The International Network of Cholesterol Skeptics

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                          Discussion March 2004 

       About vitamin C and cardiovascular disease

Morley Sutter
Can anyone explain to me why, if homocysteine is such an important factor in CHD, the epidemiology of none of the use of multivitamins shows a beneficial effect?

Eddie Vos
Dear Morley, this is a good question and not up to me to explain, since we have that man in our midst who gave the world the "concept" of homocysteine: more than a toxic molecule, the best marker of suboptimal nutrition.

I do not know which negative studies you refer to however.  Negative vitamin studies are some where excessive synthetic beta-carotene was used in smokers [not brilliant] and some where exclusively alpha-tocopherol was used -or some other silly vitamin ["antioxidant"] combinations. 

Read the 3 part series on homocysteine by McCully  (Ann Clin Lab Science, I.  Atherogenesis. 1993;23:477-493, II. Carcinogenesis and homocysteine thiolactone metabolism.  1994;24:27-59, III. Cellular function and aging.  1994;24:134-152), there's your biochemistry.

Regarding multivitamin studies, there is indeed not much but they're underway, thanks to the homocysteine concept.  There are smaller studies {Newfoundland, others] showing benefits of multi's but with a year's supply of mail ordered folic acid at 0.06$ US, and no way to patent and keep the competition out of it, and a potential huge dent out of Big Pharma revenue [if the idea works] and one can see why the data is sparse [and not the least the negative attitude of conventional MD's toward nutrition] 

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Morley Sutter
The specific study that caught my eye was Muntwyler et al, Arch Int Med. 162:1472-1476, 2002.  Theirs was a prospective study done on 83, 639 male physicians in the US.  Questionnaires were sent out to assess use of multivitamins and Vitamins A or C. with a mean follow up of time of 5.5 years and an end point of death with cause assessed by death cetificate. The use of none of the two individual vitamins or of multivitamins had an
effect on death rate due to coronary or general cardivascular disease over the study period.
I think this is as good as epidemiology gets and negative findings have meaning in such a study.  Death is a particularly important and definite end-point!

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Karl Arfors
It was vitamin E and not A which was used. Also Muntwylers study gave some additional comments (below) about a significant decreased risk for fatal CHD of 41% .  

In the question and discussion about decreased homocysteine values I can add that it is necessary in some people to increase vitamin levels of folic acid to 800 g and B6 to 100 mg and possibly also add trimetylglycine and NAC(n-acetyl-cysteine). This is generally much more than multivitamins I have tried this combination and came to values below 6 from 11.0. It should also be known that with increasing age +60 -70-80 values of homocysteine are increasing and more difficult to knock down. Kilmer McCully who told me about this age-dependence could possibly tell us more why? Kilmer you could also tell us how you think that homocystein contributes to inflammation and monocyte activation in combination with oxidized LDL in the microcirculation.  

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Joel Kauffman
As good as it gets is that 11,348 noninstitutionalized US adults aged
25-74 years examined for vitamin C intake followed up for mortality for a
median of 10 years - males have RR = 0.65 for all causes, 0.78 for all
cancers, 0.58 for all CVDs, females less effective.

Enstrom JE, Kanim LE, Klein Ma.  Vitamin C Intake and Mortality among a
sample of the United States Population.  Epidemiology 1992;3:194-202.

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Malcolm Kendrick
If I may throw a fact into the ring. The Heart Protection Study (HPS), which
was methodologically very sound. A prospective study (primarily on the use
of statins) on CHD, lasting five years. Published all over the place, and
trumpeted as proof of the wonderous effect of statins. 0.5% reduction in
absolute risk of CV events - no less.

However, they also studied the effect of various vitamins on CV risk. The
vitamins used, and the doses were : vitamin C 250mg/day, vitamin E 600mg/day
and beta-carotene 20mg/day. The result of the vitamin supplementation:

''There was no evidence of any benefit at all' from antioxidant vitamins. On
the other hand, there was no evidence of any harm.''' Dr Rory Collins BMJ
Nov 2001

Yes, I know, wrong vitamins, wrong doses, wrong patient type, incorrect
barometric pressure too, no doubt. When you get negative results it always
turns out that way...

