A recent review by published by Cochrane indicates, like earlier reports, that antioxidants are not the solution to increased longevity or disease prevention. Such supplements may not only be ineffective (as most reviews indicate), but potentially harmful (though more research is certainly needed, as the authors point out). That being said, the review is open to legitimate criticism, but gives an interesting and important statistical overview of increasingly predictable population-wide effects. One important feature of the review is that they the authors are analyzing data on the effects of antioxidant supplementation on otherwise healthy individuals (i.e. not for use in the treatment of a pre-existing disease or condition) - a widespread practice across this and other forums.

Here's LEF's rebuttal.


Vitamin Studies: Rebuttal to Allegation That Certain Vitamins May Shorten Lifespan
It is almost inconceivable to think that for the greater part of the 20th century, a “scientific” debate raged as to whether cigarette smoking was dangerous. An even longer running controversy focused on whether food choices (i.e. diet) had any effect on how long people lived. It was not until the later part of the 20th century that the FDA admitted that high saturated fat diets increase heart attack risk.

Today’s unanimous recommendation to eat lots of fresh fruits and vegetables is a relatively recent phenomenon. Back 50 years ago when mid-life heart attack rates were nearly triple what they are now, it was not unusual for people (especially men) to eat virtually no fruits or vegetables. Even now, the processed food industry heavily lobbies government agencies to not recommend disease-preventing foods to the public.

Just as companies that profited by selling cigarettes and processed foods egregiously misled the public in the past, today’s consumers are confronted with so-called “scientific” reports that question the value of some dietary supplements.

A report released on April 16, 2008 went as far as to suggest that certain vitamins might shorten lifespan. All of this is reminiscent of the scientific charade perpetrated by tobacco companies who falsely claimed that cigarettes did not cause lethal disease. In this case, the economic beneficiaries will be pharmaceutical companies who can expect increased sales of prescription drugs to those who fall for the latest media hype.

As the Life Extension Foundation has done for the past 28 years, we will succinctly separate the facts from the fiction so our members can draw a rationale conclusion about this latest hoax.

Outlandishly low and high potencies evaluated
As has been the case of previous studies conducted by mainstream doctors, the potencies of the nutrients evaluated in this negative report are far different than what knowledgeable health conscious consumers take on a daily basis.

This report condemning supplements claimed that vitamin A caused a 16% increased risk of dying. The vitamin A potencies given to study subjects ranged from 1,333 IU to 200,000 IU a day, or taken every other day, or in one case, ingested just once! Yes, a trial used to vilify this nutrient gave the participants one dose of vitamin A. When these nursing home subjects did not show greater survival benefits, the authors of this negative report blamed the single dose of vitamin A for the deaths.

We don’t know of anyone who actually takes their vitamin A in these kinds of doses, but these were the very studies used to assassinate vitamin A.

This negative report also claimed a 4% increased risk of dying in those who took vitamin E. One might speculate that the failure to supplement with gamma tocopherol may have caused this mortality increase (we discuss more about this later).

The stark reality is that the potencies of alpha tocopherol vitamin E evaluated in the negative report ranged from 10 IU to 5000 IU, which of course has nothing to do with what informed consumers are actually taking. In fact, 10 IU of vitamin E does not even meet the daily minimum requirement for this nutrient. Nonetheless, the authors of this negative report included this study with a host of others to attack vitamin E.

For beta-carotene, the authors claimed a 7% increased risk of death. Doses evaluated ranged from 2000 IU to 83,350 IU. We don’t know of anyone taking this high dose of beta-carotene, but these studies were nonetheless used to further frighten the public against this supplement.

Study periods evaluated ranged from 28 days to 12 years. The authors apparently thought that study periods as short as 28-days were long enough to include in their attack against certain vitamins.

As you will read next, these details about potencies have little meaning when one learns of the study-selection bias that resulted in 91% of evaluable vitamin studies being omitted from the analysis.

Most vitamin studies excluded from report
Out of a total of 815 vitamin studies considered for evaluation, 748 studies were excluded from the analysis (only 67 trials were included in the final report). Here are the absurd reasons given for excluding these 748 studies:

405 trials out of the 748 were removed from the statistical analysis plan because there were no deaths reported in any of the treatment arms. Therefore, this meta-analysis excluded 405 trials that showed no increase in mortality risk.

