Tuesday, April 17, 2012

Lessons From Ötzi, the Tyrolean Ice Man. Part II

Otzi's Diet



Otzi's diet would have been high in carbohydrate, mostly from einkorn wheat (and perhaps other grains) but also from fruit and possibly legumes.  It was probably moderate in protein, with the protein coming from grains, perhaps legumes and some meat.  He probably didn't eat much fat, but he did get some fat from nuts and meat.

Otzi's Health

Otzi was about 45 years old at the time of his death, had a lean and fit physique, and stood roughly 5 feet, 5 inches tall (1.65 m).  This adult male height is typical of hunter-gatherers and other non-industrial people throughout the world today (except those that rely heavily on dairy), but that's a topic for another post. 

Otzi was not exactly the picture of health.  He suffered from a number of health problems, both infectious and non-infectious in nature. 

Like nearly all non-industrial populations, Otzi probably had intestinal parasites; in his case, his colon contained whipworm eggs (4).  Lines in his fingernails showed signs of an unknown illness that occurred three times in the four months before his death.  His body also bears DNA evidence that he may have been infected with Lyme disease, a serious chronic bacterial infection transmitted by tick bites (5).

Otzi's body also shows signs of a number of non-infectious disease processes.  Several of his major arteries were calcified-- suggesting advanced vascular disease that's normally associated with an elevated heart attack risk.   He had three gallstones, which has been used to support the idea that he ate a lot of animal fat, but this seems like a major leap of faith to me.  He had arthritis in several locations, including the spine and hips (6).  He had cavities and periodontitis (6a).  His lungs were blackened, presumably from the smoke of fires used for various purposes, including smelting copper.


Otzi is probably fairly representative of early agriculturalists in some ways, and to a lesser extent, the hunter-gatherers that preceded him.  The archaeological (skeletal) record shows evidence of severe physical stress in early agriculturalists, including short stature, cavities, and skeletal abnormalities, which probably reflect both nutritional and infectious stress (Cohen and Crane-Kramer. Ancient Health. 2007; Cohen. Health and the Rise of Civilization. 1991).

The shift to agriculture involved a major change in diet, away from a hunter-gatherer diet composed of diverse wild plant and animal foods, to a diet centered around grains.  Although some humans may have eaten grains for tens of thousands of years before domesticating plants, grains clearly became a more central source of food during the Neolithic. This posed a number of nutritional problems that would have exerted selective pressure over time, favoring genetic adaptations to the new diet.  Later agriculturalists were taller and healthier than early agriculturalists, probably due to a combination of genetic and cultural adaptations (Cohen and Armelagos. Paleopathology at the Origins of Agriculture. 1984).

The more sedentary lifestyle, higher population density, and contact with livestock associated with agricultural life created new opportunities for human pathogens (Cohen. Health and the Rise of Civilization. 1991).  A number of parasites, bacteria and viruses took advantage of the situation, becoming more diverse and virulent and giving rise to many of the most problematic infectious diseases we know today.  These new infectious threats were extremely debilitating and deadly for early adopters of agriculture in Eurasia, just as they were for unexposed populations when Europeans reached the Americas.  However, the strong selective pressures they exerted on the ancestors of modern Eurasians gave rise to a number of protective genetic adaptations, the traces of which are highly visible in our modern genomes. 

Otzi's health is clearly not something to aspire to.  In some ways, it's representative of contemporary hunter-gatherers and non-industrial agriculturalists: his leanness and probable lack of metabolic disorders such as diabetes, as well as the presence of intestinal parasites and other infectious diseases.  In other ways, some of the findings are surprising: his cardiovascular disease and gallstones, which are considered "diseases of affluence" today.

I think we have to take the cardiovascular disease with a grain of salt.  Modern-day non-industrial agriculturalists typically have low levels of atherosclerosis (a thickening and degeneration of the vascular wall) compared with affluent nations, even if the diet is grain-heavy, although they are not free from atherosclerosis (7).  No one knows how much atherosclerosis hunter-gatherers have, because no one has ever done cardiac autopsies to my knowledge.  But we do know they have low blood pressure, low circulating lipids, and high physical fitness, which argues against the presence of serious vascular disease.  Otzi was exposed to high levels of copper and arsenic from smelting, particulate matter from smoke, and Lyme disease.  He also had a genetic predisposition to cardiovascular disease, which I'll discuss later.  It's likely that at least some of these factors contributed to his cardiovascular disease, and in addition it's hard to know how representative he was of his culture.

