The wrong week to quit antioxidants

Science does not exist in a vacuum. Like every other human activity it is socially, culturally and therefore financially embedded. For example, with hindsight it is easy to see that the Covid catastrophe was a toxic blend of political power-seeking, medical cowardice and pharmaceutical greed.

We might not like what we see in the rear-view mirror, but ignoring it makes it even less likely that we will arrive at anything like a correct destination.

I was scrolling through the archives when I stumbled across an article in the February 28, 2007 issue of the Journal of the American Medical Association. Researchers at Copenhagen University Hospital presented a meta-analysis which concluded that the antioxidants beta carotene, selenium and vitamins A, C and E increased mortality (1).

Bjelakovic et al was a very influential paper. I remember that ‘Killer Supplements’ headlines were the order of the day.

The pharmaceutical industry was reeling at the time from the COX-2 scandals (2). New evidence was emerging that commonly used anti-depressants might increase the risk of suicide in children (3), an association supported by later and more substantial data (4). In the wings, Karol Sikora was making the case that the new cancer drugs would bankrupt us all (5).

Against this backdrop, the anti-antioxidant story provided much-needed relief. At last, Big Pharma’s competition was taking heat. This supposedly definitive Danish study helped to break large numbers of consumers from their vitamin habits, and herd them back into the pharmaceutical fold. The quacks and charlatans were defeated, science reigned once again supreme. Phew!

When you look at the Copenhagen study in more detail, however, doubts start to creep in.

Medical quants criticized the study because of the low level of increased mortality, which at ‘about 5%’, hovered on the very boundary of statistical significance; the fact that many of the trials hoovered up into the meta-analysis were designed to test very different hypotheses; the wide range of doses of vitamins used in the different trials; and the way the trials and their data were selected.

Of the 815 studies found to be originally relevant 747 were discarded, meaning that a mere 8% of the available data base was deemed fit for inclusion. 405 out of the 747 trials were discarded because there was no mortality in either active or placebo groups.

My own view is that the meta-analysis failed the test of meaningful science on other grounds altogether. I believe the Danes ran aground on the reefs of intellectual and philosophical naivety. Their study was bad science, and rather than serving the public interest served primarily the interests of the pharmaceutical industry.

I will start with one finding which was almost certainly correct, namely that the commonly used supplemental antioxidants have little if any therapeutic benefits. Anyone who follows the literature would already be aware of this, as there is a long trail of null findings with vitamins A, C, E and beta-carotene. There are also internally consistent reports of adverse effects and/or increased mortality in certain circumstances, complete with plausible modes of action.

High doses of beta-carotene can, under certain conditions, act as a co-carcinogen (6, 7). High dose vitamin C may increase the risk of kidney stones by raising oxalic acid levels (8, 9), particularly in those who don’t hydrate sufficiently.

High dose vitamin E has anti-platelet effects that could increase the risk of hemorrhagic accidents (like aspirin does) in subjects with hypertension (10). Some cancer cells have a reduced ability to handle oxidative stress within their cell membranes (11), so it is conceivable that high dose vitamin E supplements might reduce the numbers of cancer cells killed by auto-catalytic peroxidation; and thus increase the risk of cancer (12, 13). (But see also 14).

Supplements in general are not risk-free. High doses of vitamin A are teratogenic, and probably because they increase rates of tissue turnover, are linked to an increased risk of osteoporosis (15-17) – at least, in today’s physically inactive populations depleted in multiple anabolic factors. Calcium supplements may increase the risk of death from heart disease (18), possibly by increasing CAC scores (19) – although here again, probably only in today’s populations who are riddled with chronic inflammatory stress and therefore endothelial dysfunction (20).

Anything in excess is toxic, and the use of high and supra-physiological doses of vitamins and other micronutrients can be no exception to this rule. But let’s return to the Danish study. The authors did not pinpoint any biochemical mechanism that might underlie the possible increased death risk, but suggested that ‘by eliminating free radicals from our organism, we interfere with some essential defensive mechanisms.’

There are problems with this conclusion. ‘Antioxidants’, taken in food or in supplements, might reduce numbers of free radicals but do not ‘eliminate’ them; this is careless and emotive use of words by the Danes.

