their winning any resonance in the very orthodox medical profession.

Substances such as Coenzyme Q10 cannot be patented. Is that where the dog is buried? After all, a patent opens up possibilities for absolutely exorbitant earnings and the resulting marketing, press coverage, etc., just as there are funds for further research, publications, press, etc. -A self-reinforcing wheel that just goes faster and faster.

Substances that cannot be patented easily drown in the media stream because there is no great interest when there is no big money involved. But that is precisely why one should be even more interested in the serious research that takes place with these unpatented products. Professor Alehagen’s studies have clearly shown that an expensive, patented product is not necessary to halve the risk of dying of cardiovascular disease.

It is simply incredible that the selenium and Coenzyme Q10 study has not found a place on the front pages of the media.

Take care of yourself and others.

Claus Hancke MD
Specialist in general medicine


  1. Politiken 13/11-2023
  2. U Alehagen et al. Int J Cardiol 2013;167:1860-1866.
  3. U Alehagen et al. Antioxidants 2023, 12, 759

Early old age without vitamins and minerals

January 15, 2007

Without sufficient vitamins and minerals, old age comes too early. This is because the organism ignores the future when resources are limited. If it needs to, it does what is best for the present.

Keep an eye on Bruce Ames, the American biochemist and professor from Berkeley University. He is the man behind the worldwide renown Ames test, a quick method of establishing whether or not substances in food and the environment are cancerous, which is to say whether or not they cause mutation. He is also the author of uncountable numbers of scientific articles and has proposed some very important hypothesises in the field of nutrition. In 1999 President Clinton handed him the “American Nobel prise,” the National Medal of Science, for his contributions. At an age of 78, Ames is still extremely active.

Ames is among those who insist that there is, in uncountable ways, relationships between shortages of vitamins and minerals and cancer, mutations, and aging. But earlier than others, he also sought to explain these relationships bio chemically. It is highly important that we turn to long term studies involving thousands of people for these biomechanical mechanisms to be tested. When Ames invented his mutation test, he simplified detection of cancerous substances with one blow. Long term animal studies became unnecessary. Now he also wants to make long term human studies unnecessary in the study of nutritional deprivation.

The relationship between nutritional deprivation and cancer has been documented with extensive references in last November’s Proceedings of the National Academy of Science. For example, mutations, cancer, and early aging are seen early in association with magnesium deficiency. Vitamin D deficiency is believed to be the reason for 29% of all cancer in men. There is a relationship between deficiency of n-3 fatty acids from fish oil and malignant melanoma (skin caner), between selenium deficiency and cancer, and between potassium deficiency and heart disease. Lack of the B vitamin folic acid, vitamin B12, thiamine, and niacin also are associated with mutations and cancer. Even iron deficiency leads to mutations.

If all of this, and more, is an expression of a causal relationship, then nutrient deficiency should naturally be combated. Deficiency is, as we all know, extremely widespread. We receive large amounts of carbohydrates and fats, but few vitamins and minerals. One in every two Americans receive less magnesium than recommended, 90% receive too little vitamin E, 30% receive too little vitamin C, and so on… and so on.

Mutations can wait
If these many nutrient deficiencies are really the reasons for cancer, aging, and mutation, than what is the explanation? According to Ames, cells, and therefore the organs that they compose, prioritise when they temporarily or permanently lack something. A cell which as a result of a deficiency cannot accomplish all of its tasks, choose, for example, to prioritise the production of energy over the reparation of mutations. Correspondingly, scarce resources cause the organism to prioritise the production of red blood cells over the production of white blood cells, which is to say over immune system maintenance. The principle behind this is the same as when blood is directed to vital organs, such as the heart and lung, after blood loss. The organism must survive now, even though the price is weakening in the long term.

Prioritising is nonetheless only one reason for mutation and aging. A more direct connection is that nutrient deficiencies cause problems for the cells’ energy factories, the mitochondria. They are weakened by vitamin B (biotin) deficiency, pantoic acid deficiency, riboflavin deficiency, B6 deficiency, among others. Without these nutrients, the mitochondria cannot produce the enzymes necessary for energy production. Without energy nothing works in the cell, including the defence against mutation

Ames and others are now trying to find out how much nutrients we need to hold the number of mutations to a minimum and to keep the our mitochondria intact. This is not easy, but it is easier than undertaking expensive, and in many ways, uncertain, decade(s) long population studies. Also, who would finance such expensive studies?

In recent years we have seen a number of studies of supplementary vitamins E and C, selenium, beta-carotene, and vitamin A. Many of these were poorly done, more have been misinterpreted, and some have been proven. Few have become wiser. Is this the way forward? Or has Ames again shown a better shortcut?

While we wait for better knowledge, we should, according to Ames, take reasonable supplements of vitamins and minerals. Everything points towards that this is wise. And there are no risks.

By: Niels Hertz, MD

Ames B. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. PNAS 2006; 103:17589-94.

Greater need for vitamin B-12

February 1, 2006

Middle-aged and elderly women’s need for Vitamin B-12 is with great certainty 2,5 times higher than previously believed. A daily vitamin tablet is often not enough.

How is the need for a vitamin determined? Earlier it was determined based on how much is necessary to avoid acute deficiencies. This is sometimes still the case. For example, the current recommendations for vitamin C are still based on a World War II study on 20 English military objectors. Half of them came down with scurvy and two were close to death. But this study found that scurvy can be avoided with 12 mg vitamin C per day.