The other thing to keep in mind is that having atherosclerosis doesn't necessarily mean a person will have a heart attack.  There are other important components of risk, including the tendency of the blood to clot, the tendency of the heart to enter fibrillation (irregular contraction that can be fatal), blood vessel diameter, and the stability of plaque in the artery wall.  These may explain why some non-industrial populations have a much lower heart attack risk than would be predicted from their degree of vascular disease (8).  The point is that just because Otzi had signs of advanced atherosclerosis, does not necessarily mean he was about to have a heart attack.

In the next post, I'll delve into Otzi's genome, and the insights it contains into the evolution and health of modern Europeans.


polyhex said...

I'm intrigued by this sentence. "This adult male height is typical of hunter-gatherers and other non-industrial people throughout the world today (except those that rely heavily dairy), but that's a topic for another post.

Are dairy reliant cultures taller, shorter?

N Matheson said...

If cardio vascular disease is caused (solely or largely) by chronic stress, it would be no suprise to find evidence of it in the neolithic population of the Alps which were phenomenally violent in the neolithic.

Matt said...

Is it correct to refer to Otzi as a hunter-gatherer? If he had a belly full of wheat and was a professional copper smelter, isn't he pretty clearly a neolithic agriculturalist?

gunther gatherer said...

Aren't whipworm/tapeworm also common to hunter gatherers?

I've got the "old friends" theory of parasites (especially intestinal) in mind when I say that maybe this wasn't so bad or so uncommon. The Hygiene Hypothesis claims that parasites like these attenuate the immune system so it doesn't overreact and cause inflammatory diseases like MS, allergies and rheumatoid arthritis.

Given that parasites evolved with us and other mammals, they must have developed some benefits for the host's body. Killing or otherwise debilitating your host and lowering his/her fitness doesn't make much sense from an evolutionary or species survival standpoint.

Gabriella Kadar said...

Stephen, the arsenic question: Some years ago I read that there were 'arsenic eaters'. Small amounts kept them feeling warm because it is a peripheral vasodilator. Is the latest information on the presence of arsenic in Otzi determined now to be due to copper smelting?

Also in reponse to polyhex: the tallest people in the world today, aside from the Masai are the Dutch. This has been attributed to their high dairy diet. They have made large increases in height since the second world war because dairy products are much more available. Prior to the war, the Dutch were not especially tall at all. ('The Escape from Hunger and Premature Death: 1700 - 2100' by Robert William Fogel)

MM said...

This has been an interesting series and I look forward to more. I was wondering if there is any information on Otzi's dental health. Did he have good teeth or were they riddled with decay? Perhaps you are planning another post on that topic. If not, I'd appreciate any info you have. Thanks.

The Writer said...

This is very interesting on the way the topic is handled. It could give us a chance to understand what people in the 21st century to handle their health issues.

Jane said...

Was Otzi really as young as 45 when he died? It seems the experts are not sure, and there is evidence from a study at Spitalfields in London that experts are not very good at this.

'..There has also been some controversy among human biologists concerning the criteria for determining the age at death of individuals from their skeletons. One of the most positive conclusions from Spitalfields is that methods currently in use yield inaccurate results. Only 39% of the adults of known age were correctly placed in their relevant age groups, 2% were over-aged, and 58% were under-aged.'

Jane said...

Forgot the link for the Spitalfields quote


Unknown said...

Stephen Guyenet,

I'm curious to know, if Otzi, and members of his Tribe/Community consumed Alcoholic Beverages (Beer, Wine, Liquor). If He did in fact consume alcohol, Could the autopsy determine that 5,000 years later? or would something of that nature be absorbed completely in the digestive tract, leaving no residuals? I'm under the assumption that alcohol consumed, would not be detectable in the body, 5000 years after consumption...

I know this is a somewhat of a stretch, but I think its safe to assume that people were consuming alcohol well before 5,000 years ago. Could it be possible that Otzi consumed a high level of alcoholic beverages, which then lead to a decline in his health?

I look forward to your response!


Stephan Guyenet said...

Hi polyhex,

Taller. There is fairly convincing evidence that dairy consumption increases linear growth.

