Download Vitamin K, moreover, is involved in much more than osteocalcin

Weston A. Price Foundation - Videos:
http://www.westonaprice.org/beginnervideos
On the Trail of the Elusive X-Factor: A Sixty-Two-Year-Old Mystery
Finally Solved
Written by Chris Masterjohn
Thursday, 14 February 2008 02:16
Contents
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Article Summary
On the Trail of the Elusive X-Factor (Main Article)
o A Sixty-Year Mystery
o Vitamin K: Three Discoveries Converge
o Perfect Correspondence
o Synergy with Vitamins A and D
o Vitamin K2 and Dental Health
o Vitamin K2 and Bone Health
o Vitamin K2 and Heart Disease
o Vitamin K2 and the Brain
o Other Roles of Vitamin K2
o Vitamin K2 in Foods
Figures
o Figure 1: The Structure of K Vitamins and Their Chemical Behavior
o Figure 2: Corresponding Characteristics of Activator X and Vitamin K2
o Figure 3: Vitamin K-Dependent Carboxylation
o Figure 4: Vitamin K2 Contents of Selected Foods
Sidebars
o The Activator X Test
o Interactions between Vitamins A, D, and K2
o Is Vitamin K2 an Essential Nutrient?
o The Vitamin K-Dependent Carboxylase
o Vitamin K2 and the Brain: A Closer Look
o Bacterial Production of Vitamin K2
o Supplementing with Vitamin K2
References
Follow Up Questions & Answers
Article Summary
In 1945, Dr. Weston Price described "a new vitamin-like activator" that played an influential
role in the utilization of minerals, protection from tooth decay, growth and development,
reproduction, protection against heart disease and the function of the brain.
Using a chemical test, he determined that this compound—which he called Activator X—
occurred in the butterfat, organs and fat of animals consuming rapidly growing green grass,
and also in certain sea foods such as fish eggs.
Dr. Price died before research by Russian scientists became known in the West. These
scientists used the same chemical test to measure a compound similar to vitamin K.
1
Vitamin K2 is produced by animal tissues, including the mammary glands, from vitamin K1,
which occurs in rapidly growing green plants.
A growing body of published research confirms Dr. Price's discoveries, namely that vitamin
K2 is important for the utilization of minerals, protects against tooth decay, supports growth
and development, is involved in normal reproduction, protects against calcification of the
arteries leading to heart disease, and is a major component of the brain.
Vitamin K2 works synergistically with the two other "fat-soluble activators" that Price
studied, vitamins A and D. Vitamins A and D signal to the cells to produce certain proteins
and vitamin K then activates these proteins.
Vitamin K2 plays a crucial role in the development of the facial bones, and its presence in
the diets of nonindustrialized peoples explains the wide facial structure and freedom from
dental deformities that Weston Price observed.
Main Article (On the Trail of the Elusive X-Factor)
Read in: Czech
In 1945, Weston Price published a second edition of his pioneering work Nutrition and
Physical Degeneration, to which he added a new chapter entitled, "A New Vitamin-Like
Activator."1 In it, he presented evidence of a theretofore unrecognized fat-soluble substance
that played a fundamental role in the utilization of minerals and whose absence from modern
nutrition was responsible for the proliferation of dental caries and other degenerative diseases.
Although Price quantified the relative amount of this substance in thousands of samples of
dairy products sent to him from around the world, he never determined its precise chemical
identity. For want of a better means of identification, he referred to it as "Activator X," also
sometimes referred to as the "Price Factor."
Price found the highest concentrations of this nutrient in "the milk of several species, varying
with the nutrition of the animal" and found the combination of cod liver oil and highActivator X butter to be superior to that of cod liver oil alone. In the many butter samples he
tested, Activator X was only present when the animals were eating rapidly growing green
grass. In most regions, this occurred in the spring and early fall.
