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dondigitalia

Anti-free radical enzymes

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On the Science Channel, I remember seeing a report on an enzyme which is has been shown to be very effective at combatting free radicals in other life-forms (perhaps mice or rats - it's been a while), almost doubling their life span. As far as the report indicated, no human studies were in process. What do you know about this research?

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Dear dondigitalia,

When your question was posted, I did not know which specific enzyme or species you had in mind. Concerning life span, superoxide dismutase is the most extensively studied antioxidative enzyme, and it has absolutely no beneficial effect on the life spans of mice. Its effects in simpler life forms are hotly contested, because different groups of researchers have obtained contrasting results. However, on May 5, Science magazine released an article by Samuel Schriner et al., entitled "Overexpression of mitochondrial-targeted catalase extends murine life span." This article demonstrates extension of the life span of mice when a different antioxidative enzyme is directed to a site where many free radicals are produced within the cell. The article is not yet available in print, but subscribers to Science can gain access to the electronic version at www.sciencemag.org and nonsubscribers can read the Abstract (summary paragraph) by performing a search for this title at http://www.ncbi.nlm.nih.gov/entrez/

Concerning human studies, I have heard that pills allegedly containing superoxide dismutase have been available for sale for many years. I do not recommend these pills, because I do not believe that increasing the supply of this enzyme would extend the human life span. Even if the intact enzyme was effective, enzymes are a class of proteins, which must be folded correctly in order to function, and the digestive system degrades proteins into hundreds of constituent pieces before they can be absorbed by the body. In other words, digestion would destroy the enzyme, and the pieces which were absorbed would then be used by the body to produce whatever proteins or other molecules it needed, resulting in zero increase in superoxide dismutase activity. Despite public claims by some manufacturers to have overcome this problem, one of my colleagues was unable to obtain any supporting evidence from her communications with the people making these claims.

There are also other antioxidants available for sale: vitamins E and C, coenzyme Q and beta-carotene are probably the most well-known. My colleagues and other scientists have shown that these smaller ("low molecular weight") antioxidant molecules can be absorbed through the digestive system, but that their effects are very limited in mice and rats. I should also mention that the motivation for some of these experiments was to look for harmful effects, not just beneficial ones. I personally avoid taking vitamin supplements containing vitamin C and iron in combination, because they can generate free radicals so copiously that they are used as a tool for that purpose in the laboratory. Furthermore, large-scale studies of human supplementation with low molecular weight antioxidants have generally failed to show any beneficial effect on mortality rates, and some of the studies have shown adverse effects.

My own studies of antioxidants, using fruit flies, have yielded consistently negative results, i.e. there is no increase in life span resulting from increased levels of antioxidative enzymes, and no higher levels of antioxidants in longer-lived versus shorter-lived animal strains (types). Several other scientists have reached opposite conclusions based on their own data, and each of us has expressed reservations, in print, about the experimental design used by the opposing groups.

Notwithstanding the controversies surrounding antioxidant supplementation, I still suspect that the free radical hypothesis of aging is correct, and I believe that it is supported by stronger circumstantial evidence than the alternative theories of aging. The reasons for my position are complex, and my intention is to write a separate message (as a follow-up response under the "Anti-free radical enzymes" heading) to explain the theory and my interpretation of the results in detail. I will try to start from the beginning, so that the explanation will be accessible to all readers of The Forum, but that message is likely to be fairly long, and I hesitate to predict when it will be posted (likely more than four weeks from now).

Sincerely,

Robin RJM

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Thank you, Dr. RJM, for your extremely informative response! I'm greatly looking forward to your more next message. I had no idea that a combination of C vitamins and iron caused an increase in free radicals. I'll have to check my own supplement when I get home tonight. Is that combination conducive to free radicals only in a vitamin supplement, or can food sources have the same effects? I'm a big fan of both citrus and beef, so maybe I'm doomed no matter what!