Hi Matt,

I didn't intend to refer to him as a hunter-gatherer.

Hi gunther,

Intestinal parasites are common, yes. I think there may be something to the "old friends" hypothesis.

Hi Gabriella,

I haven't heard about that.

Hi MM,

I forgot to include that. I just updated the post. He had cavities and periodontal disease.

Hi Jane,

I think you raise a legitimate question. I'm just taking the scientific reports at face value, but it's something that's difficult to estimate.

Hi Unknown,

I don't know if they drank alcohol, but that wouldn't explain calcified arteries, arthritis or dental decay.

Unknown said...
This comment has been removed by the author.
Lauren said...


Unknown said...





Anonymous said...

Re: Otzi and Old Friends

Otzi had whipworm eggs, or trichuris, found in his colon. It seems he did not have tapeworm, which is quite a different animal from Trichuris.

Whipworm are geohelminths. The eggs are ingested and hatch in the colon, whence the larvae burrow into the mucosa and mature. So the presence of eggs proves Otzi ate Trichuris (T) eggs, but not necessarily that he was colonized by T. Unless I missed something in that linked article, they did not find actual worms.

It is also possible that the T species in his colon could have derived from a bovine or cervid T species. PCR techniques might be necessary to tell for sure.

But let's assume he had colonization by TT (trichuris trichuria- human whipworm). TT, along with hookworm species, are the geohelminths that most fit the criteria for being old friends - eukaryotic gut symbionts that do not cause auto-infection and which cause relatively long infestations, and which have colonized vertebrates for most of the period during which the human immune system developed its specializations (like IgE antibody class).

It is therefor plausible that TT colonization, rather than being a "disease", might explain why Otzi had no obvious autoimmune diseases, and even why he would be more likely to tolerate wheat, as gluten enteropathy may itself be just a common autoimmune disease that affects certain haplotypes.

Anonymous said...

I cannot find the source at the moment, but I recall reading that the relatively mobile San tend to carry Necator Americanus, or hookworm, as their only prevalent gut geohelminth.

We have an idea culturally that "parasites" like geohelminths are disgusting diseases. But that is because throughout animal evolution parasite loads have always been determined by, and actually served as a check on, animal populations.

Helminths colonize most hominids without incident or ill effect until the advent of sedentism. agriculture and zoonoses.

So maybe modest infestation by helminths is a normative part of ancestral health, while at the same time disease caused by HIGH worm loads is really a disease of early civilization.

And diseases of immune dysregulation caused by complete extirpation of all these old friends are late diseases of civilization.

Dr. Curmudgeon Gee said...

i have always been interested in Otzi since i heard it.


Puddleg said...

I am with Kurt on the helminths, humans can probably be dysvermic or euvermic; with avermia as an unnatural state. (caution: made-up words).
About adption of grain-eating; with regard to small foods hard to gather, my suspicion is these only entered the diet when we were able to steal them from burrowing animals that collect and store them. This strategy is used by hunter-getherers today and results in much larger yields for much less effort than would be involved in collecting from plants.
A bit like collecting honey, or scavenging meat and marrow; we are good at exploiting the work of animals.
Man the thief.

N Matheson said...

With reference to ag, the report from Aveline's hole (UK Eearly Mesolithic) gave ages of death at the usual 40 ish mark. The archaeologist involved noted that the age at death was determined by tooth wear which given their relatively meaty diet was probably innacurate. I seem to remember reading similar in Paleopathology at the Origin if Agriculture.
With reference to height the Dutch have increased a whopping 6 1/2 inches since the 19th century. Boyd-Eaton said the Inuit started growing with the introduction of flour and sugar into the diet, despite havng no real calorie shortfall before.

gunther gatherer said...
This comment has been removed by the author.
gunther gatherer said...

Hi Kurt,

We also have to factor in the overall burden effect. One infestation may be beneficial or at least harmless to the host, but several infestations of different worms may create a very different situation. So the longer the host animal lives, the more worms it picks up and hence it gets debilitating over time.

The paleosphere is always going on about intermittent stress vs. chronic stress, and hormesis as a beneficial force that makes us stronger. I wonder how worms work into this plan. Because this seems like a chronic stress that an animal (actually its immune system) just gets used to.

Jane said...