This kind of research is brutal by today’s standards. But it is also antiquated because it does not take other deficiency symptoms into account, including those which arise after longer periods and are not coupled with bruising of the skin, brittle bones, paralyses, and other acute symptoms. Today, instead of merely recording with a study participant becomes deathly ill, we follow the processes that the vitamins in question are involved in and determine whether or not they function as they should. This methodology was used by the American, Mark Levine when he proved that our need for vitamin C is closed to 200 mg per day than the normally recommended 60 mg. If one makes due with 60 mg it is believed that the vitamin C dependant reactions become slow and that there is an significantly increased risk of cardiovascular disease and cancer.

Of current interest, there is news regarding the need for vitamin B12. The current recommendation in England has been set to 1 microgram per day. A Danish study has recently shown that the need for vitamin B12 is six times as much (6 micrograms). This was determined in a study of 98 Danish women with an average age of 60. Such a large need meanwhile created a problem; the women typically only received 4.6 micrograms via their diet.

Even though they supplemented their intake with a normal vitamin pill (1 microgram B12), half of them received too little vitamin B12. Stronger pills are needed.

Increasing recommendations
For the last 50 years B12 status has been determined by measuring the blood’s B12 content. Findings in recent years have shown that a “normal” B12 value does not necessarily mean that there is enough. Even with a normal B12 value, build op of metabolism products which B12 normally removes can occur (these include homocysteine and MMA, otherwise known as methylmalonic acid). Therefore the amount of these substances present is measured when trying to determine whether or not there is a deficiency.

Recently a third indirect measure for B12 deficiency has been put into focus: holotranscobalamin, a B12 containing protein, seems to be able to replace the above-mentioned method and may even be more sensitive to B12 deficiency. It is very important to get enough of this protein. It is responsible for delivering B12 to the cells, almost like the paperboy who delivers the paper to your door. Without the paperboy, there is no paper.

The Danish study showed that the values for Holotranscobalamin, MMA, and homocysteine no longer indicated deficiency only when a B12 intake of over 6 micrograms per day was achieved. If B12 intake is less than 6 micrograms, there is sand in the B12-works.

The researchers conclude with conviction:
”…our results, together with those of others, strongly suggest that the RDA of 2.4 micrograms/day should be increased.”
This can also been said about many other vitamins. Experience from recent years indicates that the recommendations for not only vitamin B12, but also vitamins C and E and the minerals selenium, chromium, and magnesium, should also be increased, and in some cases greatly increased. Increased intake of many of the other B vitamins as well as iodine should also be considered.

This is especially true about vitamin D, on which we at the Danish Vitality Counsel have focused. The recommended daily dosage of vitamin D should be doubled for those of us who live in northern climes.

The official recommendations have as a whole not followed developments in research, even though there are strong arguments for new recommendations. According to some, there is need for more evidence. But this is contrary to the supposition that new recommendations could prevent serious chronic disease.

The dilemma is strengthened by the fact that it is difficult or impossible to get higher doses of vitamins and minerals though our modern diet. Some suggest that it might be possible with a Stone Age diet, but we surely will not have another Stone Age.

By: Vitality Council

1. Mustafa Vakar Bor et al. A daily intake of approximately 6 {micro}g vitamin B-12 appears to saturate all the vitamin B-12-related variables in Danish postmenopausal women. Am J Clin Nutr. 2006 Jan;83(1):52-8.
2. Zouë Lloyd-Wright et al. Holotranscobalamin as an Indicator of Dietary Vitamin B12 Deficiency. Clinical Chemistry 49: 2076-2078, 2003;10.1373/clinchem.2003.020743.

Vitamins against aging

January 9, 2006

The need for many vitamins increases with age. A deficiency can be compared to radiation exposure, which causes mutations, decreased energy production, cancer, and age-related changes in the body, according to one of the World’s leading nutrition scientists.

When Bruce Ames was 70, President Clinton surprised him with U.S.A.’s highest scientific recognition, The National Medal of Science, for his research in nutrition, cancer, and aging.

Today he is 77, but still an almost incomprehensibility active researcher and professor at the famous Berkeley University in California. He is also the man behind the world renown Ames test, a lightning fast method to find out whether a specific chemical can cause mutations, and thereby cancer.

This introduction shows that Ames it a researcher to be listen to, and therefore we have decided to discuss one of Ames’s latest and most important scientific articles.

The article was published in a periodical for the European organization of molecular biologists (EMBO reports). It describes how it is possible to reduce the tendency for cancer and aging by taking more than the recommended dose of diverse vitamins and other important substances.

How does it do this? In his study Ames found that deficiencies of vitamins C, E, B6, and B12 as well as of folic acid and zinc can have exactly the same effect on cells as radioactivity. This means that such deficiency causes mutations, for example as a result of breakage of the chromosomes.

Folic acid deficiency causes such breakage because it leads to the introduction of a wrong substance (uracil) in uncountable places along the DNA molecules. These mutations affect the cells the same way as a virus affects a computer. In the worst cases, the system beaks down.

But deficiency does not only lead to mutations. Another result is weakening of the energy producing mitochondria, otherwise known as the cells’ power plants. In order for the mitochondria to function, they must have access to certain enzymes, which can be regarded as the power plant’s machinery. The enzymes work together so that the product from one “machine” is processed further by the next in a chain of reactions which result in the conversation of oxygen and hydrogen into water, and the production of energy. But where do the enzymes come from? Without the necessary building blocks they do not exist at all!

Ames has among other things proven that deficiencies of zinc or the B vitamins biotin and pantothenic acid weaken the fourth reaction in this chain of reactions. They are the building blocks of the “machines” which carry out this step in the process. Not only is the production of energy reduced by such deficiency, but oxygen is also insufficiently converted to water. As a result the mitochondria empty free radicals into the surrounding cell where they can cause mutations, cancer, and weakness.