When pravastatin proved to have zero effect on CHD events in the ALLHAT
study the investigators had a ready excuse for that, and ended up stating
(sic) 'Looking at these results, people may be tempted to think that statins
are not effective. But we know that they are.'

Looking at the results from the HPS, people may be tempted to think that
anti-oxidants are not effective. But it's okay... We know that they are.'

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Eddie Vos
Malcolm, regarding wrong vitamins: to test the homocystein-concept of health, throwing synthetic beta carotene or other "antioxidants" into the ring is pointless and one has to do trials with high-dose multivitamins -- and there the published research is limited, but underway [one really needs B2, B6, B9 [folacin], B12, Zn, Mg, may be others].

If, for example, long-term multi-vitamin use reduces colon cancer by 75% [Giovannucci et al] what's wrong enjoying lowered homocystein in the process -and recommending multivitamin use more widely?  And, if you want to be conservative about it, why not supplement to the level of nutrients found in a varied, unprocessed, raw, "primate" type diet, where  B vitamin levels would be ~2-4 times higher than current RDAs.  Death is a hard end-point and we only get one kick at the can.  While most drugs inhibit biochemistry, most nutrients promote biochemical pathways and the first-do-no-harm idea must be applied differently. 

Here's a slice re Coronary Heart Disease from the same Nurse's Study: 

 [I realize this is epidemiology but 80,000 nurses can't be all wrong]

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Morley Sutter
Lucky women!  They already live longer than males in almost every society
and now they can be seen to respond to intake of folic acid and B6 after
"correction for multivitamin intake".   Or maybe it is nurses compared to
physicians!

I am all in favour of a rounded diet with goodly amounts of fresh fruits and
vegetables and meat and a modest caloric intake. (Reducing the size of
dinner plates might be useful in reducing obesity).  Intakes of fruits and
vegetables are not necessarily equivalent to taking folic acid or B6
however.

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Eddie Vos
Morley, I may not convince you with the following 2 paragraphs but:

Regarding the NO effect in 80,000 male doctors [50% dentists] with multivitamin in Muntwyler et al, Arch Int Med. 162:1372-1476, 2002, this was after 5.5 years follow-up.  This matches the multi-vitamin / colon cancer timeline in the Nurse's Study where long-term use in primary prevention was needed.  Regarding CHD: 14 year use benefit was reported with reduced CHD/MI but intermediate dates aren't reported in the abstract.

Quoting from the previously cited colon cancer Nurse's Study: ".. Women who used multivitamins containing folic acid had no benefit with respect to colon cancer after 4
years of use (RR, 1.02) and had only nonsignificant risk reductions after 5 to 9 (RR, 0.83) or 10 to 14 years of use (RR, 0.80). After 15 years of use, however, risk was markedly lower (RR, 0.25 [CI, 0.13 to 0.51]), representing 15 instead of 68 new cases of colon cancer per 10 000 women 55 to 69 years of age." 

Pellagra, rickets, scurvy, beriberi, cardiomyopathy in China, and goiter are cheaply and simply eliminated with supplementation; the science is strong for B vitamins and Alzheimer's, cancer, CVD, cognitive decline and more [and the hub of those spokes is homocysteine].

I happen to see the science such that, if eating a Western diet if buying one's food in a store, a multivitamin is an essential food group, if only to restore what processing removed.  And, as Kilmer has pointed out: anything you do to food specifically lowers folic acid and B6.    

The "eat a varied balanced diet and you'll get all the nutrients you need" is non proven DOGMA and clearly wrong in the light of Roger J. Williams' "biochemical individuality" [1971], and in the light of our various degenerative diseases.  Regarding trace minerals: if it is not in the soil where your food is grown, it won't be in the veggie you eat [and it ain't cholesterol]

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Malcolm Kendrick
Don't get me wrong. I quite like the vitamin B homocysteine argument. My
major problem with it, is, as I have said before, that I can't see how it
fits the current pattern of CHD seen worldwide. I quite liked Linus
Pauling's vitamin C argument as well, but once again I can't see how it fits
with the current pattern of CHD across the world.