The gallstones are interesting. A recent paper links them with meat eating.

'Excessive iron intake can promote biliary cholesterol crystal formation in experimental studies. The absorption of heme iron is more complete than that of non-heme iron in humans... Our findings suggest that a higher consumption of heme iron is associated with a greater risk of gallstone disease among men.'

Stephan Guyenet said...

Hi Kurt,

Thanks, I corrected the post. I agree with you about intestinal parasites. They may well be beneficial at the right dose.

Hi George Henderson,

Euvermic. I like it.

Anonymous said...

Hi Gunther

"We also have to factor in the overall burden effect.

Well, yes and no. The burden of one particular species, at least with species that do not auto-infect, goes up with more sedentism and crowding. Otherwise they tend to stay at quite tolerable levels throughout life. Some species, like E vermicularis, predominate in kids, and some, like necator americanus tend to have higher burdens in adults. As far as being colonized by more than one species, that is actually very common and not harmful per se as it depends more on what you are infected by and whether you are continually getting more organisms by, say, fertilizing crops with human waste.


The way helminths work is not really hormesis, as there is nothing intermittent about it when they actually work for you to prevent immune dysregulation. Instead, helminths that meet the criteria of "old friends" actively and continuously elaborate chemical signals that change our immune responses in very specific ways, including induction of Treg cells. Intermittent or short term infections provide no benefit at all, only long term and stable ones.

As they are complex eukaryotic animals, they might be thought of as accessory immune organs.

Swede said...

Has anyone here ever had a known parasite worm?

My brother once coughed one out of his nose. We were quite disgusted. As far as I know I have never had the fortune to be so employed.

Stephan Guyenet said...

Hi Swede,

Probably a lot of people here have had pinworms. It's a common childhood parasite.

allison said...

The tallest people (by national statistics) are the Dutch, who are slightly taller on average than the Maasai. Both consume large quanities of dairy.

Puddleg said...

Pinworm good for you?


Infection with Syphacia obvelata (Pinworm) Induces Protective Th2 Immune Responses and Influences Ovalbumin-Induced Allergic Reactions

(actually this doesn't seem to provee much, exept that pinworms influence immunity, but I'm sure there's more out there)

Because pinworm has a life-cycle easily controlled by behaviour (handwashing) it should perhaps be considered as the first "old friend" to call on in avermic times of need?

The problem with worms, lice etc, is that at times of low nutrition they can deplete minerals; headlice are connected to anaemia.

Carnosine protects against at least one parasite, bilharzia.

I'm not convinced that meat causes gallstones. They are more likely to be caused by prolonged deficiency of fat in the diet resulting in biliary stasis.
We can pay too much attention to what Otzi ate and not enough to the possibility that he starved more often than was good for him.

Anonymous said...


SO is a murine pinworm I take it. I am aware of one anecdotal report of a person with Crohn's who flared upon taking Mebendazole for E. vermicularis (human pinworm) so pinworm may indeed be an old friend. The natural history seems to be that pinworm does not normally infect adults. Whether that is due to acquired immunity or the change in hand washing and butt-scratching behavior as we get older is not clear.

It's good to note that the average parasite. when you take all comers, is NOT likely to be an old friend. Low virulence and long persistent infections are typical. Only one virus is a candidate and that is Hep A, although it may be a marker for fecal oral contact as much as anything.

The best candidates for Old Friends are Necator Americanus and Trichuris trichuria among helminths, and H Pylori among the protozoans, and soil saprophytes like Mycobacterium Vaccae and low virulence salmonella species among the prokaryotes.

Pinworm might work immunologically but therapeutically it is not so good. It is easy to spread and hard to control and you are scratching your butt all the time.

M. Vaccae as a killed vaccine is undergoing clinical trials as an immune modulator. M. vaccae may cure eczema in dogs and has shown anti depressive effects in humans.

I also agree with you that fat deficiency is much more likely to associate with gallstones than meat consumption. I never saw a single person with gallstones in 25 years who ate a high fat diet. Sugar and cereal grains and skimmed milk seemed more typical in my practice.

Puddleg said...