245 studies out of the 748 were removed from the statistical analysis plan because the authors’ inclusion criteria were not fulfilled. Double-blind, randomized, controlled intervention studies were excluded in the analysis for a number of reasons that can only be described as so exacting that many studies published in the New England Journal of Medicine, JAMA, and other top-tier medical journals would fail these criteria. Here were reasons given for excluding these 248 studies:

Specific allocation methods for study participants were not described in detail.
A combination of dates and/ or ‘admittance’ numbers was used to randomize participants rather than complex study participant identifier codes.
Methods used to hide the method of vitamin allocation were not described in detail.
The specific method of blinding was not described in detail
There were no drop-outs or withdrawals but the exact reason(s) for the lack of drop-outs or withdrawals were not described in detail
In trials with participants that dropped out or withdrew, the exact number and/ or specific reason for drop-out or study withdrawal was not described in detail
So while the media was running headlines like “Taking Vitamins May Shorten Your Life”, the report the headline was based on omitted most of the vitamin studies that should have been included. This obvious bias rendered the findings meaningless, and we applaud certain news networks who withdrew this defective report from their websites within hours of posting it. One news network even followed with a positive report on the value of antioxidants.

Flawed statistical analysis
The authors used a variety of statistical tools and models to manipulate the data used in the negative report. One way they did this was to use both a ‘random effect’ model, and a ‘fixed effect’ model.

Much of what we are going to say here will be confusing to lay people. The reason we have to include it is that this entire report was based on statistical models chosen by the report’s authors. As many of you know, when attempting to conduct a meta-analysis this extensive, statistical methods can be used to create conclusions that may differ considerably from what the underlying data reveal.

The ‘random effect’ model can be used to identify for difference of effect of antioxidant vitamins on separate patient populations (for example, to assess for the effect of vitamins on cancer patients as against heart disease patients). The ‘random effect’ model can also be used to help determine if different doses of an antioxidant vitamin have different effects (for example, whether a high dose of vitamin A is associated with mortality risk in contrast to a low dose of vitamin A).

For this meta-analysis, the ‘random effect’ model can be used to evaluate if different doses and/ or single or combined antioxidants and/ or interventions significantly affects mortality. Out of the 67 studies included in the meta-analysis, antioxidants were administered alone, or in combination with other interventions (e.g. drugs, minerals, other antioxidants) daily or on alternate days for 28 days to 12 years at a very wide range of dosages, such as 10 IU to 5000 IU for vitamin E.

In this meta-analysis, the authors found that the ‘random effect’ model was not significant, meaning it failed to show an increase in mortality. So they used instead the ‘fixed effect’ model to show a 4% increased risk.

In essence, the results of this meta-analysis suggest that different doses of vitamins, different patient populations, and single vs. combined antioxidants had absolutely no effect upon mortality risk when the initial statistical model is used, but that vitamins increase mortality risk regardless of dose or patient population when a different statistical model is substituted. This is patently absurd, and calls into question the entire legitimacy of this meta-analysis.

In point of fact, the authors of this flawed meta-analysis were asked to only include the ‘random effects’ model in a prior presentation of this data in the Journal of the American Medical Association (JAMA) (Bjelakovic 2007a). By using the ‘fixed effect’” statistical model and excluding fully 91% of the eligible studies for the analysis, the authors succeeded in achieving headlines by selectively emphasizing models that achieved statistical significance.

Most of the analyzed studies were done on sick people
This negative report attacking certain supplements recommends that healthy people should not take these nutrients, yet 46 out of the 67 studies that were evaluated were conducted on subjects that were diagnosed with disease.

The studies cannot relate mortality differences based on these vitamins
More than 60% of Americans regularly ingest some sort of dietary supplement. The question is, are the 60% of Americans taking supplements going to live longer than those who don’t? An analysis of the scientific literature indicates they probably won't.