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Dear dondigitalia,

I share your enthusiasm for citrus - and beef on occasion, in moderate amounts. The main concern with vitamin C is that it can promote free radical reactions to a dangerous degree in the presence of high body stores of iron. This problem may be particularly severe for patients undergoing repeated blood transfusions for certain diseases, but it is an issue for about 10% of the total U.S. population. Thus, it is advisable to learn one's iron status before consuming large amounts of vitamin C and iron as supplements, and it might be worthwhile for many people, most often men, to donate blood in order to get rid of excess iron. I should note that completely different advice would be appropriate for people with iron deficiency, most often premenopausal women, and that vitamin C deficiency must also be avoided.

Concerning supplements versus dietary iron and vitamin C, I will quote from Victor Herbert, "The antioxidant supplement myth" (American Journal of Clinical Nutrition, Vol. 60, pp. 157-158, 1994):

"The answer to the question "If I drink orange juice for vitamin C, why not take a vitamin C pill for the same effect?" is that the effect is entirely different." [RM: emphasis in original.]

His argument is that the vitamin supplements in pills are "unbalanced biochemistry" because they are present only in the reduced form, which is normally antioxidative but which is precisely the form that facilitates free radical generation by iron. I think the phrase "entirely different" is too strong, even though the distinction between food and pills is justified. If the vitamin C in food is only partly in the reduced form, and is not as highly concentrated in proximity to high concentrations of iron as it would be in a pill, that should diminish the effect but not make it entirely different.

With all of that as background, my position is actually quite simple: the best way for most people to avoid either a deficiency or overload/overdose of iron or vitamin C is to get these nutrients from food rather than pills; however, some people should be taking pills to correct deficiencies, some should be avoiding pills and maybe donating blood to avoid an overload, and only your doctor can do the blood test and give you advice about your own individual circumstances.

Two closing thoughts: (1) most people don't need to panic about this, and (2) even though the optimum ranges of intake are quite broad, so one is trying to hit the dart board rather than the bull's eye, it is still the case that you need vitamin C, you need iron, and they and many of life's other necessities (like food and air) are contributing to free radical reactions which possibly cause the aging process.

A further sampling of references on this topic, albeit far from a complete list:

Jerome L. Sullivan, "Iron and the sex difference in heart disease risk" The Lancet, June 13, 1981, pp. 1293-1294.

Clement A. Finch et al., "Effect of blood donation on iron stores as evaluated by serum ferritin" Blood Vol. 50, pp. 441-447, 1977.

Sincerely,

RJM

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Dr. RJM,

I am concerned about what kinds of damage the free radicals released by an iron + C reaction might do. Can you be more specific? Are we talking about random cell death thoughout the body?

The reason I ask is that I suffer from IBD, and my digestive system is extremely sensitive. Would the C and Iron reaction take place in the stomach (localized), or would it be more something that occurs in the blood over my entire system?

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On May 16 (post # 2 on this topic), I stated my intention to post a long follow-up message, some time in the future, explaining the free radical hypothesis of aging and my interpretation of the evidence, "from the beginning". However, other questions prompted me to provide much of my interpretation - effectively, "Part II" of the follow-up message - in a separate post (#9 on the topic of "Stopping Aging", May 18). Here, my purpose is to provide "Part I": some basic definitions and explanation of the free radical hypothesis, which are also needed to provide context for my answers to the questions posed by tgrundon (next post).

Definitions: First, the molecules which make up the cells in our bodies are formed by bonding between atoms. These bonds consist of pairs of electrons. A "free radical" is a molecule with an unpaired electron. Generally, molecules are more stable when their electrons are paired, so free radicals tend to react with other molecules by extracting an electron. Rather than resolving the chemical instability, such reactions shift it to the next molecule, which is then more likely to react with a third molecule, and so on. In other words, free radical reactions are propagated, i.e. chain reactions occur. Some of the molecules from which electrons are extracted become broken into pieces as a result, while others become attached to each other and/or to the remains of the original free radicals. The unsaturated fatty acids in cell membranes are an important example of molecules which become fragmented, while DNA (the stuff of genes, required for the cell to make proteins) may be fragmented or attached to the debris resulting from the breakage of fatty acids. Free radical reactions may also change the shape of proteins or cause them to become attached to each other or to the remnants of sugars or fatty acids. The free radical hypothesis posits that these kinds of reactions are the cause of aging.