It's easy to catch pinworm off young kids, but as easy to get rid of it right away.
It's probably quite common, intermittently, in adults with junior school-age kids, who haven't learned much food hygiene.
It doesn't seem to have much noticable effect as an immunomodulator in adults, but may be important to kids.

the killed vaccines are very interesting. An example in common use is Buccaline Berna. A killed probiotic (rhamnosus) extract, Del Immune V, is popular and tho there is not much research to date its popularity is not without good cause. It seems to have antidepressive effects, that is, it made me burst out laughing for no reason on one occasion and is useful for PMS.
But I would really like to see theese effects quantified; there is a sublingual rhamnosus extract currently approaching a proof of concept trial that I have a watching brief on.
Treg activation also requires vitamin A (all-trans retinol) in humans, and there is a synergy with vitamin D.

fr said...

On the subject of worms, biologists have observed chimpanzes in the wild eating some sort of leaf that mechanically scrapes away the worms from the intestine. Biologists have also observed bears that had worms somehow got rid of them just before going into hibernation. And herbal medicine has all sorts of vermifuge remedies. All this suggests that our ancestoers were quite capable of getting rid of many types of worms, if they felt that the worms were causing problems.

Stephan Guyenet said...

Hi Frank,

That's true, although these remedies aren't as effective as modern drugs or getting rid of worms. Worms can definitely be a problem, particularly if there is a major infestation. I don't think anyone would dispute that they've been responsible for many health problems over the millennia. But having a few worms of the right species may actually be beneficial. I'm looking forward to more research on it.

Jin said...

Awhile ago, the radio show, Radio Lab, had a fascinating program called Parasites. I particularly enjoyed the story of the man who sought out hookworm to wrestle back his debilitating seasonal allergies.

colin henley said...

We know little about the human settlement of the Austrian, Swiss, and French Alps, which goes back to prehistoric times. But we really ought to consider how it was that people who farmed and raised livestock moved into the wild, impassable valleys of the High Alps, where to begin with they could at best eke out a hard, meagre, and risk-filled existence. The most likely explanation is that these people preferred an uncertain life in the wilds to subjugation by more powerful neighbours. Despite the uncertainty and the danger, they chose freedom. I often like to play with the idea that the Swiss and Tyrolean tradition of freedom, in particular, goes back to those days of the prehistoric settlement of Switzerland.
- Karl Popper
from All Life Is Problem Solving

LeonRover said...

I wonder if that other Viennese scientist, Konrad Lorenz, had anything to say about these high-Alpine ancestors?

The colloquial history of some Alpine valleys - Alagna, Valsesia, on the southern slopes of Monte Rosa - recalls that the Walser inhabitants arrived there from about 1200's, and were offered the highest, least productive land by the local baron. As herders, they practised "vertical transhumance" of their cattle to the pasturage in the highest Alps.

Jurmaine Health said...

Nice information about diet, disease, diseases of civilization, evolution, infection, native diet etc. You really made your blog a good source of learning.Good work keep it up !!

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Jane said...

I just looked up 'ancient egyptians gallstones' and discovered they didn't really have them. A single case in 30,000 mummies examined by Elliot Smith & Dawson in 1924.

Ancient Egyptians ate wheat, which makes it unlikely that Otzi's wheat bread was responsible for his gallstones.

I think we have to say Otzi had oxidative stress, because vascular calcification, osteoarthritis and gallstones are associated with oxidative stress today.

One way to get oxidative stress is to eat red meat + white bread, which provides a lot of highly available iron and hardly any manganese, which is needed to counteract the pro-oxidative effects of excess/deregulated iron.

Another way, at least in theory, is to eat red meat and have Lyme disease. Otzi seems to have had Lyme disease. The bacterium uses manganese where other bacteria use iron, and cannot grow if its manganese transporter isn't working. It seems possible that the symptoms of Lyme disease are due at least in part to manganese depletion.

Jane said...

Postscript: I am a bit doubtful now about the idea that only one ancient Egyptian out of 30,000 had gallstones. Apparently Elliot Smith did examine 30,000 mummies, but did not make detailed notes on each one, perhaps not surprisingly. I think the most we can say is that gallstones were rare.

David said...

Stephan, interesting that Otzi has atherosclerosis - do wild animals show atherosclerosis or is it an exclusive human condition?

Don S said...

David, Yes wild animals do also get atherosclerosis.

Take a look at this very old article:


commoncents said...


Common Cents

Kyle said...