Has Eastern Europe suffered a sudden drop in vitamin(s) B and folic acid
consumption during the last twenty years? Can you relate the Russian rate of
CHD to vitamin B and folic acid consumption? Have the Finns suddenly started
to consume more Vit B/folic acid to expalin their four fold reduction in CHD
since the nineteen seventies? Do the Japanese really consume a high level of
vit B/folic acid? These are the type of questions that my brain needs to see
answered before I move a hypothesis from 'possible' to 'probable.'

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Morley Sutter
I quite agree with Malcom's drawing attention to the waxing and waning of
CHD in various places at various times.  This phenomenon was first described
by Skrabanek and McCormick in 1988 and I referred to it as possible suport
for an "infectious" basis of atherosclerosis in stuff I wrote.  Such a basis
has yet to be made supportable by solid evidence.

Does anyone know the pathology which occurs in homocysteinurics who have
high levels of blood homocysteine due to an inborn error of metabolism?
I seem to remember that abnormal clotting and thromboses were common in such
individuals.  Abnormal haemostasis could account for the relationship
between elevated homocysteine and deaths due to AHD/CHD.  It might even
explain why many years are required for "anfi-homocysteine" vitamins to show
a beneficial effect.  Bleeding and clotting in plaques are rather late
events in the atherosclerotic process.
Any comments?

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Kilmer McCully
In answer to Morley Sutter's question about the pathology of homocystinuria, I can refer to my original article in the field, "Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis." (Am J Pathol 1969;56:111-128).  In this article I show that the vascular pathology of homocystinuria is similar in children with hyperhomocysteinemia caused by cystathionine beta synthase deficiency and by methionine synthase deficiency, allowing the conclusion that homocysteine causes arteriosclerotic plaques by a direct effect on the cells and tissues of the arteries.  Briefly, homocysteine causes intimal injury and rapidly progressive fibrous arteriosclerotic plaques in children with homocystinuria.  These plaques are of the fibrotic type, with little evidence of deposition of lipids or cholesterol.  Many of the patients with homocystinuria develop arterial and venous thromboses in heart, brain, kidneys and lungs, accounting for their shortened life expectancy.  Older survivors with homocystinuria develop typical atherosclerotic plaques with complex fibrocalcific plaques containing lipid and cholesterol deposition, and occlusive thrombosis.  A good example is the common development of typical aortic atherosclerotic aneurysms in older patients with homocystinuria. 

I agree with Morley's comment that many years may be needed to show a beneficial effect of B vitamins in preventing the vascular disease that is induced by hyperhomocysteinemia.  In my first monograph on the subject, Homocysteine Theory of Arteriosclerosis: Development and Current Status. Atherosclerosis Reviews 1983;11:157-246, I point out that the increased human consumption of synthetic pyridoxine (B6) may account for the decline in cardiovascular mortality in the US since the 1960s.  Both synthetic pyridoxine and folic acid began to be added to the US food supply in appreciable quantities in the 1960s and 1970s in the form of fortified breakfast cereals and vitamin supplements.  Since the 1960s there has been a steady decline in cardiovascular mortality of approximately 1% per year in the US, which can only be explained by B6 and folate fortification of the food supply.  In a recent news report, epidemiologists from the CDC reported in the recent 2004 Cardiology meeting in San Francisco that the annual decline in mortality from heart disease and stroke suddenly increased in 1998 to 5% per year, as judged by review of death certificates, accounting for about 48,000 fewer deaths per year since 1998.  That was the year when folate fortification of flour and refined grain products in the US was mandated by the FDA.  The investigators attributed this dramatic reduction in mortality to the effect of folate on lowering homocysteine levels in the population.  This effect agrees well with the observed 20% reduction in incidence of neural tube defects in the US population since 1998, when folate was introduced into the US food supply. Studies by the Framingham Heart Study showed that folic acid fortification of refined grain foods in the US in 1998 caused a doubling of blood folate levels and a 15% reduction in blood homocysteine levels in elderly study participants.  It seems to me that these observations support the validity of the homocysteine theory of arteriosclerosis in the population at risk.

