March 20, 2005
Antioxidant Supplements Helpful Or Harmful?

Many studies have been published with conflicting and confusing results on whether long term use of assorted antioxidants is beneficial or detrimental to human health. In the latest chapter in the search for antioxidant regimens that might slow the rate of aging vitamin E supplementation has been found to raise the risk of heart failure for a coronary high risk group of older people.

Eva Lonn, M.D., of the Population Health Research Institute and McMaster University, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada, and colleagues conducted a study to evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. The randomized, double-blind, placebo-controlled trial ( Heart Outcomes Prevention Evaluation [HOPE] ) was initially conducted between December 21, 1993, and April 15, 1999, and included patients at least 55 years old with vascular disease or diabetes mellitus. This trial was extended ( HOPE-The Ongoing Outcomes [HOPE-TOO] ) to between April 16, 1999, and May 26, 2003.

...

The researchers found: "In the HOPE and HOPE-TOO trials, the daily administration of 400 IU of natural source vitamin E for a median of 7.0 years had no clear impact on fatal and nonfatal cancers, major cardiovascular events, or deaths. We observed an increase in the risk of heart failure, which is of concern. Although this adverse effect of vitamin E was unexpected and cannot be confirmed at this time by other trials, our data are internally consistent. Therefore, a meta-analysis of heart failure events including all completed large vitamin E trials is strongly recommended."

Sounds either neutral or bad for vitamin E supplementation, right? Well, this study got a lot of (mostly negative) press. However, there still tons of studies that show benefits from vitamin supplementation. Also it is very likely that there is an optimal level of dosage of vitamin E which might be lower than the 400 IU of alpha tocopherol used in this trial. For example,

Simin Nikbin Meydani of Tufts University in Boston says that lower doses of vitamin E might offer health benefits without adding risks. In her tests ... older people developed fewer respiratory infections while taking half the amount of the vitamin E they received in Lonn's study.

She notes that many of the people in the new study were on medication for heart disease. "Maybe vitamin E increases degradation of some of the drugs these people take," she suggests.

Also, from a dim faded old memory of mine I recall a study on vitamin E and old folks which found that smaller amounts of vitamin E boosted immune response whereas larger doses decreased immune response. This is not surprising. Antioxidants quench free radicals. Some free radicals are harmful and so quenching them is good. But the body also uses free radicals for intercellular and intracellular communication. Quenching those free radicals will prevent needed signals from getting through and that is certainly going to be harmful. Denman Harman MD, the guy who first proposed the free radical theory of aging way back in 1954, said in an interview (sorry, I can no longer find it on the web) that excess antioxidant supplementation will make one feel mentally and physically sluggish and that he discovered this effect on himself many years ago.

One unanswered question about antioxidant supplementation is what is the optimal dose for each antioxidant that would do more quenching of bad free radicals than it did of good free radicals? Another important question is at what absolute doses and ratios of doses of antioxidants do the antioxidants become oxidants? You see, many antioxidants neutralize free radicals by becoming free radicals themselves. Then other antioxidants quench those radicals to turn them back into antioxidants once again. In theory one could have, for example, so much vitamin E in one's body that other compounds (e.g. vitamin C) will be comparatively too rare in the body to recycle vitamin E back into its antioxidant state. So balance between antioxidants is probably very important. Does supplementation with just vitamin E upset some balance? Is one better off eating foods that have lots of different vitamins and other antioxidant compounds rather than take supplements? I wish I knew exact and detailed answers to alll these questions.

While the HOPE and HOPE-TOO trials on vitamin E, heart disease, and cancer were getting a lot of press a potentially more important study on antioxidants, genetics, and cancer risk attracted very little attention. But, hey, lucky you read me! So now pay close attention to a report with important implications for nutrigenomics. Whether selenium, vitamin E, and lycopene lower the risk of aggressive prostate cancer may depend on which genetic variation you have for the antioxidant enzyme manganese superoxide dismutatase (MnSOD).

PHILADELPHIA Greater levels of selenium, vitamin E and the tomato nutrient lycopene have been shown to reduce prostate cancer in one out of every four Caucasian males -- those who inherit a specific genetic variation that's particularly sensitive to oxidative stress.

Conversely, if carriers of this genetic variant have low levels of these vitamins and minerals, their risk of aggressive prostate increases substantially, as great as 10-fold, over their cohorts who maintain higher levels of these nutrients.

These results, published in the March 15 issue of the journal Cancer Research, were based on the analysis of 567 men diagnosed with prostate cancer between 1982 and 1995, and 764 cancer-free men from the Physicians Health Study (PHS).

"This large prospective study provides further evidence that oxidative stress may be one of the important mechanisms for prostate cancer development and progression, and adequate intake of antioxidants, such as selenium, lycopene and vitamin E, may help prevent prostate cancer," said Haojie Li, M.D., Ph.D., a researcher at the Brigham and Women's Hospital and Harvard Medical School.

Destructive molecules known as "free radicals" have been shown to team up with oxygen in the human body resulting in oxidative stress and what some scientists believe is an assortment of age-related ailments. As a result, many believe that consumption of antioxidants can slow that process.

"Our study, as well as many other epidemiological studies, encourages dietary intake of nutrients such as lycopene from tomato products, or supplements for vitamin E and selenium to reduce risk of prostate cancer," said Li.