A Sixty-Year Mystery
For over sixty years, all attempts to identify this elusive "X" factor have failed. In the 1940s,
Dr. Royal Lee, founder of the whole food supplement company Standard Process, suggested
that activator X was the essential fatty acids.2 In 1980, Dr. Jeffrey Bland suggested more
specifically that it was the elongated omega-3 essential fatty acid called EPA.3 Although these
fatty acids exert some effects on calcium metabolism,4 neither the distribution of these
unsaturated fatty acids in foods nor their chemical behavior corresponds to that of Activator
X. Cod liver oil is much richer than butter in essential fatty acids including EPA, and the oils
of plant seeds are even richer in these fats, but Price found little, if any, Activator X in these
foods. Moreover, Price tested for Activator X by quantifying the ability of a food to oxidize
iodide to iodine; essential fatty acids, however, do not possess this chemical ability.
2
In 1982, one author wrote to the Price-Pottenger Nutrition Foundation that after pursuing a
number of false leads while attempting to identify the X factor, he had concluded that the
"peculiar behavior" observed in Price's chemical test might be due to a "special kind of
oxygen-containing heterocyclic ring," and suggested a compound called 6methoxybenzoxazolinone (MBOA) as a likely candidate.5 Although researchers first
identified MBOA as an antifungal agent found in corn,6 later studies showed that it was found
in many other plant foods and acted as a reproductive stimulant in some animals by
mimicking the hormone melatonin.7 Although it is present in young, rapidly growing grass,
no research has ever established MBOA as an essential nutrient, attributed to it any of the
physiological roles of Activator X, or demonstrated its presence in the foods that Price
considered to be the richest sources of this nutrient. MBOA, then, was just another false lead;
we will soon see, however, that the writer's observations about the chemical nature of
Activator X were largely correct.
Vitamin K: Three Discoveries Converge
The test that Price used for Activator X, called iodometric determination, was traditionally
regarded within the English language literature as a test for peroxides (carbon-containing
molecules that have been damaged by oxygen).8,9 Since peroxides do not have any activity as
vitamins, the relationship between the test and any nutritional substance remained a mystery.
Although researchers publishing in other languages were using the test to detect a class of
chemicals called quinones at least as far back as 1910,10 it was not until 1972 that Danish
researchers published a paper in the British Journal of Nutrition showing that the test could be
used to detect biological quinones such as K vitamins in animal tissues.12
K vitamins (Figure 1) possess oxygen-containing ring structures that are capable of oxidizing
iodide to iodine and would therefore be detected by Price's Activator X test. The K vitamins
are likely to go down in history as the most misunderstood group of vitamins of the twentieth
century. In many ways, however, modern researchers are now rediscovering properties of
these vitamins that Price had discovered over sixty years ago. It has now become clear that
both Activator X and its precursor in rapidly growing grass are both members of this group.
There are two natural forms of vitamin K: vitamin K1 and vitamin K2. Vitamin K1, also called
phylloquinone, is found in the green tissues of plants, tightly embedded within the membrane
of the photosynthesizing organelle called the chloroplast. As the chlorophyll within this
organelle absorbs energy from sunlight, it releases high-energy electrons; vitamin K1 forms a
bridge between chlorophyll and several iron-sulfur centers across which these electrons travel,
releasing their energy so that the cell can ultimately use it to synthesize glucose.13
When animals consume vitamin K1, their tissues convert part of it into vitamin K2,14 which
fulfills a host of physiological functions in the animal that we are only now beginning to
understand. The ability to make this conversion varies widely not only between species14 but
even between strains of laboratory rats,15,16 and has not been determined in humans. The
mammary glands appear to be especially efficient at making this conversion, presumably
because vitamin K2 is essential for the growing infant.17 Vitamin K2 is also produced by lactic
acid bacteria,18 although bacteria produce forms of the vitamin that are chemically different
from those that animals produce, and researchers have not yet established the differences in
biological activity between these forms.
Although both K vitamins were discovered and characterized over the course of the 1930s,
3
two fundamental misunderstandings about these vitamins persisted for over sixty years: the
medical and nutritional communities considered blood clotting to be their only role in the
body, and considered vitamins K1 and K2 to simply be different forms of the same vitamin.