More Energy
Why does Ames believe that it is necessary to take more vitamins than recommended? This is as a result of the third and last point in his thought process. It regards the consequence of the uncountable mutations which by the aforementioned methods unavoidably arise during ones life. These mutations cause the cells to produce less effective enzymes that bind less effectively to the vitamins which they need to aid their function. Ames maintains that this poor binding can be overcome simply by increasing the amount of vitamins. This makes the enzymes work again.

A particular problem in this regard is the weakening of the mitochondria which occurs with age. Without energy, nothing functions within the cell and the degeneration of the mitochondria is central to what we call aging. But Ames emphasizes that it is possible to make old rats faster by giving them supplements of the two vitamin-like substances lipoic acid and carnitine.

Both substances are important intermediates for energy production in the mitochondria. With age they bind poorly to the enzymes which cause the mitochondria to function poorly. But this poor binding can also be overcome with supplements. As well as making the rats faster it was possible to measure that their mitochondria once again functioned normally. Clinically such treatment has been able to result in improvement in people with mild Alzheimer’s.

The unique thing about Ames is that his arguments are based on biochemistry. This means that he refers to elementary chemical reactions which are demonstrable in the organism. Many others base their views of more or less uncertain clinical trails, sometimes without knowledge of the biochemistry behind them. It might not be coincidental that The Nobel Prise in medicine typically is given to a biochemist.

By: Vitality Council

1. Bruce N Ames. Increasing longevity by tuning up metabolism. EMBO reports 2005;6:S20- S23.
2. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-a-lipoic acid. J. Liu et al. Proc Natl Acad Sci USA.2002;99:2356-61.
3. B N Ames et al. High-dose vitamins stimulate variant enzymes with decreased coenzyme-binding affinity (increased Km): Relevance to genetic diseases and polymorphisms. Am J Clin Nutr 2002;75:616-58.

Vitamin Pills Prevent Infection

January 24, 2005

The increased predisposition to infections in diabetics can be reduced with a daily multivitamin-mineral pill.

Skeptics have doubted that ordinary vitamin pills can strengthen the immune defence. In 1992, the Canadian nutritionist R.K. Chandra did establish that a daily vitamin pill reduced the number of infections in a small group of healthy elderly people by 50%. However, critics questionned his independence and the succeeding year, French scientists could not find any similar effect in an – albeit short-term – study.

The situation is now completely different. An American study has shown that an ordinary vitamin pill almost halves the incidence of infections. The study that lasted nearly a year included 130 trial subjects who were predominantly middle-aged, overweight women; of these women, approximately 1/3 had type II diabetes – also called non-insulin-dependent diabetes or adult-onset diabetes. Their lifestyle, however, was not necessarily unhealthy; more than every other woman exercised moderately or intensely.

During the study, half the trial subjects were given placebo (a non-effective tablet) and the other half were given a daily vitamin-mineral tablet. In the placebo group, 73% suffered infection while this was the case for only 43% in the vitamin group.

The diabetics were apparently the ones who benefited most from the vitamin pill as most of the difference between the two groups could be ascribed to them. Indeed, it is well-known that diabetics are more susceptible to infections than other people; 93% of the diabetics in the placebo group suffered infection while this was the case for only 17% of the diabetics in the vitamin group.

The obvious explanation could
be that the diabetics were vitamin-deficient; this would weaken their immune defence, but when given a vitamin pill, their health would be restored. However, the figures do not confirm this theory. It was estimated that approximately 1/3 of all the trial subjects – i.e. both diabetics and non-diabetics – were deficient in the vitamins A, -E, and -C. Therefore, the conclusion must be that not all diabetics had eaten unhealthily.

There is also the question of diabetics perhaps having a particularly large need for vitamins in order to maintain a healthy immune defence. During the trial, they were given a substantial supplement. The vitamin pill used in the trial contains fairly large amounts of the vitamins A, -B, -C, and -D, and it also contains folic acid, vitamin B12, vitamin K, chromium, and iodine which are not always present in standard vitamin pills.

Six months ago, the French 7-year SU.VI.MAX study showed that small amounts of antioxidants dramatically reduce mortality and the incidence of cancer in men. The men were given vitamin C and -E plus beta-carotene and selenium in the same dosage as in the American study; however, the Americans were given all the other vitamins and minerals as well.

Around the same time, a study in Tanzania showed that multivitamins significally strengthen the immune

There is reason to believe that, on a long view, a multivitamin pill – preferably a strong one of the kind – will be of benefit to most people. On a short view it is quite certainly a significant advantage to diabetics, men, and HIV positive people in particular.

By: Vitality Council

1) Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992;340:1124-7.
2) Chavance M et al. Does multivitamin supplementation prevent infections in healthy elderly subjects ? A controlled trial. Int J Vitam Nutr Res 1993;63:11-16.
3) Barringer TA et al. Effect of a multivitamin and mineral supplement on infection and quality of life. Ann Int Med 2003;138:365-71.
4) Hercberg S et al. The SU.VI.Max study. Arch Int Med 2004;164:2335- 2342.

DNA damage from micronutrient deficiencies is likely to be a major cause of cancer

Mutation Research 475 (2001) 7–20
Bruce N. Ames
University of California, Berkeley, CA 94720-3202, USA
Received 11 May 2000;
received in revised form 10 August 2000;
accepted 8 November 2000


A deficiency of any of the micronutrients: folic acid, Vitamin B12, Vitamin B6, niacin, Vitamin C, Vitamin E, iron, or zinc, mimics radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both. For example, the percentage of the US population that has a low intake (<50% of the RDA) for each of these eight micronutrients ranges from 2 to >20%.