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Eddie Vos
I don't know but I always assumed that when the East Block fell apart, nutrition went down, not infection went up.  Kilmer McCully wrote the book on homocysteine and I believe that much of what I said, as well as my own understanding of the science, supports the micronutrient deficiencies hypothesis.  

Let me attach, again, at the end of this e-mail, two figures I pulled off my website with what I think are hard data regarding sclerosis in the arteries, and the multi-vitamin supplementation solution to that phenomenon. Enough epidemiology, these are measurements and interventions, with blinding at the appropriate locations.
Eddie [links on the site http://www.health-heart.org --and on page http://www.health-heart.org/comments.htm
section 11.]

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Dag Viljen Poleszynski
Agree with Eddie. The general finding is a lack of vital nutrients, not the
same for everyone except Vitamin C as shown by Pauling and the three B's as
shown by McCully, plus minerals dependent on soil conditions etc. Since we
need about 40 nutrients, many of them could be implicated. The trick is to
find out which ones and at what lever. Since nutrients are cheap and safe, I
favor taking all vitamins several times the RDA and minerals about the
RDA... Nutrition comes first. If anyone hasn't read McCarrison, Weston
Price, Francis Pottenger, Kollath, Irvin Stone, Frederick Klenner, etc. they
should.

In addition, the International Bibliographic Information on Dietary Supplements
offers a few hundred thousand studies, many of which show the benefits of supplements. 
As said by one of you, the problem is to find the right combination

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Cory Mermer
Take a look at this:

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Eddie Vos
That benefit from C and folate [and I would guess the omega-3 EPA -not listed] is good but that LDL/chol being detrimental in this study may not be causal and contradicts to some degree the Framingham stuff I sent around in the last 24 hours.  

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Malcolm Kendrick
Eddie, It doesn't contradict to some degree, it utterly contradicts as the
conclusions are the exact opposite - with regard to LDL and dementia. This
is yet another example of the fact that studies appear to be able to
demonstrate utterly contradictory findings, and yet no-one even raises an
eyebrow. This type of things makes research into the whole area almost
impossible, as you can prove (or disprove) almost anything you want. This is
not science it is something else too rude to type before the nine o'clock
watershed.

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Eddie Vos
Malcolm, I could not agree more -and 82 non demented old people's brains do not 
say much for all mankind.  The Framingham study at least covered several thousands, decades ~ 20 measurements each [and it found little regarding cholesterol] 

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Chris Allan
As we all know a careful look at the specifics of a study can usually reveal its shortcomings. In my opinion these shortcomings are inherent in most studies, but it is the actual interpretation of the results that is also important. An objective conclusion is difficult to make for the researcher who has certain ideas imbedded in their thought process (and we all do to some extent). I have always felt, and still maintain, that one of the most significant areas where studies mislead are epidemiology for non-infectious disease. This statement is pretty harsh because it states in effect that we are wasting money and time on these types of studies. This is why I don't say much on this board anymore, because many discussions are centered on epidemiology, of which the whole lot, in my opinion, are a waste of time. So discussing the results as if they have actual practical meaning is not useful.

But I do believe that since epidemiology has been used extensively to support the low-fat camp that we should do our best to point out when these types of studies also support a high fat diet. I would prefer to have the THINCS group actually focus on the lack of information provided by these studies in general, but surely many of you do not agree with my statements. And I do understand that we might be labeled as a fringe group if we started discussing the fact that many studies reveal absolutely nothing.

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Barry Groves
I have to agree with Malcolm too. Nature, who in my book can't be wrong, made foods that are complete, and our bodies have complex autonomic systems that sort out exactly what they need from the raw materials we supply. If a natural, fresh food diet is eaten, I see no need to supplement with anything else. You only have to look around the health world to see the mess we get into when we try to interfere with Nature and do consciously what our bodies
can do far better without our help.

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Malcolm Kendrick
There are two arguments here, and they shouldn't really get mixed up. No-one can disagree that if we lack an essential nutrient/vitman/element that is required for the body to function e.g. iron, magnesium, vitamin B6/B12, iodene then we will not do well, and probably die. The question is, are we really deficient in these things?