More tellingly, and according to their own findings, the antioxidant vitamin C which eliminates – sorry, reduces free radical activity – had no impact on mortality. Neither did selenium, which, by increasing GPH activity in the many who are selenium-depleted, also reduces free radical exposure.

Another peculiar aspect of the Danish study which, if correct, rather undermined its concerns about the ‘elimination of free radicals’, is that the reported increase in mortality associated with vitamin E did not appear to be dose-related. This enough to throw substantial doubt on the validity of the meta-analysis.

There is yet another difficulty. In many of the trials, synthetic versions of the antioxidant vitamins were used. With vitamin C this is not a problem, as synthetic ascorbate is identical to naturally derived ascorbate. With beta carotene, however, and with vitamins A and E where stereoisomerism prevails, synthetic forms are significantly different to those occurring in our diet.

Synthetic beta-carotene generally contains only all-trans forms of the molecule, whereas foods contain a mixture of all-trans and cis-forms.

Synthetic vitamin E (dl-alpha-tocopherol) is a mix of 8 stereoisomers of tocopherol. In foods the ratios may be very different with d-alpha-tocopherol predominating, and generally in combination with the 4 tocotrienols, which may be cis or trans. As the body handles the different forms of vitamin E quite differently (21), and as the various tocopherols and tocotrienols have quite different effects on, for example, cancer cells (22-24), synthetic vitamin E is not equivalent to natural vitamin E.

There is a fourth, deeper problem. In the results section of the Danish paper you find that in the different trials included in the meta-analysis, the ‘antioxidant’ vitamins were given in a wide range of doses, and either singly or in arbitrary and limited combinations.

The mono- or oligo-therapeutic approach makes sense if you are concerned with identifying simple cause and effect, and is the most commonly used in pharmaceutical research and pharmaco-centric medicine. But herein lies the rub … Micronutrients, unlike xenomolecules, do not work in isolation. They network.

Most people are depleted in most micronutrients (ie 25, 26) due to a combination of low calorific throughput and dietary shift.

As the aetiology of most degenerative diseases involves multiple metabolic imbalances driven by multiple dietary imbalances and multiple micronutrient depletion, administering high doses of an arbitrary few micronutrients makes no sense. Monotherapy is a strategy that derives from successful 19th-century medical attempts to cure infectious diseases, but when applied to the degenerative diseases of the 20th and 21st centuries, it guarantees failure.

In short, the Copenhagen study tells us no more than that if you give people supra-physiological doses of often synthetic versions of a small and random group of micronutrients, there may be a borderline increase in mortality in people who were in many cases already seriously ill.

The Danes’ conclusion? Throw away your vitamin pills, and eat fruit and vegetables instead.

This is a curate’s egg of a statement. It is partly true (there is a deal of evidence to support eating more fruits and vegetables), but is wholly flawed in that the case for eschewing supplements has not been made at all. The conclusions are not only not good science, they are not useful.

Despite governmental recommendations to eat more fruit and vegetables, consumption of these foodstuffs has fallen fairly consistently in the OECD nations since 1900, in line with increasing prosperity and the growing popularity of ultra-processed products. Increased prosperity also leads to reduced energy life-styles. Cheap energy and modern technology enable many of us to get though a typical day on around 2000 calories.

This is a far cry from the 3 to 7 thousand calories / day needed to fuel a physically active population, which prevailed as recently as the mid-Victorian period. At this time daily consumption of fruits and vegetables was between 10 and 12 portions (27), compared to today’s paltry 2 to 3 portions (28). On a 2000 calorie / day throughput it is hard to eat 5 or more portions of fruit and vegetables per day, as is currently recommended (29).

The ahistoric Danes failed to understand that due to dietary and lifestyle shift, their contemporary subjects were consuming abnormally low levels of micro- and phytonutrients, and therefore dietary antioxidants. By taking antioxidant supplements, their test subjects were in many cases doing nomore than partly  restoring former nutritional profiles which were manifestly healthier, as they were associated with relative freedom from degenerative disease (27).

Now we must turn to the choice of supplements studied in the meta-analysis. To begin with, considering these compounds as the key antioxidants is an insidious error of thought. They do indeed have antioxidant capacity, but so do uric acid, albumen, the sex hormones, and many other metabolites and dietary ingredients. The ‘antioxidant’ compounds studied by the Danes have many other roles in the body besides their ability to quench free radicals.