A level of folate deficiency causing chromosome breaks was present in approximately 10% of the US population, and in a much higher percentage of the poor. Folate deficiency causes extensive incorporation of uracil into human DNA (4 million/cell), leading to chromosomal breaks. This mechanism is the likely cause of the increased colon cancer risk associated with low folate intake. Some evidence, and mechanistic considerations, suggest that Vitamin B12 (14% US elderly) and B6 (10% of US) deficiencies also cause high uracil and chromosome breaks.

Micronutrient deficiency may explain, in good part, why the quarter of the population that eats the fewest fruits and vegetables (five portions a day is advised) has about double the cancer rate for most types of cancer when compared to the quarter with the highest intake.

For example, 80% of American children and adolescents and 68% of adults do not eat five portions a day. Common micronutrient deficiencies are likely to damage DNA by the same mechanism as radiation and many chemicals, appear to be orders of magnitude more important, and should be compared for perspective. Remedying micronutrient deficiencies should lead to a major improvement in health and an increase in longevity at low cost.

1. Introduction
Approximately 40 micronutrients (the vitamins, essential minerals and other compounds required in small amounts for normal metabolism) are required in the human diet [1]. For each micronutrient, metabolic harmony requires an optimal intake (i.e. to give maximal life span); deficiency distorts metabolism in numerous and complicated ways many of which may lead to DNA damage.

The recommended dietary allowance (RDA) [2–4] of a micronutrient is mainly based on information on acute effects, because the optimum amount for long term health is generally not known. For many micronutrients, a sizable percentage of the population is deficient relative to the current RDA [5]. Remedying these deficiencies, which can be done at low cost, is likely to lead to a major improvement in health and an increase in longevity.

The optimum intake of a micronutrient can vary with age and genetic constitution, state of well being, and be influenced by other aspects of diet. Determining these optima, and remedying deficiencies, and in some cases excesses, will be a major public health project for the coming decades.

Long term health is also influenced by many other aspects of diet. Though this paper uses most examples from the US, the situation seems similar in many other countries. Micronutrient deficiency can mimic radiation (or chemicals) in damaging DNA by causing single-and double-strand breaks, or oxidative lesions, or both.

Chromosomal aberrations such as double strand breaks are a strong predictive factor for human cancer [6]. Those micronutrients whose deficiency mimics radiation are folic acid, B12, B6, niacin, C, E, iron, and zinc, with the laboratory evidence ranging from likely to compelling.

The percentage of the US population, for example, that is deficient (<50% of the RDA) for each of these eight micronutrients ranges from 2 to >20%, and may comprise in toto a considerable percentage of the US population (Table 1).

We have used <50% of the US RDA as a measure of low intake because these numbers are available [5]. However, the level of each micronutrient that minimizes DNA damage remains to be determined. Micronutrient deficiency is a plausible explanation for the strong epidemiological evidence that shows an association between low consumption of fruits and vegetables and cancer at most sites.

2. Dietary fruits and vegetables and cancer prevention
Greater consumption of fruits and vegetables is associated with a lower risk of degenerative diseases including cancer, cardiovascular disease, cataracts, and brain dysfunction [7].

More than 200 studies in the epidemiological literature have been reviewed and show, with great consistency, an association between low consumption of fruits and vegetables and the incidence of cancer [8–10]. The quarter of the population with the lowest dietary intake of fruits and vegetables has roughly twice the cancer rate for most types of cancer (lung, larynx, oral cavity, esophagus, stomach, colon and rectum, bladder, pancreas, cervix, and ovary [8] when compared to the quarter with the highest intake.

In a different survey, the lowest quartile of adults consumed 2.7 portions or less and the highest quartile 5.6 portions or more (Krebs–Smith, personal communication). These observations are consistent with data on the Seventh Day Adventists, who are non-smokers and mostly vegetarians, and have about half the cancer mortality rate and a longer life span, than the average American [11].

About 80% of American children and adolescents [12]: and 68% of adults [13] did not meet the intake recommended by the National Cancer Institute and the National Research Council: five servings of fruits and vegetables per day. Publicity about hundreds of minor hypothetical risks, such as that from pesticide residues in the diet [14], has contributed to a lack of perspective on disease prevention.

Half of Americans do not list fruit and vegetable consumption as a protective factor against cancer [15] and two-thirds think that for good health only two servings per day need to be consumed [16]. Fruit and vegetable consumption is lowest among the poor, for example, African-Americans in the US [13,17].

Many components of fruits and vegetables may be responsible for their protective effect; such as micronutrients, plant phenolics, and fiber. This paper argues that inadequate intake of many micronutrients, such as folic acid, Vitamin C and B6 contributes to DNA damage, cancer, and degenerative disease.

A major part of the protective effect of fruits and vegetables may be due to their micronutrient content. In addition, dietary deficiencies of micronutrients whose sources are not primarily fruits and vegetables, such as zinc, iron, niacin, Vitamin E, and Vitamin B12, also appear to contribute to DNA damage and are also common in the US population. Other micronutrients are likely to be added to this list in the coming years.

3. Folic acid
Folate deficiency, a common vitamin deficiency in people who eat few fruits and vegetables, causes chromosome breaks in human genes [18]. Approximately, 10% of the US population [19,20] are deficient at the level causing chromosome breaks in humans. In two small studies of low income (mainly African-American) elderly [21] and adolescents [22] done nearly 20 years ago about half had a folate deficiency at this level, though the issue should be reexamined.