The reason is that few Americans are taking enough of the proper nutrients to duplicate the clinical studies showing that the diseases of aging may be preventable.* Twenty-eight years ago, the Life Extension Foundation began a systematic review of published scientific findings relating to the prevention of degenerative disease and aging. The results of this painstaking investigation provided convincing evidence that the killer diseases of aging could be largely prevented by the proper intake of nutrients, hormones, certain drugs, and lifestyle changes.*

The phenomenon known as aging is a result of a number of pathological changes that are somewhat controllable using existing technologies. By prolonging our healthy life span, we put ourselves in a position to take advantage of future medical breakthroughs that may result in dramatic extensions of the human life span. Here are some of the underlying controllable causes of the diseases of aging we know of today:

1. Chronic inflammation.
Aging people suffer an epidemic of outward inflammatory diseases such as arthritis, but chronic inflammation also damages brain cells, arterial walls, heart valves, and other structures in the body. Heart attack, stroke, heart valve failure, and Alzheimer’s senility have been linked to the chronic inflammatory cascade so often seen in aging humans.*

2. Glycation.
It is well known that diabetics age prematurely, but even non-diabetics suffer from a devastating chemical reaction called glycation, where protein molecules bind to glucose molecules in the body to form nonfunctioning structures. Glycation is most evident in senile dementia, stiffening of the arterial system, and degenerative diseases of the eye.*

3. Methylation Deficit.
Cellular DNA requires constant enzymatic actions (methylation) for maintenance and repair. Aging cripples youthful methylation metabolism causing DNA damage that can manifest as cancer, liver damage, and brain cell degeneration.*

4. Mitochondrial Energy Depletion.
The cell’s energy powerhouse (the mitochondria) requires a complex series of chemicals to be present in order to maintain critical functions such as transporting nutrients through the cell membrane and purging the cell of toxic debris. Mitochondrial energy depletion can result in congestive heart failure, muscle weakness, fatigue, and neurological disease.*

5. Hormone Imbalance.
The trillions of cells in the human body are delicately synchronized to function by chemical signals called hormones. Aging creates a severe hormone imbalance that is often a contributing cause to many diseases associated with aging including depression, osteoporosis, coronary artery disease, and loss of libido.*

6. Excess Calcification.
Calcium ions are transported into and out of cells through calcium channels in the cell membrane. Aging disrupts calcium transport, and the result is excess calcium infiltration into cells of the brain, heart valves, and middle arterial wall (causing arteriosclerosis).*

7. Fatty Acid Imbalance.
The body requires essential fatty acids to maintain cell energy output. Aging causes alterations in enzymes required to convert dietary fats into the specific essential fatty acids the body requires to sustain life. The effects of a fatty acid imbalance may manifest as an irregular heart beat, joint degeneration, low energy, hyper-coagulation, dry skin, or a host of other common ailments associated with normal aging.*

8. DNA Mutation.
Numerous synthetic and natural compounds mutate cellular DNA and cause cancer cells to form. Aging cells lose their DNA gene repair mechanisms and the result is that DNA genetic damage can cause cells to proliferate out of control, i.e., turn into cancer cells.*

9. Immune Dysfunction.
For a variety of reasons, the aging immune system loses its ability to attack bacteria, viruses, and cancer cells. In aging humans, excessive levels of dangerous cytokines are produced that cause the immune system to turn on its host and create autoimmune diseases associated with aging such as rheumatoid syndrome.*

10. Non-Digestive Enzyme Imbalance.
Internal cellular functions depend on multiple enzymatic reactions occurring with precise timing. Aging causes enzyme imbalances primarily in the brain and liver, which results in severe neurological diseases such as Parkinson’s or the persistent memory loss aging people so often complain about. Impaired liver function results in toxic damage to every cell in the body.*

11. Digestive Enzyme Deficit.
The aging pancreas often fails to secrete enough digestive enzymes, while the aging liver does not secrete enough bile acids. The result is chronic indigestion people complain about as they age.*

12. Excitotoxicity.
The aging brain loses control of its release of neurotransmitters such as glutamate, resulting in devastating brain cell damage and destruction.*

13. Circulatory Deficit.
Microcapillary perfusion of blood to the brain, eye, and skin is impaired as a part of normal aging. The result is that disorders of the eye (such as cataract, macular degeneration, and glaucoma) are the number one aging-related degenerative disease. Major and mini-strokes are common problem associated with circulatory deficit to the brain. The skin of all aged people show the effects of lack of nutrient-rich blood to the upper layers.*

14. Oxidative stress.
Free radicals are unstable molecules that have been implicated in most diseases associated with aging. Antioxidants have become popular supplements to protect against free radical-induced cell damage, but few people take the proper combination of antioxidant supplements to adequately compensate for age-induced loss of endogenous antioxidants such as SOD and catalase.*