The initial goal of the PHS study was to assess the effect of aspirin and beta carotene on men's health. Since blood samples collected in 1982 were available from many of the study's participants, the research team decided to review variants for the gene that codes for manganese superoxide dismutatase (MnSOD), an important enzyme that works as an antioxidant in human cells to defend against disease. The MnSOD gene is passed from parents to offspring in one of three forms: VV, VA or AA.

"Compared with men with the MnSOD VV or VA genotype, people with the AA genotype seem to be more sensitive to the antioxidant status," said Li. "Men with the AA genotype are more susceptible to prostate cancer if their antioxidant levels are low."

People with the AA genotype for MnSOD will derive more benefit from antioxdant supplementation than those with other MnSOD phenotypes.

The study's results found that a quarter of the men in the study carried the MnSOD AA genotype, half carried the VA genotype, and the remaining quarter carried the VV genotype.

The results indicated that the VA and VV men were at equivalent risk for developing prostate cancer across all levels of antioxidants in their blood. Compared to MnSOD VV or VA carriers with low selenium those men in the lowest quartile of the study group MnSOD AA males had an 89 percent greater risk for developing aggressive prostate cancer if blood levels for selenium were low.

On the other hand, MnSOD AA carriers with high selenium those men in the highest quartile had a 65 percent lower risk than the MnSOD VV or VA males who maintained low levels of selenium.

"The levels of selenium in the highest quartile of these men are not abnormally high," Li said. "Our range is neither extremely high nor extremely low."

While similar trends were observed for lycopene and vitamin E when tested independently, the contrast in relative risk was most pronounced for the men who had high blood levels for all three antioxidants combined.

"Among men with the MnSOD AA genotype, we observed a 10-fold difference in risk for aggressive prostate cancer, when comparing men with high versus low levels of antioxidants combined," said Li. "In contrast, among men with the VV or VA genotype, the prostate cancer risk was only weakly altered by these antioxidant levels."

Similar interactions between dietary antioxidants and the variations in the MnSOD gene have previously been linked to risk for breast cancer.

So should you take vitamin E and selenium and eat lots of tomato products to get the lycopene? The answer probably depends on your genes. Here is a demonstration that nutrigenomics (the use of genetic information to customize diets) clearly is going to become very beneficial. Some people may derive a net harm from vitamin E supplementation whereas others may derive a net benefit. Big studies like the HOPE-TOO trial that do not examine genetic differences between study participants are going to miss the existence of genetic subgroups that are experiencing even greater harm or greater benefit than what appears to be the case when all the study participants are looked at as a single aggregate.

We need advances in gene sequencing technologies that drive down costs by orders of magnitude so that personal DNA sequencing becomes a reality. With detailed knowledge of all our genetic variations we can choose much more optimal custom diets and supplement regimens.

Share |      Randall Parker, 2005 March 20 07:27 PM  Aging Diet Studies


Comments
Robert Silvetz said at March 20, 2005 8:24 PM:

I sit here always in amazement at what is considered an intelligent clinical trial by the powers that be.

RP's point on antioxidants acting in unison and recycling needs to be underscored and enhanced.

Unless one is supplementing the full electron cascade and it's resulting oxidative stress with the FULL RANGE of antioxidants, all you get is a pileup of radicals at the step involving the antioxidant in shortest quantity. So piling on Vitamin E (and measuring heart status no less!) without increasing, taurine, n-acetyl-cysteine, TMG, CoQ10(!!!), alpha-lipoic acid, Vit C, Vit A, and probably some sundry group of trace minerals is doomed to give exactly the results indicated. Assuming non-megadoses, the kidneys and cells will discard excess. So figuring out "optimal" dosing might be a moot issue. Oh and by the way, the so-called expensive urine that doctors like to criticize so much, is almost certainly protective against renal and bladder cancer.

Also, free radicals in the intercellular space are all alarm signals, (possible exception of NO), typically degrading protein or lipids rather quickly. Peroxidized lipids are, amongst other things, toxic to all cells but even more preferentially toxic to cancer cells. Which is another mechanism by which excersize keeps you healthy. Intracellularly, free radicals beyond a certain level trigger apoptosis, and beyond that at higher levels, cell death necrosis style.

Jim said at March 21, 2005 5:39 PM:

Could you recommend a good primer or better yet, provide a brief description of the mechanism of free radicals and antioxidants for the lay person?

It seems that free-radicals are negatively-charged or oxidizing compounds in the body, and that antioxidants are essentially buffers that neutralize these compounds?

Are free-radicals the result of improper 'burning' of cellular fuel similar to a combustion engine running with the wrong air/fuel mix?

And the implication is that if one understood the exact operating mechanism for a given set of genes, then an optimum mix of anti-oxidants could be recommended to minimize the damage?

Thanks.

Invisible Scientist said at March 22, 2005 2:13 AM:

Antioxidants also seem to boost the mental functions.
I have experimented with all the food supplements mentioned in Dr Ray Sahelian's book, "Mind Boosters".
Alpha Lipoic Acid and Acetyl L-Carnitine definitely give mental energy.

That book is strongly recommended. But the fish oil that contains omega acids, may also contain
heavy metals and other pollutants, and so be careful with that.

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