(B.N. Ames / Mutation Research 475 (2001) 7–20 9, 10 / B.N. Ames / Mutation Research 475 (2001) 7–20)

The mechanism of chromosome breaks has now been shown to be deficient methylation of uracil to thymine, and subsequent incorporation of uracil into human DNA (4 million/cell) [18]. Uracil in DNA is excised by a repair glycosylase with the formation of a transient single-strand break in the DNA; two opposing single-strand breaks cause a double-strand chromosome break, which is difficult to repair. Both high DNA uracil levels and chromosome breaks in humans are reversed by folate administration [18]. Folate supplementation above the RDA minimized chromosome breakage in an Australian study [23].

Folate deficiency has been associated with increased risk of colon cancer [24,25], and the 15 year use of a multivitamin supplement containing folate lowered colon cancer risk by about 75% [26]. Folate and B12 deficiencies are associated with cognitive defects in humans [18] and neurotoxicity in children is caused by methotrexate, which lowers folate pools if folate is not replenished [27]. Chromosome breaks could contribute to the increased risk of cancer, and possibly cognitive defects, associated with folate deficiency in humans [18].

Folate deficiency causes increased homocysteine accumulation, which has been associated with neural tube defects in the fetus and an estimated 10% of US heart disease, both of which could be eliminated by folate supplements, food fortification, or better diets [28–34]. Homocysteine damages endothelial cells in culture and is a risk factor for arterial endothelial dysfunction in humans [35].

A polymorphism (a common, alternate, form of a gene) in the gene for methylene-tetrahydrofolate (THF) reductase, the enzyme responsible for reducing methylene-THF to methyl-THF, results in homozygotes having a decreased activity and a two-fold increase in plasma homocysteine.

Homozygotes, 5–25% of individuals depending on the ethnicity [36,37], have an increased risk of heart disease [31], stroke [29,38], and neural tube defects [37,39]. This polymorphism increases the methylene-THF pool at the expense of the methyl-THF pool, resulting in decreased DNA uracil levels and increased serum homocysteine.

The potential role in human carcinogenesis of uracil misincorporation is supported by two studies which show a two- to four-fold lower risk of colon cancer for individuals who are homozygous for the mutant alleles of methylene-THF reductase compared to controls [33,40]. Acute lymphocytic leukemia has been associated with the polymorphism which suggests folate deficiency as a major cause [41,42].

Folates were measured in seminal plasma from smokers and nonsmokers, and evaluated relationships between seminal plasma folates and both folate status and semen quality measures [43]. Total seminal plasma folate concentrations were higher than blood plasma folate. Total and 5-methyltetrahydrofolate concentrations correlated significantly with blood plasma folate and homocysteine concentrations. Seminal plasma non-methyltetrahydrofolates correlated significantly with sperm density and total sperm count suggesting importance for male reproductive function, and a likely mechanism of DNA damage as uracil incorporation into sperm DNA.

4. Vitamin B12
The main dietary source of B12 is meat. About 4% of the US population consumes below half of the RDA of Vitamin B12 [5]. About 14% of elderly Americans and about 24% of elderly Dutch have mild B12 deficiency, in part accountable by the Americans taking more vitamin supplements [44].

Vitamin B12 would be expected to cause chromosome breaks by the same mechanism as folate deficiency. Both B12 and methyl-THF are required for the methylation of homocysteine to methionine. If either folate or B12 is deficient, then homocysteine, a major risk factor for heart disease [29,30], accumulates.

When B12 is deficient, then tetrahydrofolate is trapped as methyl-THF; the methylene-THF pool, which is required for methylation of dUMP to dTMP, is consequently diminished. Therefore, B12 deficiency, like folate deficiency, should cause uracil to accumulate in DNA, and there is accumulating evidence for this (Ingersoll et al., unpublished; [45]). The two deficiencies may act synergistically.

In a study of healthy Australian elderly men [23], or young adults [46], increased chromosome breakage was associated with either low intakes of folate, or B12, or with elevated levels of homocysteine [47]. The B12 supplementation above the RDA was necessary to minimize chromosome breakage [46,47]. The B12 deficiency is known to cause neuropathy due to demyelination and loss of peripheral neurons (reviewed in [18]).

(B.N. Ames / Mutation Research 475 (2001) 7–20 11)

5. Vitamin B6
About 10% of the US population consumes less than half of the RDA (1.6 mg/day) of Vitamin B6 [5]. Vitamin B6 deficiency causes a decrease in the enzyme activity of serine hydroxymethyl transferase, the only source of the methylene group for methylene-THF [48]. If the methylene-THF pool is decreased in B6-deficiency, then uracil incorporation, with associated chromosome breaks, would be expected, and evidence for this has been found in women at a level of 32 nmol/l of Vitamin B6 in blood (0.5 mg/day intake) that were part of a previous intervention study ([49]; Ingersoll et al., unpublished).

In a case-control study of diet and cancer, Vitamin B6 intake was inversely associated with prostate cancer [50]. Vitamin B6 deficiency appears to contribute to heart disease and supplementation reduces risk [51]; levels above the RDA may be necessary to minimize risk [32].

A level of Vitamin B6 in blood below 23 nmol/l is a risk factor for stroke and atherosclerosis [52]. Diets low in Vitamin B6 are associated with brain dysfunction in children and adults [53]. Good sources of Vitamin B6 are whole grain bread and cereal, liver, bananas and green beans. A major source in the US is fortified breakfast cereal and multivitamins.

6. Vitamin C
About 15% of the population consumes less than half the RDA (60 mg/day) of ascorbate [5] which comes from dietary fruits and vegetables. The new RDAs for Vitamin C (90 mg/day for men, 75 mg/day for women and >35 mg for smokers) will make this percentage even higher.