Notice that oxidative stress is listed as number 14 on the above list of controllable factors that cause aging-related diseases. While suppressing the free radicals that cause oxidative stress protects against many disorders, there is clearly much more that can be done to stave off aging than merely taking antioxidant supplements.* Children can benefit by taking vitamin supplements, but it is the aging human whose body is depleted of the endogenous antioxidants, hormones, enzymatic repair systems, and other biological chemicals needed to sustain life. What is optional in childhood turns out to be mandatory as humans enter middle-age and become vulnerable to the plethora of degenerative diseases that await them if they do not adequately protect themselves.*

The Life Extension Foundation has designed a scientific program to counteract the known biochemical processes proposed (by gerontologists) as primary causes of aging. The TOP TEN Most Important Steps for Achieving Ultimate Health provides recommendations to neutralize many of these known causes of premature aging.* Based on the 14 known mechanisms of aging, it is ludicrous to look at a group of mostly ill study subjects taking unusual doses of vitamin A, vitamin E or beta-carotene and then expect to see a significant benefit. There are too many other nutrients and hormones that even healthy aging people need to extend their healthy lifespan. Fortunately, most Life Extension members are taking these nutrients and hormones in the proper doses. Read more about the epidemic deficiency of vitamin E.

Conclusion
In today’s Western world, a large percentage of the population fails to ingest optimal potencies of many essential nutrients. As you will read in part two of this report, a shocking majority (93-96%) of people of people who don’t supplement with vitamin E are deficient in vitamin E.

This negative report attacking supplements is fatally flawed because it:

Omitted 91% of the studies that measured the effects of these vitamins on human subjects including all studies for which there was no mortality!
Included studies that used doses far below or far above what health conscious people actually supplement with.
Chose to bias the reporting of the results by emphasizing one type of statistical model that showed a significant effect rather than another statistical model that did not show a significant effect.
Failed to account for the 14 mechanisms involved in aging and premature death. For example, it is absurd to think that taking 1,333 IU to 200,000 IU of vitamin A is going to have meaningful impact when there are more than one hundred individual components to a science-based death reduction program.
The final shocker is that this meta-analysis report attacking vitamin A, beta-carotene and vitamin E is not new. It was in fact published last year and drew a lot of criticism for the obvious flaws it contains. Perhaps the reason this story was quickly removed from media websites on the day it appeared is that the broadcasters realized they were not relaying “news”, but instead regurgitating anti-supplement propaganda.

Needless to say, even this brief exposure was a public relations score for pharmaceutical interests, as millions of people worldwide may be frightened away from supplements that could reduce their future need for expensive prescription drugs.

There are thousands of antioxidants, these are a select few micronutrients (specific forms of them mind you) with antioxidant potential.

Surely your wording should be changed (as should the authors').

Here is the 191 page full text if anyone wants to dig through it: http://www3.interscience.wiley.com/homepag...53/CD007176.pdf

LEF gets it right again. And again. And again.

This article criticizes previous anti-oxidant studies.

http://www.vrp.com/articles.aspx?ProdID=art2067&zTYPE=2

So I dunno.

These studies are often just rehashing, and in this instance a biased selection used for their meta-analysis.

We keep seeing the same thing with the SAME vitamins:

E, C Beta Carotene, Vitamin A and Selenium.

Although C in normal doses I dont recall seeing any negative study results on, they are all routinely clumped together as 'the antioxidants' or 'the vitamins' or "the supplements" - as if these are the only antioxidants, and the presentation clearly tarnishes all nutrient supplementation rather than negative results in context with certain nutrients.

ACE Selenium formulas we had already criticised because as they are presented as 'the standard bearer' for antioxidant supplements and vitamins the relative ineffectiveness of these formulas was actually a threat to the reputation of all other supplements - as we are now finding. We had a thread warning of this problem.

Some facts:

Key side effects of Vitamin A are associated with a lack of Vitamin D - they naturally occur in high amounts in natural diets / lifestyles with no known harmful effects. Their action is in some areas oppositional therefore they are needed in balance - the known deficiency of vitamin D3 does not argue against supplementation of nutrients.

Vitamin E in large doses may disturb gamma tocopherol and have other detrimental effects. Too much gamma tocopherol may be harmful as lowering nitric oxide has effects depending on where it occurs - it could weaken immune response, and endothelial Nitric Oxide has a potent anti-inflammatory effect by blocking a cascade of inflammatory proteins. Therefore large doses of either vitamin E are possibly counter-productive. A suggestion is a modest dose of both.