In order to understand this hypothesis and the associated literature more thoroughly, several additional terms must be defined. For instance, "reactive oxygen species" (ROS) are either (1) free radicals in which an oxygen atom 'carries' the unpaired electron, or (2) non-free radical molecules containing high-energy oxygen atoms which are reactants or products of free radical reactions. "Reactive nitrogen species" (RNS) may be defined similarly, substituting "nitrogen" for "oxygen".

Some ROS and RNS are not free radicals. Conversely, some free radicals are neither ROS nor RNS, because the atom with the unpaired electron is not oxygen or nitrogen. A broader concept, encompassing free radicals, ROS, RNS and some other damaging agents, is "oxidant".

An atom or molecule which pulls electrons away from other molecules is an "oxidant", or "oxidizing agent". A "reductant" or "reducing agent" has the opposite effect: it tends to supply or donate electrons. An "antioxidant" neutralizes an oxidant (or "pro-oxidant") before it can react with a target molecule. Often, this is achieved by antioxidants acting as reducing agents, donating electrons in order to neutralize an oxidant. The antioxidant itself becomes oxidized in the process of sparing other target molecules, but it can be regenerated or replaced through an investment of cellular energy, usually with less risk of structural damage to the cell than was posed by the original oxidant. However, "antioxidant" and "reductant" are not equivalent terms. The antioxidant enzyme, superoxide dismutase, is an "oxidoreductase": it oxidizes one free radical and reduces another, generating two non-free radical products, one of which is an ROS. Catalase, also an antioxidant and oxidoreductase, converts two non-free radical ROS to non-ROS products.

"Oxidative stress" denotes an 'imbalance' between oxidants and antioxidants, which results in incomplete protection of the target molecules by antioxidants. Cells are always under some oxidative stress, because some oxidants react very rapidly with target molecules in their immediate vicinity, and some of these reactions occur at sites inaccessible to the bulkier antioxidants. The resulting structural changes in target molecules are referred to collectively as "oxidative damage". Some of it has no functional effect, but some of it results in inactivation, degradation, or aggregation of the target molecules. Oxidative damage can compromise the cell's ability to function, either because important structural or functional components are lost more quickly than they can be repaired or replaced, because the processes of repair and replacement divert too much energy from other activities, or because the by-products simply occupy too much space and cannot be removed.

The "oxidative stress hypothesis" posits that these oxidizing reactions, largely initiated by free radicals or ROS/RNS, are the cause of aging. The phrases "free radical hypothesis" and "oxidative stress hypothesis" are often used interchangeably. Technically, this is not correct, because not all of the oxidative damage is caused by free radicals. However, the reactions and their consequences are mostly the same in both cases.

I hope the terminology in this post is not too tedious. In future messages, I will use it without definition, and will encourage readers to use this post as a reference, as needed.

Sincerely,

RJM

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Thanks again, Dr. RJM, for an extremely interesting post. It's really facinating to learn about all of the little things that go on in our bodies that we are unaware of. It's even more amazing that our scientists have been able to discover that it's happening!

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Dear tgrundon,

In the interests of clarity, which is important here, I should start by saying that the best advice regarding intake of iron and vitamin C appears to be different for sufferers of IBD (inflammatory bowel disease) than for people with no diagnosed medical condition. Consequently, the first part of my answer is intended for a general audience, i.e. most readers of THE FORUM, and the second part is for you and any other readers who share the same specific interest in IBD.

General audience:

There are three likely responses of cells to oxidative stress, which depend upon the severity of the stress. Low-level stress triggers defense and repair processes, enabling the cell to survive (not necessarily unscathed). Higher levels of stress can leave the cell 'critically wounded', triggering apoptosis - programmed cell death. Effectively, the cell commits 'suicide' because the damage is irreparable and its continued existence would do more harm than good to the organism as a whole. Such harm could range from the cell occupying space in a tissue while no longer functioning correctly through to dividing and spreading out of control, i.e. posing a risk of cancer. Apoptosis prevents this risk from arising. The highest levels of oxidative stress cause necrosis - killing the cell directly, rather than triggering its self-destruction.