There is a large literature on supplementation studies with Vitamin C in humans using biomarkers of oxidative damage to DNA, lipids (lipid oxidation releases mutagenic aldehydes), and protein. Though there are positive and negative studies, if the fact that the blood cell saturation occurs at about 100 mg/day [54,55] is taken into consideration, then the evidence suggests that this level minimizes DNA damage [56–59].

Cataracts appear to be due to oxidation of lens protein, and antioxidants, such as Vitamin C and E and carotenoids, appear to protect against cataracts and macular degeneration of the eye in rodents and humans [60–62]. The use of Vitamin C supplements for 10 years or more reduced lens opacities by about 80% [63].

Spontaneous oxidative damage in the DNA of an old rat is about 66,000 adducts per diploid cell [64,65], and unlike uracil misincorporation, is likely to be equally frequent on both strands. Glycosylase repair of oxidative adducts also results in transient single-strand breaks in DNA.

Therefore, increased oxidative damage from low Vitamin C intake, chronic inflammation, smoking, or radiation, together with elevated levels of uracil in DNA, would be expected to lead to more double-strand (chromosome) breaks in individuals who are deficient in both folate and antioxidants. There is some evidence for this synergy [66–68], which may be important because 10–15% of men in the US had serum ascorbate levels close to the scurvy threshold [5,69].

Some studies suggest that Vitamin C protects against cancer, which would be plausible based on the mechanistic data, though other studies show no effect, the variability of tissue saturation again is critical. A significant protective effect was observed for renal cancer in non-smokers, though not in smokers [70].

In a review of nutrition and pancreatic cancer, fruit and vegetable intake and Vitamin C were protective, though it is difficult to rule out that Vitamin C is a surrogate for some other compounds in fruits and vegetables [71].

Both experimental and epidemiological data suggest that Vitamin C protects against stomach cancer [72], a result that is plausible because of the role of oxidative damage from inflammation by Helicobacter pylori infection, which is the main risk factor for stomach cancer. The role of Vitamin C in inhibiting oral cancer has recently been reviewed [73].

Vitamin C improves endothelial dysfunction, an early stage of atherosclerosis, in heavy smokers [74]. Vitamin C supplementation was associated with a reduction in overall mortality and in cardiovascular disease in a follow up of the NHANES I study [75].

The effect of smoking on blood plasma antioxidant status was investigated by measuring ascorbic acid, a-tocopherol, g-tocopherol, b-carotene and lycopene and, subsequently, tested the effect of a 3-month dietary supplementation with a moderate dose vitamin cocktail [76]. Only ascorbic acid was significantly depleted by smoking per se (P < 0:01). Following the 3-month supplementation period, ascorbic acid was efficiently repleted in smokers (P < 0:001). Plasma a-tocopherol and the ratio of a- to g-tocopherol increased significantly in both supplemented groups (P <0:05).

(12 B.N. Ames / Mutation Research 475 (2001) 7–20)

The data suggests that previous reports of lower levels of plasma Vitamin E and carotenoids in smokers compared to non-smokers may primarily have been caused by differences in dietary habits between study groups. Plasma ascorbic acid is thus depleted by smoking and repleted by moderate supplementation.

Men with low consumption of antioxidants, or who smoke, oxidize the DNA of their sperm as well as their somatic DNA. When the level of dietary Vitamin C is insufficient to maintain seminal fluid Vitamin C, the oxidative lesions in sperm DNA are more than doubled [57,77]. Oxidative lesions in sperm DNA are higher in smokers than non-smokers [78].

Smoking is a severe oxidative stress, and the nitrogen oxides (NOx ) in cigarette smoke depletes antioxidants [76,79]. Thus, smokers must ingest much more Vitamin C than non-smokers to achieve the same level in

blood, but they rarely do. Inadequate Vitamin C levels are more common among the poor and smokers. Smokers also have more chromosomal abnormalities in their sperm than non-smokers [80].

Germ line mutations, and their associated cancer and genetic abnormalities, are predominately of paternal origin [81]. Smoking by fathers, therefore, may plausibly increase the risk of childhood cancer and birth defects, a thesis supported by epidemiological evidence [77,79].

The evidence on smoking fathers’ offspring having an increased rate of childhood cancer is becoming more persuasive [82–85]. A new epidemiological study from China makes the case stronger; acute lymphocytic leukemia, lymphoma, and brain cancer are each increased three- to four-fold in offspring of male smokers [82].

The studies on paternal smoking and childhood cancer did not examine the effect of diet. It seems likely, given the above evidence, that the cancer risk to offspring of male smokers would be higher when dietary antioxidant intake is low. Maternal use of multivitamins lowers the risk of childhood cancer in offspring [86].

In one study, the maternal use of vitamins throughout the pregnancy lowered the risk of brain tumors in the offspring by about half [87]. In a study of children with childhood cancer, serum levels of b-carotene, Vitamin E, and zinc were significantly lower than controls [88]. Thus, a multivitamin supplement (or a better diet) for both parents might markedly lower childhood cancer. In addition, several studies suggest an increased rate of birth defects in offspring of smoking fathers (reviewed in [77,79]).

Diets deficient in fruits and vegetables are commonly low in folate, antioxidants, (e.g. Vitamin C) and many other micronutrients, and it seems plausible that the higher cancer rates associated with consuming de- ficient diets are due, in good part, to increased DNA damage [8,18,89].