The first vitamin K-dependent protein relating to skeletal metabolism was not discovered until
1978. It was not until 1997, nearly twenty years later, that the recognition that vitamin K was
"not just for clotting anymore" broke out of the confines of the fundamental vitamin K
research community.19
Since the amount of vitamin K1 in typical diets is ten times greater than that of vitamin K2,20
researchers have tended to dismiss the contribution of K2 to nutritional status as insignificant.
Yet over the last few years, a growing body of research is demonstrating that these two
substances are not simply different forms of the same vitamin, but are better seen as two
different vitamins: whereas K1 is preferentially used by the liver to activate blood clotting
proteins, K2 is preferentially used by the other tissues to place calcium where it belongs, in the
bones and teeth, and keep it out of where it does not belong, in the soft tissues.21
Acknowledging this research, the United States Department of Agriculture, in conjunction
with researchers from Tufts University, finally determined the vitamin K2 contents of foods in
the U.S. diet for the first time in 2006.22
Perfect Correspondence
Because vitamin K1 is directly associated with both chlorophyll and beta-carotene within a
single protein complex and plays a direct role in photosynthesis,13 the richness of the green
color of grass, its rate of growth, and its brix rating (which measures the density of organic
material produced by the plant) all directly indicate its concentration of vitamin K1. Animals
grazing on grass will accumulate vitamin K2 in their tissues in direct proportion to the amount
of vitamin K1 in their diet. The beta-carotene associated with vitamin K1 will also impart a
yellow or orange color to butterfat; the richness of this color therefore indirectly indicates the
amount of both vitamins K1 and K2 in the butter. Not only are the K vitamins detected by the
Activator X test and distributed in the food supply precisely as Price suggested, but, as shown
in Figure 2, the physiological actions that Price attributed to Activator X correspond perfectly
to those of vitamin K2. It is therefore clear that the precursor to Activator X found in rapidly
growing, green grass is none other than vitamin K1, while Activator X itself is none other than
vitamin K2.
Ironically, Price discovered the roles of vitamin K2 in calcium metabolism, the nervous
system and the cardiovascular system more than sixty years before the vitamin K research
community began elucidating these roles itself, while vitamin K researchers discovered the
chemical structure of activator X several years before Price even proposed its existence. Had
Price been aware that his chemical test had been used for decades outside of the English
language scientific community to detect quinones, a class to which the K vitamins belong, the
two independent discoveries of this one vitamin may have converged sooner.
Instead, English-speaking researchers continued for decades to labor under the illusion that
the iodometric method detected only peroxides; by the time this illusion was corrected, better
methods for detecting peroxides had already been developed, Activator X had been forgotten,
and the opportunity to make the connection between these three discoveries was lost. The
twenty-first century, however, is already making radical revisions to our understanding of the
K vitamins, which now make it clearer than ever that Activator X and vitamin K2 are one and
the same.
4
Synergy with Vitamins A and D
Price showed Activator X to exhibit dramatic synergy with vitamins A and D. Chickens
voluntarily consumed more butter and died more slowly on a deficiency diet when the butter
was high in both vitamin A and Activator X than when it was high in vitamin A alone. Cod
liver oil, which is high in both vitamins A and D, partially corrected growth retardation and
weak legs in turkeys fed a deficiency diet, but the combination of cod liver oil and highActivator X butter was twice as effective. Likewise, Price found that the combination of cod
liver oil and a high-Activator X butter oil concentrate was more effective than cod liver oil
alone in treating his patients for dental caries and other signs of physical degeneration.
Vitamin K2 is the substance that makes the vitamin A- and vitamin D-dependent proteins
come to life. While vitamins A and D act as signaling molecules, telling cells to make certain
proteins, vitamin K2 activates these proteins by conferring upon them the physical ability to
bind calcium. In some cases these proteins directly coordinate the movement or organization
of calcium themselves; in other cases the calcium acts as a glue to hold the protein in a certain
shape.33 In all such cases, the proteins are only functional once they have been activated by
vitamin K.