Pauling would claim, with regard to vitamin C, that the amount we really need is huge ~ 2g/day. Frankly, I cannot believe that we need that much to be healthy, otherwise 99% of mankind would have dropped dead at any given point in history.

Omega-3 advocates claim that we need much more of this substance than most
people currently believe.

Is there a danger in eating too many vitamins and Omega-3s? Probably not,
unless you go completely mad.

Is a lack of these substances the true underlying cause of CHD? I cannot see
a pattern of rates of CHD that fits with a lack of micronutrients.

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Ulf Holmbäck
Eddie, you're not alone in omega-3 land, although I wouldn't describe myself as a high-profile citizen. I think it might be useful to straighten out if we talk about adequate or optimum health. Perhaps one can look at it like this: 

Adequate health - being healthy enough so your genes are passed on ("Darwinian health"). 

Optimum health - added quality of life (extended life span, decreased
morbidity) on top of "Adequate health".

For adequate health it may not be critical that your n-3/n-6 ratio is around 1, but may very well be for optimum health, same for many other nutrients. Moder Nature is not perfect, just good enough. Regarding that different populations eat differently, according to Cordain, the majority of the hunter-gatherers used similar food strategies, see Cordain et al.  As Dag just pointed out, getting vitamins and minerals just from natural food sources is not easy.

I would be somewhat careful ingesting large amounts of vitamin A in
the light of the findings of Michaelson et al

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Eddie Vos
Hello All, 2 more lost tennis games later: thanks for the support and interesting feed back.  It could be argued that since we have 3 of the 4 enzymes that animals use to make mega-dose vitamin C, and since lab/zoo-primate food is supposed to have several grams of C for our body weight, C may well be needed in gram amounts.   I would suggest to Malcolm that 99% of some tribes [like the early sea mariners] would have died out from lack of C, until some of our northern strains developed Lp(a) in order not to bleed to death in times when no leaf or fruit type nutrition was available. 

Re Ulf's point about vitamin A excess: that study was NOT adjusted for vitamin D intake which I saw as the greatest flaw/confounder of that study. 

H Sapiens is the only species using heat in their food preparation, and I wonder how the "eaters of raw flesh", Eskimos, did in the A and D departments.  Whatever, Greenland Inuit [the preferred designation] seem to have had little CVD to speak of as they got their C from fresh meats and, reportedly, from stomach content, and in summer from berries. 

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Ulf Holmbäck
That may very well be true but I'm not sure that adjusting for vitamin D would have altered the conclusion, see Rohde and DeLuca (although it's a rat study). Furthermore, according to Håkan Melhus, they could not find a protective effect of physical activity when serum retinol levels were high = retinoic acid is powerful stuff. I don't think that Inuit levels of vitamin A in a person eating an American/Western Europe diet is a good idea.

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Eddie Vos
Totally agree: messing with the carotenoids is very tricky stuff [think: ATBC, the alpha-tocopherol beta carotene study in smokers study].  Inuit would have been low in carotenoids and high in retinol, and I would think D.  D [especially without sunshine] is massively important for bone health, maybe more so than calcium, and also it is reported to be vital for pelvic opening in women.  Low D ingesting or dark skinned tribes in northern climes are no longer with us.  Maybe the bone strength promoting D [NEJM Chapuy] compensates for excess retinol reducing bone strength ...  although the rat study you refer to seems to contradict that idea.  Ergo: easy on the A and splurge on the D.  

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Dag Viljen Poleszynski
Of course we need vitamin C, a vital cofactor for all hydroxylation reactions in the body (many transmittor substances, collagen formation, etc.) and a redox compound which can regenerate many other antioxidants!

Japanese researchers have shown that the gene coding for gamma-lactone oxidase was lost several tens of millions of years ago, as suggested by biochemist Irwin Stone.

Pauling explained in his landmark articles from 1968 and 1974 why there was an evolutionary advantage in not producing vitamin C when there was enough of it in the environment.

Traditional peoples were getting more vitamin C than us. Furthermore, their ample selenium intake etc compensated for the not so high vitamin C... This does not mean that their vitamin C intake was optimal - otherwise they might have had a longer life span than the maximum 90-100 years reported by Stefansson.