Hey Stehphan, I know you are getting away from discussing food reward but I saw this over at Tom Naughton's site. Looks like the ultimate in removing every single type of reward food could give you: taste, smell, even texture. http://gma.yahoo.com/k-e-diet-brides-using-feeding-tubes-rapidly-080053646--abc-news-health.html

Puddleg said...

On second thoughts, I can think of two related reasons why pinworm might not be the most desirable immunomodulator;
1) pinworm depends on causing irritation, so is not wholy antiinflammatory in its interaction with the host
2) this means that our ability to tolerate it for long periods is reduced compared to other helminths.
In fact, I remember being treated for pinworm as a child with the same antihelmetic drugs that kill off other "old friends".
Betel nut is antihelmetic, BTW.

@ Jim, I saw that story on "monsters inside me" on the Animal channel. It seemed to work very well indeed. He waded barefoot through the sewage of several African villages to get the hookworm infestation he needed.

Is the meat that supposedly causes gallstones the dreaded "lean protein" beloved of trendy nutritionists?
That actually wouldn't surprise me.

Galina L. said...

My husband has a mild asthma and he was intrigued when I told him about different evidence about potential benefits on helminthic therapy. He is a very skeptical guy, check out rates of asthma in Africa, found it high, and it was it for him.

Puddleg said...

There's probably more to asthma than just autoimmunity. Smoky or mouldy housing, toxic work environments, deficiency of vit A, glutathione and other antioxidants.
Hookworm was useful for life-threatening allergies, Crohns, etc.
He could try probiotics for a milder version of the same, or similar effect, for example rhanmosus-reuterii mixtures.
These quickly fixed my and my partner's hay fever one summer when taken for another purpose.

Jane said...

A 2006 paper links asthma with a low manganese intake.

'..Increasing intake of vitamin C, folate, calcium, and manganese were individually associated with a reduced risk of diagnosed asthma. However, after mutual adjustment, only the association with dietary manganese remained significant... Moreover, dietary manganese has been reported to be inversely associated with bronchial hyperreactivity19 and asthma in adults,22... Manganese has antioxidant properties36 and dietary intake of manganese may modify the activity of manganese dependent superoxide dismutase.37 The role of this enzyme in protecting the lung from oxidative damage has recently been reviewed38 and reduced levels of superoxide dismutase activity have been reported in both the lung39 and blood monocytes of people with asthma.40..'

Galina L. said...

@George Henderson &Jane,
thank you for your responses, I think my husband's diet is pretty decent, I cook all our meals, liver is present in our menu ones a week, I make my own sauerkraut, he eats everyday a soup made with good broth and veggies. Probably I should add some filberts as a manganese source and try the probiotic supplement George Henderson suggested. I think the main reason my husband has a problem with his asthma is a toxic work environment. He works as a chemist in RD facility, obviously deals with chemicals and a chemical production plant is nearby.

Puddleg said...

@Galina, I really meant that those factors were likely to skew the African asthma associations.
And that probiotics are an easy way to test whether the hygiene hypothesis applies to any allergic/inflammatory situation, without having to wade through sewage. The effect may not be as good as hookworm, but if it's there, it should be noticable.
If the asthma is being triggered by solvents, as seems likely, it gets tougher to prevent; perhaps medicinal fungi like ganoderma lucidum or cordyceps


these have some effects in common with probiotics and helminths, but also contain terpenoid, polyphenolic and other antioxidant and antiinflammatory molecules.

@Jane, good study.
This site http://www.ithyroid.com/
has a great collection of papers about minerals and how they interact.
If you haven't already been there, you might find some new Mn data.

Puddleg said...


this is a better link, the site isn't as easy to search as it once was.

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Brenda said...

Lot of great info! Look forward to reading more!

Brenda said...

Lot of good info. Looking forward to reading more.

Jens said...

I'm just gonna chime in and say that I really like your blog, man.

You're like a voice of reason amongst the somewhat crazy paleo bunch.

patienttrackmate App said...

very useful.......


Jane said...

George, thanks, yes I remember seeing that site and liking it. Interesting that violent prisoners have high hair manganese, isn't it. I wonder if it's because they have high cortisol, which releases manganese from the liver, I suppose as part of the stress response. Perhaps it's meant to protect your brain from stress-induced damage.

Jane said...

George, I forgot, violent prisoners have LOWER cortisol. Sorry.