Osteocalcin, for example, is a protein responsible for organizing the deposition of calcium and
phosphorus salts in bones and teeth. Cells only produce this protein in the presence of both
vitamins A and D;34 it will only accumulate in the extracellular matrix and facilitate the
deposition of calcium salts, however, once it has been activated by vitamin K2.35 Vitamins A
and D regulate the expression of matrix Gla protein (MGP),36,37 which is responsible for
mineralizing bone and protecting the arteries from calcification; like osteocalcin, however,
MGP can only fulfill its function once it has been activated by vitamin K2.33 While vitamins A
and D contribute to growth by stimulating growth factors and promoting the absorption of
minerals, vitamin K2 makes its own essential contribution to growth by preventing the
premature calcification of the cartilaginous growth zones of bones.38
Vitamin K2 may also be required for the safety of vitamin D. The anorexia, lethargy, growth
retardation, bone resorption, and soft tissue calcification that animals fed toxic doses of
vitamin D exhibit bear a striking resemblance to the symptoms of deficiencies in vitamin K or
vitamin K-dependent proteins. Warfarin, which inhibits the recycling of vitamin K, enhances
vitamin D toxicity and exerts a similar type of toxicity itself. Similarly, the same compounds
that inhibit the toxicity of Warfarin also inhibit the toxicity of vitamin D. I have therefore
hypothesized elsewhere that vitamin D toxicity is actually a relative deficiency of vitamin
K2.39 The synergy with which vitamin K2 interacts with vitamins A and D is exactly the type
of synergy that Price attributed to Activator X.
Vitamin K2 and Dental Health
Weston Price was primarily interested in Activator X because of its ability to control dental
caries. By studying the remains of human skeletons from past eras, he estimated that there had
been more dental caries in the preceding hundred years than there had been in any previous
thousand-year period and suggested that Activator X was a key substance that people of the
past obtained but that modern nutrition did not adequately provide. Price used the
combination of high-vitamin cod liver oil and high-Activator X butter oil as the cornerstone
of his protocol for reversing dental caries. This protocol not only stopped the progression of
5
tooth decay, but completely reversed it without the need for oral surgery by causing the dentin
to grow and remineralize, sealing what were once active caries with a glassy finish. One 14year-old girl completely healed 42 open cavities in 24 teeth by taking capsules of the highvitamin cod liver oil and Activator X concentrate three times a day for seven months.
Activator X also influences the composition of saliva. Price found that if he collected the
saliva of individuals immune to dental caries and shook it with powdered bone or tooth meal,
phosphorus would move from the saliva to the powder; by contrast, if he conducted the same
procedure with the saliva of individuals susceptible to dental caries, the phosphorus would
move in the opposite direction from the powder to the saliva. Administration of the Activator
X concentrate to his patients consistently changed the chemical behavior of their saliva from
phosphorus-accepting to phosphorus-donating. The Activator X concentrate also reduced the
bacterial count of their saliva. In a group of six patients, administration of the concentrate
reduced the Lactobacillus acidophilus count from 323,000 to 15,000. In one individual, the
combination of cod liver oil and Activator X concentrate reduced the L. acidophilus count
from 680,000 to 0.
In the 1940s, researchers showed that menadione and related compounds inhibited the
bacterial production of acids in isolated saliva.47 Menadione itself is a toxic synthetic
analogue of vitamin K, but animal tissues are able to convert a portion of it to vitamin K2. The
ability of vitamin K-related compounds to inhibit acid production in isolated saliva had no
relationship to their vitamin activity, and the most effective of these compounds had
practically no vitamin activity at all.48 Researchers unfortunately assumed that because
vitamin K did not have a unique role in inhibiting acid formation in saliva within a test tube
that it had no nutritional role in preventing tooth decay within living beings.