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Herbert Nehrlich
Hi Dag: How does an abundance of Selenium, which of course can be toxic in amounts one would call abundant, say  upward of 1500 mcg, reduce the need for Vitamin C? And would you please elaborate on the 90 to 100 year max. life span quoted by V.Stefansson? I suspect that there is a mechanism at work that has not been illuminated. Is there an "ascorbate-sparing effect" through the presence of some abundant nutrient, micro or macro ?

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Bogdan Sikorski
This is indeed an odd thing! - why would we loose the ability to make vit C if it were to be detrimental? Where is Darwin when one needs him? 

Anyway, my spin on this is rather speculative and unlikely to satisfy a sk(c)eptic (oops!). Firstly, I might be a bit forgetful on that, but I recall that Stefansson actually cured scurvy in few people who cheated with food on his expedition by feeding them cooked meat in a broth rather than organ meats - or possibly both (will re-read his article to confirm).

Secondly, we know that vit B1 is virtually obsolete for metabolic use other than carbate metabolism, but there is no such a case for vit C. As far as I know, we can accumulate water-soluble vits, particularly those of B variety (but also C) although to a relatively min extent. Consequently, since there is a low urinary threshold for elimination of all water soluble vits, it might follow that it is better (as for instance with Fe) to have few lower doses/day (or week) than to have one or few large ones, because this threshold is adjustable according to the intake (i.e. more means less). Overall, lower regular doses might lead to a better storage of some vits. (?)

Thirdly, just recently I have stumbled yet again on some work suggesting that there are other substances/compounds which may posses a similar function to vit C in some metabolic processes. [I go through so many papers that I have lost a memory when I saw this one - and I am not on Lipitor!] Clearly its antioxidant function can be replicated by many compounds. If I
recall correctly, one or two of those compounds were multi-ring-like in structure, even cholesterol like, and looked to be very lipophilic.

Finally, we really have no idea what are the vit requirements for various types of human nutrition, but a simplistic logic suggests that some foods or groups of foods would come loaded with particular nutrients necessary or helpful for their digestion and maintenance of life when diet becomes orientated on such a group - an example different diets of gorillas and
chimps (the killer ominivores) living in the same regions of Congo (from a recent TV program). Those chimps (males!) were real nasty characters!!!

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Chris Allan
I recall reading somewhere that the Inuit occasionally would eat the contents of the stomachs that contained moss and they also had a few berries preserved in whale oil.

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Dag Viljen Poleszynski
Herbert: The speculation was that ample Selen would partly be able to compensate for low C intake, since GSHpx is an important antioxidant... Inuits don't ingest toxic Se levels - the figures I have seen are 1000-1200 µg/d, well below the toxic levels found in parts of China (well above 2000, even as high as 5000 µg/d). Would be interesting to know their homocystein level.... Perhaps Kilmer knows something about that.

As to life span of Inuits, Stefansson wrote about old people in his cancer book and stated something to the effect that although the average age was not that impressive, some people lived to be between 90 and 100.

Your hypothesis is well put, and I don't have the answer. If Bogdan and Kwasniewski are right, eating a lot of saturated fats will reduce the need for vitamin C because there is less peroxidation of PUFAs. Inuits probably ingested enough of total antioxidants to prevent excessive oxidation, but nobody knows if they would have been even better served by adding at least 2-3 g/ascorbic acid per day. I presume that Klenner, Stone, Pauling, Cathcart, Levy and others would bet that this would be the case...

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Herbert Nehrlich
Dag: Reminds me of what Barry mentions in his book about the probable link between PUFA's and melanoma incidence. A local researcher in my neck of the woods is convinced that plenty of Vit. C will make melanoma extremely unlikely. Myself, I have always worshipped the sun and -even though I am a fair-complexioned Northern European I tan easily and have no fear of
melanoma. But then, I have never been into PUFA's very much and get plenty of saturated fats (and Vitamin C).

Also wanted to mention that the late scoundrel  Dr. Victor Herbert  who said of Pauling's 18 g/d Vitamin C  "habit" that  "it very probably shortened his life"  (this 2 weeks after Pauling died at age 94, in full command of his mental faculties ).  No cognitive impairment there and never a need for Lipitor.