Puddleg said...

In the cognitive dysfunction associated with liver cirrhosis, high levels of free Mn are sometimes seen. Perhaps it is released by mitochondrial breakdown or non-completion of MnSOD synthesis.
There is a parallel here with iron; it may be how well the mineral is bound in proteins, and how well levels are regulated, rather than how much is present,that decides the effect?

Jane said...

Yes, I'm sure that's right, at least in the case of iron. It's free iron that's the problem. Free Mn doesn't seem to be a problem at all, rather the reverse, unless the levels are unrealistically high. Have you seen this remarkable paper showing that iron-induced Parkinsonism in rats can be completely prevented by Mn?

I wonder how much of the cognitive dysfunction associated with liver cirrhosis is due to failure of the urea cycle so ammonia gets into the brain. In that case, the excess Mn would be there 'on purpose' to activate glutamine synthetase and detoxify the ammonia.

Puddleg said...

And also detoxify glutamate, which can damage the brain?
The ammonia seems to be produced by gut dysbiosis and removed by bifidus bactera.
Acetyl-carnitine also protects mitochondria in HE

"The benefits of ALC in comparison with placebo are demonstrated in greater reductions in serum ammonia levels, as well as in improvements of neuropsychological functioning"

Puddleg said...

This classic review by Douglas Kell


Covers the regulation and utilization of iron in the body, and what can go wrong when it isn't chelated properly, from every angle.

Puddleg said...

This is a better version of the Douglas Kell classic

It is mentioned here:

9.Weightlifting with citations Contestants write long review papers. The person who can cite the most papers in a single publication wins. Current world-record unknown but 2,184 references in a single paper is a pretty high score [2,3]. If you’ve ever written a scientific paper, what is your “personal best”?

Jane said...

Thanks, yes I've read Iron Behaving Badly, who could resist that title? And yes, I've published some papers, see 'jane karlsson drosophila'. My Drosophila work led me to believe that modern disease is caused by micronutrient deficiencies (especially of Mn and Cu) and not genes. I tried to tell my Oxford college and it terminated my fellowship.

Interesting about gut bacteria and ammonia. There are people who think ammonia is important in Alzheimer's, and we know certain B vitamins are also important. All three of these B vitamins can be made by gut bacteria. Gut dysbiosis in Alzheimer's? I think so.

Iron overload too of course, and we now know that the function of the Amyloid Precursor Protein is to enable iron efflux from neurons. It's a copper protein like ceruloplasmin and hephaestin which also enable iron efflux. Surprisingly, Iron Behaving Badly does not mention copper.

So carnitine activates the urea cycle. Very interesting. Carnitine synthesis involves methylation, which needs both the B vitamins implicated in Alzheimer's, and copper.

Jane said...

Forgot to say, yes indeed, glutamine synthetase does detoxify glutamate as well as ammonia, and both are implicated in Alzheimer's.

Puddleg said...

The role of thiamine in preventing Wernicke-Korsakoff syndrome relates in part to its role in the GABA shunt for glutamate metabolism.
Too little glutamate = loss of memory, but the glutamate is probably being converted to GABA here to protect the brain.

As for the hypothesis that some micronutrient deficiencies are responsible for gluten intolerance, I have really tested this over the years and think it is not the case.
It is true that coeliac etc. causes micronutrient deficiencies, but not that correcting these is all it takes to digest grains again.

It's possible that optimum nutrition could help prevent coeliac in the first place, but if you look at type 1 diabetes, which seems to often be a gluten-sensitivity disease, it has proved very hard to prevent this reliably, though some nutrients reduce risk it makes more sense to avoid grains altogether.
Bifidobacteria create an immune milieu which can reduce sensitivity to gliadin, so perhaps early dysbiosis (say, antibiotic use before weaning) is causative in coeliac and DM1.

Not something Otzii had to deal with perhaps. Grains were a cause of disease as sub-optimal foods but he may have avoided the worst forms of intolerance.

Puddleg said...

Bifidobactera and Coeliac


Jane said...

George, could I ask please, how have you tested the idea that micronutrient deficiencies are responsible for gluten intolerance?

It seems to me that it all boils down to the health of the gut immune system. If it's working properly, gluten won't be a problem because of 'oral tolerance'. If you eat micronutrient depleted food all your life, and your mother did too, your gut immune system will be lucky to escape.