In 1945, American researchers conducted a double-blind, placebo-controlled trial of
menadione-laced chewing gum and showed it to reduce the incidence of new cavities and
cause a dramatic drop in the L. acidophilus count of saliva.49 The next year, the Army
Medical Department attempted to repeat these results but failed, and research on vitamin K
and dental health in the United States was subsequently abandoned.50 The authors of the
original study assumed that the menadione exerted its effect simply as a topical anti-bacterial
agent, even though it was highly unlikely to sustain a sufficient concentration in the saliva to
exert this effect. Ten years later, German researchers showed that injecting menadione into
the abdominal cavities of hamsters more effectively prevented tooth decay than feeding it
orally.51 Although they could not rule out the possibility that some of this menadione was
secreted into the saliva, their results argued in favor of a nutritional role for the vitamin K2
that would have been produced from it. Despite this finding, to this day no one has
investigated the role of natural K vitamins in the prevention of dental caries.
Nevertheless, our continually expanding understanding of the physiology of both K vitamins
and teeth now makes it clear that vitamin K2 plays an essential role in dental health. Of all
organs in the body, vitamin K2 exists in the second highest concentration in the salivary
glands (the highest concentration is found in the pancreas). Even when rats are fed only K1,
nearly all of the vitamin K in their salivary glands exists as K2.15 Both vitamin K52 and
vitamin K-dependent proteins53 are secreted into the saliva, although their function is
unknown.
We now know that the growth and mineralization of the dentin that Price observed in
response to the combination of cod liver oil and Activator X concentrate would primarily
6
require three essential factors: vitamins A, D, and K2. There are three calcified tissues of the
teeth: the cementum forms the roots, the enamel forms the surface, and the dentin forms the
support structure beneath it. Cells called odontoblasts lining the surface of the pulp just
beneath the dentin continually produce new dentin material. If a cavity invades the dentin and
reaches these cells they can die. The pulp tissue, however, contains stem cells that can
differentiate into new odontoblasts that could regenerate the lost dentin if the right conditions
were present.54
Dentin is unique among the tissues of the teeth for its expression of osteocalcin, a vitamin Kdependent protein better known for its role in organizing the deposition of calcium and
phosphorus salts in bone. In the infant rat, whose teeth grow very rapidly, dentin
manufactures much more osteocalcin than bone does, suggesting that osteocalcin plays an
important role in the growth of new dentin. Matrix Gla protein (MGP), which is required for
the mineralization of bone, is also expressed in dentin.55 Vitamins A and D signal
odontoblasts to produce osteocalcin,56,57 and probably regulate their expression of MGP as
well. Only after vitamin K2 activates these proteins' ability to bind calcium, however, can they
lay down the mineral-rich matrix of dentin. The remarkable synergy between these three
vitamins exactly mirrors the process Price observed.
Vitamin K2 and Bone Health
Price also believed that Activator X played an important role in bone health. Butter oil
concentrate cured rickets and increased serum levels of calcium and phosphorus in rats
consuming a mineral-deficient diet. In a four-year-old boy who suffered from rampant tooth
decay, seizures and a tendency to fracture, the combination of a large helping of this
concentrate and a meal of whole wheat and whole milk rapidly resolved each of these
symptoms.
Although the small amount of vitamin D in the butter oil was probably sufficient to cure
rickets and the combination of vitamins A and D most likely produced the rise in serum
calcium and phosphorus,58 vitamin K2 has a definite role in bone health. There are at least two
vitamin K-dependent proteins that fulfill important functions in skeletal metabolism: matrix
Gla protein (MGP) and osteocalcin.
In 1997, researchers from the University of Texas and the University of Montreal developed
mice that lacked the gene that codes for MGP. These mice appeared normal for the first two
weeks of their lives, after which they developed faster heart beats, stopped growing and died
within two months with the rupture of their heavily calcified aortas. The disorganization of
their cartilage cells not only produced short stature, but also produced osteopenia and
spontaneous fractures.38
The bones of mice that lack the osteocalcin gene mineralize just as well as those of mice that
do not lack the gene, but the mineral deposits are organized differently. This could mean that
osteocalcin is important to the functional quality of bone and the ability to regulate its shape.59
Isolated human osteoblasts, the cells that lay down the calcified matrix of bone, secrete
osteocalcin in response to vitamins A and D.34 The protein-rich matrix surrounding these cells
will only accumulate this osteocalcin, however, if it is activated by vitamin K2. Calcification
of the extracellular matrix occurs in parallel with the accumulation of osteocalcin, but it is not
clear whether this protein plays a direct role in laying down the calcium salts or if its
accumulation simply reflects the higher amount of vitamin K2 that is available to activate
7
other proteins involved more directly in mineralization such as MGP.35
When there is an insufficient amount of vitamin K to keep up with the production of vitamin
K-dependent proteins, many of these proteins are secreted into the blood in an inactive form.