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Kilmer McCully
There is only one small published study of homocysteine in Inuit subjects, showing no difference in homocysteine levels from a control group.  The publication is by Moller et al, "Homocysteine in Greenland Inuits."  Thromb Res 1997;86:333-335.  They studied 19 healthy Inuits eating "a traditional Greenland diet high in n-3 PUFA..." and 29 age and sex matched Danes eating "a standard Western diet."  Although there was no difference in the mean homocysteine levels of the two groups (approximately 9 mcM for Inuits and 10 mcM for Danes, exact figures are not given in the paper), a larger sample might have shown a significant difference.  Also 6 of 29 Danes had homocysteine levels greater than 15 mcM, while only 2 of 19 Inuits had homocysteine levels greater than 15 mcM. Also, two of the Danes had very high levels of 43 and 77 mcM, while the two Inuits had only moderately elevated levels of 18 and 26 mcM.  Obviously more data and a much larger study are needed to conclude anything significant regarding homocysteine levels in Inuits compared with controls.  Contrary to the conclusions of the paper, I believe that the differences observed might be significant if they were documented in a much larger sample size.

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Morley Sutter
My (admittedly 1957 vintage) book of Nutritional Data lists Calf liver as having 36 mg of Vitamin C per 100 grams of "edible portion".  To ingest the RDA amount of 60 mg would be quite feasible, but to get gram amounts of vitamin C would require approximately 3 Kilograms of liver. Happy hunting.

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Uffe RavnskovT
The issue about the role of vitamins in cardiovascular disease seems extremely complicated and confusing for me. One of the reasons may be that the mechanisms for uptake of vitamins and other substances from the gastrointestinal system are limited. Several substances may be using the same pathway and if one of them is given in large amounts its uptake may compete with other ones that are just as important. High intake of one substance may thus create deficiency of another. Is there anyone who can tell us more about these physiological mechanisms? 

For personal rasons I have recently trawled the literature about the use of vitamins in cancer prevention and treatment and this issue seems just as intricate. Let me as an example mention a few things about vitamin C. In cultures of carcinoma cells Vitamin C inhibits their growth in a dose-dependent manner. However, low doses stimulate the growth of certain cancer cells, but not all. One of the mechanisms seems to be that cancer cells take up more antioxidants than normal cells. Whether such studies can be translated to clinical effects is questionable because of the mentioned problem with intestinal absorption. In one experiment high doses have inhibited the growth of cancer tumours and prolonged life (Cameron, Pauling, Leibowitz. Cancer Res 1979;39:663-81), but not in another (Creagan et al. NEJM 1979;301:687-90). The difference may be due to another problem, the use of different preparations of the vitamin. The best effect, at least in animal experiments and in cell cultures, has been the use of several antioxidant vitamins at the same time, but there is a general lack of large controlled, randomised trials, probably because, as mentioned by Eddie, it is not possible to make big money from vitamins.

I am not familiar with the literature on vitamins and CVD but I assume that the problems are just as great. Let us therefore look at the issue with an open mind without drawing too hasty conclusions. 

Another issue. I agree with Chris that far too many meaningless epidemiological studies have been performed and far too much stress has been laid on their results. Again and again we can read that a certain factor can “explain” so and so much of a certain morbidity or mortality. Causality can never be proved by epidemiology and 80.000 nurses may certainly be wrong. For instance, the Nurses´ Health Study has not shown that folic acid intake reduces risk of colon cancer by 75% - intake of folic acid was associated with a reduced risk of colon cancer, but the reduction may have been caused by anything associated with a high intake of folic acid. People who eat much fruit and vegetables may differ from other people in many other ways. Results from epidemiological studies, if they are performed impeccably, may at best give rise to the creation of hypotheses, nothing more.  

But let us not forget that they are excellent to falsify a hypothesis. For instance, high cholesterol cannot be an important cause of cardiovascular disease because in most cohort studies of old people, those who represent the overwhelming amount of cardiovascular morbidity and mortality, high cholesterol predicts good health and longevity (references). It is that simple!

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