7. Vitamin E
Vitamin E, the major fat-soluble antioxidant, is consumed primarily from dietary vegetable oils and nuts. The RDA is 10 mg/day for men and 8 mg/day for women. About 20% of the population consumes less than half of the RDA [5]. Evidence is accumulating that the optimum intake may be higher, as discussed below.

Studies on Vitamin E supplementation have all been done with a-tocopherol, but g-tocopherol, the main form in the US diet, has a different function than a-tocopherol, and the two complement each other [90]. g-Tocopherol is a powerful nucleophile, and thus, traps electrophilic mutagens that reach the membrane.

In the soluble part of the cell, glutathione acts as both an antioxidant and a nucleophile. In the membrane, a-tocopherol is the antioxidant and g-tocopherol (or lycopene) can act as a nucleophile. An important electrophilic mutagen destroyed by g-tocopherol is NOx . g-Tocopherol reacts with NOx to form nitro-g-tocopherol, thus, protecting lipids, DNA, and protein [90–92]. g-Tocopherol is also an anti-inflammatory agent [93].

People taking Vitamin E supplements (200 IU/day) appear to lower their risk for colon cancer [94,95] and evidence suggests a marked protective effect of a supplement (50 IU/day) on prostate cancer [96,97]. Vitamin E appears to protect against brain dysfunction [98,99] and deficiency leads to various neuropathologies [100].

Vitamin E supplements (100–400 IU), also reduced the risk of coronary heart disease by about 40% [101–106] as well as mortality from all causes [103]. The role of oxidants and the protective role of antioxidants in heart disease have recently been reviewed [107,108]. Vitamin E is regenerated by Vitamin C.

In a study of a population with low levels of Vitamin C and E, (B.N. Ames / Mutation Research 475 (2001) 7–20 13) doses of Vitamin E from 70 to 560 IU lowered lipid peroxidation while a very high dose appeared to increase it [109] emphasizing that information on the toxic level, as well as the optimum level, of each micronutrient is desirable.

Both Vitamin E and selenium enhance the immune system in animals [110], and Vitamin E supplementation (200–400 units/day) enhances human immunity [111]. Vitamin E [112] or Vitamin C [113] reduced oxidative stress and malformations in offspring of diabetic rats.

8. Selenium
Selenium is important in enzymatic defenses against oxidants, and deficiency would be expected to lead to oxidative DNA damage [114]. An RDA of 70 mg/day of selenium and an upper limit of 350mg/day has been proposed [115]. The average intake in the US is about 100mg/day, though different areas of the country have different selenium levels in the soil, and the bioavailability depends on the selenium form in foods [114].

A growing body of evidence suggests that selenium plays an important role in the prevention of cancer in a variety of organs and species [116,117]. Prostate cancer incidence was reduced by two/thirds in the selenium supplemented group (200 mg/day) compared to the placebo group in a randomized, double-blind, cancer prevention trial; total cancer mortality, lung and colorectal cancer were also significantly reduced [118,119].

In a cohort study [120], men in the highest selenium quintile of intake had only 1/2 the odds ratio of prostate cancer as men in the lowest quintile. In a nested, case-control prospective study on ovarian cancer, serum selenium was associated with decreased risk [121].

In a study of post-menopausal breast cancer patients, a strong inverse relationship was observed between triiodothyronine (T3) levels and cancer (OR D 0:17; CI (95%/ D 0:08–0.36) between the highest and lowest tertiles [122]. Toenail selenium was positively associated with T3 levels in both cases and controls; the selenoenzyme iodothyronine deiodinase synthesizes T3. Prostate and breast cancer cells were about 25 times more sensitive than normal cells to selenomethionine, a major form of selenium in cells [123].

In a study of selenium intake and colorectal cancer that adjusted for possible confounders, the individuals in the lowest quartile of plasma selenium had four times the risk of colorectal adenomas compared to those in the highest quartile [124]. Selenium and glutathione peroxidase levels were found to be lowered in patients with uterine cervical carcinoma [125].

In a Chinese study, cervical cancer mortality was inversely associated with several factors, including serum selenium levels [126]. Selenoprotein-P level was inversely associated with several types of cancer [127]. Selenium deficiency causes human cells in culture to be more sensitive to two mutagens causing single strand breaks in DNA [128].

Several hypotheses have been proposed to explain the protection against carcinogenesis by supplemental selenium [114]. One of these is its protection against oxidative damage involving selenium as an essential component of the antioxidant enzyme glutathione peroxidase [129], or selenoprotein-P [130–132].

A recent review discusses the 11 selenoproteins and selenium’s role in preventing disease [133]. Excess selenium intake appears to cause oxidative damage and cancer in rodents [134]. The case for selenium supplementation is becoming stronger, though the toxicity of high selenium levels must be taken into account.

9. Niacin
The main dietary sources of niacin include meat and beans. About 2.3% of the US population consumes less than half the RDA of niacin [5]. Tryptophan from protein can also provide niacin equivalents [135]. About 15% of some populations have been reported to be severely deficient [136]. Niacin contributes to the repair of DNA-breaks by maintaining nicotinamide adenine dinucleotide levels for the poly-ADP ribose protective response to DNA damage [137–139]; deficiency compromises repair of DNA nicks and breaks, and thus, is expected to act synergistically with folate and antioxidant deficiencies in causing DNA damage and cancer [140].

10. Iron
A major dietary source of iron is meat. The United Nations Food and Agriculture Organization has estimated that the world has about two billion people 14 B.N. Ames / Mutation Research 475 (2001) 7–20 at risk for iron deficiency, mainly women and children. In the US, about 19% of women, aged 12–50, and about 7% of the population, ingest below 50% of the RDA [5]; about nine million people have been estimated to be clinically deficient [141].