Circulating cells then take up these useless proteins and destroy them.40 By drawing a person's
blood and testing the percentages of circulating osteocalcin that are active and inactive, we
can determine whether that person's bone cells have enough vitamin K to meet their needs.
People with the highest percentages of inactive osteocalcin are at a more than five-fold
increased risk of hip fracture,60 confirming the value of the test.
By using this test, we can also show that vitamin K2 is the preferred K vitamin of the bones. It
takes one milligram per day of a highly absorbable pharmacological preparation of vitamin K1
to maximally activate osteocalcin in human subjects;28 it appears, however, that humans are
not capable of absorbing much more than one fifth this amount from whole foods.24 By
contrast, large amounts of vitamin K2 are readily absorbed from foods.26 Even when using
highly absorbable forms of these vitamins, vitamin K2 is much more effective. Researchers
from the University of Maastricht in the Netherlands recently showed that over the course of
40 days, vitamin K2 was three times more effective than vitamin K1 at raising the percentage
of activated osteocalcin. Moreover, the effect of vitamin K1 reached a plateau after just three
days, whereas the effect of vitamin K2 increased throughout the entire study. Had it lasted
longer, the study may have shown an even greater superiority of vitamin K2.32
We can therefore regard the percentage of inactive osteocalcin primarily as a marker for
vitamin K2 status. In the healthy adult population, one hundred percent of the vitamin Kdependent blood coagulants produced by the liver are in their active form. By contrast, in this
same population between ten and thirty percent of circulating osteocalcin is in its inactive
form. Researchers rarely encounter individuals whose osteocalcin is fully activated.31 This
suggests that vitamin K2 deficiency is universal, and that variation in K2 status within the
population simply reflects varying degrees of deficiency.
Vitamin K1 supplements produce modest decreases in bone loss in the elderly. A number of
Japanese trials, on the other hand, have shown that vitamin K2 completely reverses bone loss
and in some cases even increases bone mass in populations with osteoporosis.31 The pooled
results of seven Japanese trials show that vitamin K2 supplementation produces a 60 percent
reduction in vertebral fractures and an 80 percent reduction in hip and other non-vertebral
fractures.61 These studies used extremely high amounts of vitamin K2 and did not observe any
adverse effects over the course of several years. Since they used such high doses of K2,
however, and no studies have tested lower doses, they do not constitute definitive proof that
the vitamin activity rather than some drug-like action unique to the high dose produced such
dramatic results. The balance of the evidence, however, suggests that vitamin K2 is essential
to skeletal health and that it is a key substance that modern diets do not adequately provide.
Vitamin K2 and Heart Disease
Price analyzed more than 20,000 samples of dairy products sent to him every two to four
weeks from various districts of the United States, Canada, Australia, Brazil and New Zealand.
Dividing the total area into many districts, each producing dairy products with different
patterns of seasonal fluctuation in vitamin A and Activator X content, he found an inverse
relationship in each district between the vitamin content of butterfat and the mortality from
pneumonia and heart disease.
8
The role of vitamin A in the immune system is well established. We do not currently know,
however, whether vitamin K2 plays an important role in the immune system. Nevertheless,
lymph glands and bone marrow accumulate large amounts of it62 and a vitamin K-dependent
protein called gas6 plays a role in phagocytosis,33 a process wherein immune cells destroy and
consume foreign cells or the body's own cells when they are infected or no longer needed. It is
therefore possible that K vitamins could play an important role in protecting against infectious
diseases such as pneumonia.