If we consider other antioxidant phytonutrients such as the flavonoids, carotenoids other than beta carotene, the capsiates, vanilloids, limonoids, etc, their antioxidant capacity is clearly unlikely to be the most significant attribute of these pluripotent molecules.

This introduces yet another flaw in the JAMA paper. The trials in the meta-analysis used the wrong micronutrients, because they were based on faulty models of disease. I have already pointed out that when it comes to micronutrients, mono- or oligotheraputic interventions are inappropriate. To exacerbate this error, it is likely that the wrong micronutrients were studied.

In the context of cardiovascular disease, the ‘antioxidants’ C, E and beta-carotene were primarily used to reduce the formation of vaso-toxic lipid and cholesterol oxidation products in the bloodstream, as it was believed that such oxidation was a critical step in the formation of atheroma. However, it now appears that the primary lesion that underlies and drives atheroma formation is endothelial dysfunction, which is actually chronic, sub-clinical arteritis (ie 30).

Lipid and cholesterol oxidation products undoubtedly contribute to this condition, but if we scan the list of dietary factors that play key roles in determining the degree of inflammation in the artery walls, it is the polyphenols and omega-3 PUFAs that emerge at the top of the list (ie 31, 32).

These anti-inflammatory agents have an array of vaso- and cardio-protective properties that makes them better candidates for intervention studies than the ‘antioxidants’ the Danes chose to review.

In the context of cancer, too, the ‘antioxidant’ vitamins seem, even in retrospect, to be an odd choice. The Danish group singled out gastrointestinal cancers in the introduction to their paper, and stated unequivocally that the ‘antioxidant’ supplements had no significant effects on these. I believe this statement is correct, but why did they choose to single out this type of cancer?

Anyone interested in such matters will know that the food derivates most closely linked to reduction of risk of gastrointestinal cancers are no longer the ‘antioxidants’ at all, but such compounds as lycopene, the organo-sulphur compounds, calcium, salicylates and the fermentable carbohydrates.

If you do tests using wrong interventions, based on incorrect hypotheses, you will probably generate wrong answers. The JAMA paper’s advice may have been well meaning, but it was meaningless.

Finally, let us consider the uncritical statement still made by many that there is something in fruits and vegetables so special, and so indefinable, that it cannot be reproduced by supplements. The supplements used to date may have been ineffective, but the idea that fruits and vegetables have magical properties over and above their increasingly well-defined phytochemistry is not science, but the last gasp of vitalism.

Data trawlers who seek correlation between individual foods or nutrients and our public health problems are not addressing the root causes of our appalling public health. They should instead consider the socio-economic context of science, and the murderous irresponsibility of the food industry.

The chairman, president and CEO of WK Kellogg Co. is Gary Pilnick (from the Yiddish piln = to stuff). In 2024 this frosted flake suggested that families facing financial difficulties should save money by serving cereal for dinner (33).

‘Stuffer’ Pilnick was hardly thinking outside the cardboard box. Similar ideas had been mooted during the Great War and the subsequent Great Depression, but early cereals such as puffed rice, cornflakes and Washburn’s Gold Medal Whole Wheat Flakes were simple and relatively healthy foods (34).

In the 1950’s industry started adding sugar and artificial colors, and breakfast cereals became a nutritional disaster zone. They have become even worse over the last decade. Since 2010 levels of fat, sodium and sugar have increased, while protein and fiber have fallen (35).

Gary is aware that his latter-day cereals kill (36), but he and his colleagues persist with their nutritional crimes against humanity because they know that this diet creates changes in brain structure (37) and chemistry (38) which lead to neuroinflammation and addiction (37-39). And this leads to increased sales.

USA Surgeon General Luther Terry’s ground-breaking report on the adverse health effects of smoking was published in 1964 (40). By a remarkable coincidence, the tobacco companies started to buy food and drink companies in 1963 (41). They ported across the colors, flavors and marketing techniques they had used on children to create future smokers, into the sodas, breakfast cereals and other ultra-processed foods that are killing our sons and daughters today.

This might be the right week to quit breakfast cereals.

Coming soon: Wilder.

Referances:

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