Iron deficiency, or iron excess, leads to oxidative DNA damage [142,143]. Iron deficiency in children is associated with cognitive dysfunction [144,145]. Low iron intake results in anemia, immune dysfunction, and adverse pregnancy outcomes such as prematurity [145]. Excess iron appears to also lead to oxidative DNA damage in rats that is reversed by Vitamin E [146]. Increased risk of human cancer [145,147] and possibly heart disease [148–150] is associated with excess iron.

11. Zinc
Major sources of zinc are meat, eggs, nuts, and whole grains. Zinc deficiency causes a variety of health effects which have been reviewed in depth [151]. About 18% of the US population consumes less than half the RDA for zinc (12 mg women, 15 mg men) [5]. Mean daily intakes reported for poor children (5 mg), middle income children (6.3 mg) and vegetarians (6.4 mg) in the US appear insufficient [151].

Zinc is a component of over 300 proteins, over 100 DNA-binding proteins with zinc fingers, Cu/Zn superoxide dismutase, the estrogen receptor, and synaptic transmission protein [151]. Functioning of p53, a zinc protein which is mutated in half of human tumors, is disrupted on loss of zinc [152]. Mutation is being prevented by p53, which inhibits cell division and induces apoptosis in response to DNA lesions [153].

Chromosome breaks in rats have been reported with a zinc deficient diet [154]. The offspring of zinc deficient rhesus monkeys also have increased chromosome breaks [155]. The chromosome breaks might be due to increased oxidative damage [155,156], perhaps due to loss of activity of Cu/Zn superoxide dismutase or the zinc-containing DNA-repair enzyme, Fapy glycosylase, which repairs oxidized guanine [157].

Zinc deficiency has been suggested as a contributor to esophageal cancer in humans, and has been shown to cause esophageal tumors in rats in conjunction with a single low dose of a nitrosamine [158–160]. Severe zinc deficiency by itself can cause esophageal tumors in rats [160].

Zinc is known to be an essential trace element for testicular development and spermatogenesis [161]. Zinc concentrations in seminal plasma are hundreds of times greater than that in blood plasma, which suggests a specific function for this trace element in spermatogenesis and stability of spermatozoa [151].

Zinc concentrations are correlated positively with sperm cell density, and lower zinc concentrations are found in infertile men compared with fertile men [162]. Zinc deficiency leads to increased oxidative damage to testicular cell DNA (as measured by oxo8dG) and increased protein carbonyl content [163].

A considerable literature in experimental animals and humans suggests that zinc deficiency slows growth and development of the neonate. Severe deficiency in animals is teratogenic [155].

In a pair-matched, double-blind, study in Chile of preschool boys of low socio-economic status, those supplemented with 10 mg zinc/day grew significantly more rapidly than the placebo group [164]. This is consistent with earlier reports in the US and other countries on growth stimulation of poor children supplemented with zinc [151].

Zinc deficiency leads to alterations in brain development and growth [144]. Zinc deficiency in pregnant rats, at a level that does not impair the pregnancy or the growth of the pups, impairs cognitive function in adult offspring [151]. Zinc deficiency in adult rats impairs hippocampal and behavioral functions [151].

Several studies on monkeys show that maternal zinc deficiency leads to learning and behavioral disabilities in offspring [151]. Six studies in humans suggest that zinc deficiency leads to cognitive defects [151]. Several animal and human studies indicate that mild zinc deficiency impairs the immune system [151,165].

The incidence of respiratory infections in a group of institutionalized elderly was decreased by over two-fold (P _ 0:01) when they were given a supplement of zinc (20 mg) plus selenium (100 mg) in a double-blind placebo study; in other studies very high doses of zinc (100–150 mg/day) had an adverse effect on the immune system [166].

12. Conclusion
Optimizing micronutrient intake (through better diets, fortification of foods, or multivitamin-mineral pills [167]) can have a major impact on public health at low cost. (B.N. Ames / Mutation Research 475 (2001) 7–20 15) Other micronutrients are likely to be added to the list of those whose deficiency causes DNA damage in the coming years. Tuning-up human metabolism, which varies with genetic constitution and changes with age, is likely to be a major way to minimize DNA damage, improve health and prolong healthy lifespan.

This work was supported by National Foundation for Cancer Research Grant M2661, National Institutes of Health Grant AG17140, US. Department of Energy Grant DE-FG03-00ER62943, Tobacco-Related Disease Research Program Grant 7RT-0178, Wheeler Fund for the Biological Sciences at the University of California Berkeley, the Ellison Medical Foundation Grant SS-042-99 and National Institute of Environmental Health Sciences Center Grant ESO1896.



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This paper was adapted, in part, from the work by B.N. Ames [168] and [169].
Present address: Children’s Hosp ORI, 5700 M.L.K. Way Jr., Oakland, CA 94609, USA. Tel.: C1-510-450-7625; fax: C1-510-597-7128.
E-mail address: bnames(at) (B.N. Ames).
0027-5107/01/ – see front matter © 2001 Elsevier Science B.V. PII: S0027-5107(01)00070-7 8 B.N. Ames / Mutation Research 475 (2001) 7–20 © 2001 Elsevier Science B.V. All rights reserved.

Nutrient Research References

A collection of good nutrient references from before 1999.

Links to the different categories:

Minerals in general, Research references

January 1999

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Joseph E. Pizzorno Jr., Michael T. Murrey & Melvyn R. Werbach.

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Joseph E. Pizzorno Jr., Michael T. Murrey & Melvyn R. Werbach.

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January 1999

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Joseph E. Pizzorno Jr., Michael T. Murrey & Melvyn R. Werbach.