Vitamin K2's ability to protect us from heart disease is much more clearly established.
Research is in fact rapidly redefining heart disease largely as a deficiency of this vitamin.
While it is most clearly established that vitamin K2 deficiency causes calcification of the
cardiovascular system, vitamin K2 appears to protect against the inflammation and
accumulation of lipids and white blood cells that characterize atherosclerosis as well.
Cardiovascular calcification can begin as early as the second decade of life, and is nearly
ubiquitous in the population by the age of 65.33 There are primarily two types: calcification of
the heart valves and tunica media constitutes one type, while calcification of the tunica intima
constitutes the second. The tunica media is the middle layer of the artery; it contains elastic
fibers that allow the artery to stretch and accommodate varying degrees of pressure. The
elastic fibers of the tunica media and the valves of the heart calcify during diabetes, kidney
disease and aging. The tunica intima is the innermost layer of the artery and is the site where
atherosclerosis develops. In atherosclerosis, calcified deposits rich in lipids and white blood
cells accumulate on the debris left behind by the blood vessel's smooth muscle cells once they
have died.63
In healthy arteries, the vitamin K-dependent matrix Gla protein (MGP) congregates around
the elastic fibers of the tunica media and guards them against the formation of crystals by the
calcium that circulates in the blood. The inactive form of MGP, which cells produce when
they do not have sufficient K vitamins to meet their needs, does not exist in healthy arteries.
In early atherosclerosis, by contrast, most MGP exists in its inactive form and associates with
calcified structures containing lipids, white blood cells, and the remnants of dead smooth
muscle cells. Inactive MGP also accumulates within the calcified deposits of the medial
sclerosis that occurs during diabetes, kidney disease and aging. Although blood tests for the
percentage of inactive and active MGP are not available, patients with severe calcifications
have high percentages of inactive osteocalcin, indicating a general deficiency of vitamin K2.63
Two other vitamin K-dependent proteins are likely to play a role in the development of
atherosclerosis: gas6 and protein S. Gas6 promotes the survival of the smooth muscle cells
that line the intima and the rapid clearance of those that die. The rapid clearance of these dead
cells may be important for preventing the accumulation of the calcified lipids and white blood
cells that gather around them. Protein S guides the immune system to clear away this debris
from the intima gently rather than mounting a dangerous inflammatory attack against it.33 As
these observations all predict, experimental and epidemiological evidence both show that
vitamin K2 is a powerful inhibitor of cardiovascular disease.
Mice that lack the gene for MGP develop extensive calcification of the aorta, aortic valves
and arteries soon after birth and bleed to death within two months when their heavily calcified
aortas rupture.38 Warfarin, which inhibits the recycling of K vitamins40 and the conversion of
K1 to K2,64 causes calcification of the tunica media in rats within two weeks,21 increases
arterial stiffness, decreases the ability of the artery to accommodate moderately high levels of
9
blood pressure, and causes the death of the artery's smooth muscle cells.65 Marcoumar, a
similar drug, doubles the degree of aortic valve calcification in humans over the course of one
to three years.42
Large amounts of vitamin K2 completely inhibit the ability of Warfarin to cause arterial
calcification in rats. Vitamin K1, by contrast, has no inhibitory effect at all.21 Researchers
from the University of Maastricht recently showed that both K vitamins can reverse
calcification that has already occurred in Wistar Kyoto rats.65 The K vitamins also reduced the
number of dead smooth muscle cells after Warfarin treatment, showing that vitamin Kdependent proteins not only promote cell survival but also facilitate the safe clearance of cells
that have died. Although both K vitamins were effective, these rats convert vitamin K1 to
vitamin K2 with great efficiency. In the absence of Warfarin, two-thirds of the vitamin K in
the blood vessels of the rats that consumed K1 alone existed as K2. In the presence of
Warfarin, however, which inhibits the conversion, none of the vitamin K in these blood
vessels existed as K2. Apparently, vitamin K1 is effective after but not during Warfarin
treatment because it can only protect against arterial calcification insofar as it is converted to
vitamin K2.