Under normal conditions, the oxidative stress associated with aging or with free radical production by iron plus vitamin C would be of the first type: it would likely cause random cell damage throughout the body, rather than widespread cell death. However, in the case of iron overload due to transfusion therapy (patients with thalassemia or sickle cell disease), cell death does become an issue, because treatment with vitamin C without simultaneous chelation therapy can mobilize so much iron that death of the patient from heart failure results within hours (V. Herbert et al., Stem Cells, Vol. 12, pp. 289-303, 1994). Vitamin C supplements should also be avoided in hereditary haemochromatosis patients, who have iron overload due to increased absorption from the digestive system (J. K. Limdi and J. R. Crampton, Q J Med., Vol. 97, pp. 315-324, 2004).

Both vitamin C and iron are absorbed, so the reactions are not localized to the digestive system.

The specific reaction catalysed (allowed to occur more quickly and easily) by iron and vitamin C is the Haber-Weiss reaction: the conversion of superoxide anion plus hydrogen peroxide (both moderately reactive ROS; see post #6 on this topic for definitions) to the extremely reactive hydroxyl free radical (plus hydroxide and oxygen). The hydroxyl radical is the one thought to cause most of the molecular damage I outlined in post #6.

Inflammatory Bowel Disease:

I had no particular knowledge about IBD before reading your question, and I start with that statement to underscore the fact that advice on specific medical questions should come from your doctor (I am not a medical doctor). With that said, I will add that I did a bit of literature research and came up with the following information:

1. From The Bantam Medical Dictionary, IBD is "any of a group of inflammatory conditions of the intestine that include (among others) ulcerative colitis and Crohn's disease."

2. From "Altered plasma and mucosal concentrations of trace elements and antioxidants in active ulcerative colitis" (G. C. Sturniolo et al., Scandinavian Journal of Gastroenterology, Vol. 33, Issue 6, pp. 644-649, June 1998), "The production of free radicals is increased in inflammatory bowel disease, and trace elements are crucial components of several antioxidants. Trace elements deficiency may therefore compromise the defense against oxidative damage. ... Patients with ulcerative colitis have altered plasma and tissue levels of trace elements and antioxidant-related enzymes. The resulting reduced protection against free radicals may contribute to the inflammatory process."

3. From A. Tsitsika et al. (Journal of Pediatric Hematology/Oncology, Vol. 27, Issue 2, pp. 93-96, Feb 2005), "Iron deficiency anemia (IDA) and anemia of chronic disease (CDA) are often encountered in patients with inflammatory bowel disease (IBD). Inadequate intake or loss of iron is a clear cause of IDA, ..."

4. From D. N. Seril et al. (Digestive Diseases and Sciences, Vol. 50, Issue 4, pp. 696-707, April 2005), " Ulcerative colitis (UC) patients frequently require iron supplementation to remedy anemia. ... These results [in mice] suggest that iron supplemented systemically could be used to remedy anemia in UC patients without exacerbating inflammation or enhancing colon cancer risk. These findings need to be verified in clinical studies."

5. I also found an entire issue of the journal Alimentary Pharmacology and Therapeutics (Vol. 20, Issue s4, pp. 1-110, October 2004) devoted to IBD, and read one article (M. A. Gassull, pp. 79-83), which I can recommend: "Review article: the role of nutrition in the treatment of inflammatory bowel disease". A relevant quotation is "...administration of vitamins E and C for 4 weeks in mild to moderate cases of Crohn's disease induces a significant reduction in oxidative stress...".

My impression from this reading is that levels of iron and vitamin C are too LOW in IBD patients, but that injection rather than supplementation may be the best way to get iron where it is needed. The effects of diet on the progression or remission of IBD are not yet fully known, but they are complicated, involving many nutrients other than iron and vitamin C.

Sincerely,

RJM

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