Selenium. Studies done in selenium-sufficient populations will produce negative results, as the beneficial effect of selenium is seen in a narrow dose range and overdose is easy. The effects of selenium supplements in selenium deficient populations will be different. With minerals like selenium or fat soluble nutrients you expect to find both good and bad study results depending on accumulation and the presence of other counterbalancing nutrients.

Beta Carotene - probably not beneficial in states of stress or disease, but other carotenoids show potential. Beta Carotene is used by plants in an odd way so it may, as once suspected, be part of host defenses, but it is probably still much too early to conclude a negative effect from it.

Do you mean too much alpha " may be harmful as lowering nitric oxide..

Its the gamma that lowers the NO. Alpha may effectively raise it because it blocks Gamma.

And depending on where and in whom this happens the effects will vary.

First of all, this review has no references or citations. That says quite a bit.

Yes, the FDA and other government agencies are slow to change, they're bureaucracies. The author of the critique apparently believes the authors of the review are part of some kind of broad conspiracy to make people less healthy, in crafting a perverse connection with cigarette and food companies' commercial interest. One aspect of the equation LEF fails to mention is their own economic incentive.



This kind of non-sense is a large part of the problem in the dietary supplement industry; any study that shows negative effects from supplements must be motivated by big pharma, while those that confirm pre-existing beliefs are obviously valid. The consequence of the latter is increased sales for LEF, but again that goes unmentioned. No reference is made to who the authors are and what biases they may have based on evidence other than that contained in the critique.



The only rational conclusion LEF wants its readers to reach is the position being argued by the author of the critique, as clearly there isn't any consideration or the least bit of acceptance of contrary evidence.



It appears as though the author of the critique shuffled through the studies used by the reviewers and tried to pick out an anecdote that seems discrediting, even though there is no citation or reference to where that information is found in the full-text article.



I may have missed something, but I didn't get the idea that the author's were "attacking" vitamins, but were rather conducting a statistical review of the available data, which is peer-reviewed (unlike LEF's writings).



LEF can't seem to accept that reviewers don't include poorly designed trials, and it may simply be that studies showing a positive effect are not well controlled. Again, no specific references are made to the trials the reviewers excluded, making the claims about exlusionary criteria nearly impossible to accept without references to information outside the LEF critique.



Because the reviewers used two different models in considering mortality, and chose one for presumably a number of reasons, means the legitimacy of the meta-analysis is drawn into question?



Finally one parenthetical reference, though in this case it is to another review from JAMA that LEF strongly disagrees with. Why other references are not included is revealing of the critique's general nature (i.e. non-scholarly, one-point argumentative).



They're called "Secondary Prevention Trials," this is not a flaw or hidden feature of the review and is stated in the summary and abstract.



The review may very well be flawed, but this isn't an acceptable critique of a scholarly writing given the lack of citations and generally self-serving nature of the assertions.

--There are many many antioxidants so posting a thread with a title like that tells you where the poster's bias lies.

--Antioxidants ain't a panacea, but I do believe the proper ones should be part of a supplementation regimen.

"The present systematic review includes 67 randomised clinical trials"

So unless I review all 67 of thost studies to see if they did it right (I'm skeptical) this study adds nothing.

The title is actually borrowed from an article on the topic in USAToday. Yes there are many antioxidants, and all work in different ways, but nevertheless represent a category out which come certain general representatives of antioxidant supplements (e.g. those examined in the review). The title "Antioxidants" simply represents the category and nomenclature of the substances being discussed and reviewed, not meant as an all-encompassing generalization of every chemical structure that is technically an antioxidant.



No, it means that you read the writing like any other peer-reviewed article, and recognize what the aims and purposes of the study are. But I don't get the impression that you are interested in doing that.

Then the issue is with the overblown reporting of this review.

These are the worst of the antioxidants.

And Vitamin A's primary effects are not via antioxidant function

Beta Carotene is not the most promising of the carotenoids

Selenium can easily be overdosed

Alpha Tocopherols influence on gamma tocopherol action is not evaluated


Question: Why do a review of these compounds together? Because of cheap and non effective combinations which are fairly popular. Its right to rubbish the bad designs, just not to in any way insinuate there is something wrong with nutrients or nutrient combinations in general. To do so would equally be to argue against a varied diet, which is nothing more than a particularly large combination of nutrients.