Puddleg said...

Well I don't think my childhood diet was poor in micronutrients, but there was always gluten and sugar to hand.
I've tried pretty much anything and everything in the way of foods and supplements with the idea that there has to be an antidote.
Then I realised, I don't have to eat foods that need antidotes or extra micronutrients in the first place.
I'd rather keep my gut immunity healthy for pathogens. It doesn't need to get over-involved in the digestion of food.
There is a technical reason why proline-rich peptides such as gliadorphin or BCM7 are more likely to go imperfectly digested.
Proline is a bulky molecule and the bond it forms in peptides is especially resistant to proteolysis.
Jane, see
This excellent summary backs both your view of the causes of grain toxicity and my plan of avoiding grains for the rest of my life.

Jane said...

Did you give me the wrong link? That one is about cellulite.

Yes proline bonds are difficult to break. There are suggestions in the literature that at least some of the the gut peptidases that break them are dependent on metals and especially manganese.

I think your childhood diet may have been poorer in micronutrients than you think. Here in the UK, the copper content of vegetables has fallen in the last 60 years by an astonishing 75%.

Jane said...

'..Since the intestinal enzymes that hydrolyze other peptides such as glycylglycine and prolylglycine are also activated by Mn [refs], it becomes clear that there are in intestinal mucosa several metal-containing proteases. ..'


Puddleg said...

I'm impressed.
It would be interesting to see if low Mn is associated with other autoimmune conditions besides asthma.
A connection to type 1 diabetes woul be very interesting.
Or lymphoma.
Or, of course, coeliac itself.

Puddleg said...

Here we go: Non-hodgkins lymphoma
(the coeliac-associated sort)

Several studies indicated significant associations with increased vegetable and fruit intake and reduced incidence of lymphoid cancers. Vegetables and fruits contain many potentially protective substances, including several antioxidants, as well as phytochemicals with antiproliferative capabilities. They are also a rich source of folate, which plays an important role in the synthesis, repair, and methylation of DNA. A recent cohort study (the Iowa Women’n Health Study) based on about 35,200 women found a protection for specific antioxidants (relative risk, RR= 0.8 for vitamin C; RR=0.7 for both beta-carotene and proanthocyanidins) and dietary manganese (RR=0.6). Greater intake of total fruits and vegetables were associated with lower NHL risk. There were no associations with multivitamin use or supplemental intake of vitamins C, E, selenium, zinc, copper or manganese (Thompson 2010).

Puddleg said...

I will probably never find that gluten link again; it was a goody.
Hope the cellulite link helps the guy who asked about that...

Jane said...

Thanks George. Interesting about lymphoma. Actually if you look up 'MnSOD cancer' you will find a lot of interesting stuff.

'Manganese superoxide dismutase (MnSOD) activity is generally lower in cancer cells compared with their normal counterparts. Many studies have shown that replacing the diminished MnSOD activity leads to inhibition of the malignant phenotype.'

MnSOD also plays a central role in insulin resistance.

'..insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD.'

It's also involved in autophagy. The hydrogen peroxide it produces goes to the nucleus and induces transcription of a lot of genes associated with longevity - extra MnSOD makes flies and worms live longer - and some of these are autophagy genes.

Jane said...

George, I tried posting a reply to you and it isn't here. If this one succeeds, I'll write it again.

Puddleg said...

SOD isn't an antioxidant enzyme;
it converts a reducing radical (superoxide) to an oxidising ROS, peroxide.
This can be quenched by Se peroxidase or Fe catalase, but it can also act as a messenger, as you describe.
Regarded in isolation, SOD is a pro-oxidant enzyme that quenches a reductive stessor.

Christine Eubanks said...


I suggest in order for you to enjoy meals, you must do and enjoy EFT also known as tapping.

Puddleg said...

So why is SOD considered part of antioxidant defenses?
1) because superoxide radical left unquenched can reduce free or lightly bound iron (or copper); Fe2+ can then produce hydroxyl radical, which is much more reactive than peroxide
2) superoxide can quench nitric oxide to produce peroxynitrite (and low-nitric oxide states).
There are no doubt other free-radical generating actions of superoxide which SOD mitigates. Peroxide is both useful and the lesser evil. And catalase and peroxidase exist to control any excess.