In the Nurses' Health Study, the risk of heart disease was a modest 16 percent lower for those
consuming more than 110 micrograms per day of vitamin K1, but there was no benefit from
consuming any more than this.66 This small amount is equivalent to consuming only three
servings of kale per month. The Health Professionals Follow-Up Study generated a similar
finding in men, although it lost significance after adjustment for other dietary risk factors.67 It
isn't clear whether the slight increase in risk associated with only the lowest intakes reflects
the possibility that only very small amounts of vitamin K1 are absorbed, or simply reflects the
association between K1 intake and a healthy lifestyle. People who consume more vitamin K1
weigh less, smoke less, eat more fruits, vegetables, fish, folate, vitamin E and fiber,68 and are
more likely to use vitamin supplements.67
The inverse association between heart disease and vitamin K2 intake is more straightforward.
In The Rotterdam Study, which prospectively followed just over 4,600 men aged 55 or older
in the Netherlands, the highest intake of vitamin K2 was associated with a 52 percent lower
risk of severe aortic calcification, a 41 percent lower risk of coronary heart disease (CHD), a
51 percent lower risk of CHD mortality, and a 26 percent lower risk of total mortality. Even
though the study population consumed ten times more K1 than K2, vitamin K1 had no
association with either the degree of aortic calcification or the risk of heart disease.20 The
profound effects of variations in such small amounts of dietary K2 emphasize just how
powerful this substance is in the prevention of degenerative disease.
Vitamin K2 and the Brain
Price supplied several anecdotes suggesting that Activator X plays an important role in the
nervous system. Price administered a daily meal of nutrient-dense whole foods supplemented
with high-vitamin cod liver oil and high-Activator X butter oil to the children of impoverished
mill workers who suffered from rampant tooth decay. The treatment not only resolved the
tooth decay without the need for oral surgery, but resolved chronic fatigue in one boy and by
the report of their school teachers produced a marked increase in learning capacity in two
others.
Price also administered the butter oil concentrate to a four-year-old who suffered from
10
rampant tooth decay, a fractured leg and seizures. A dessert spoonful of the butter oil served
over whole wheat gruel with whole milk once before bed and five times over the course of the
following day immediately resolved his seizures. Rapid healing of his fracture and dental
caries followed soon after. The fact that these three symptoms appeared together and resolved
following the same treatment suggests a common cause for each of them. Sixty years later,
modern research is now elucidating the essential role that vitamin K2 plays not only in the
dental and skeletal systems, but in the nervous system as well. This strongly suggests it was
the key unidentified factor in Price's protocol.
The brain contains one of the highest concentrations of vitamin K2 in the body; only the
pancreas, salivary glands, and the cartilaginous tissue of the sternum contain more. When
male Wistar rats consume vitamin K1 alone, 98 percent of the vitamin K in their brains exists
as K2, demonstrating the overwhelming preference of the nervous system for this form. The
K2 contents of these four tissues remain remarkably high on a vitamin K-deficient diet,
suggesting either that the vitamin is so essential to their function that they have developed a
highly efficient means of preserving it, or that it plays a unique role in these tissues that does
not require as high a rate of turnover as is required by the roles it plays in most other tissues.15
An analysis of three autopsies showed that vitamin K2 makes up between 70 and 93 percent of
the vitamin K in the human brain.69 It is not clear why humans exhibit greater variation in this
percentage than rats, although it could be that we convert K1 less efficiently and are therefore
more dependent on dietary K2.
Vitamin K2 supports the enzymes within the brain that produce an important class of lipids
called sulfatides. The levels of vitamin K2, vitamin K-dependent proteins and sulfatides in the
brain decline with age; the decline of these levels is in turn associated with age-related
neurological degeneration.46 Comparisons of human autopsies associate the early stages of
Alzheimer's disease with up to 93 percent lower sulfatide levels in the brain.70 Warfarin
treatment or dietary vitamin K deficiency causes lack of exploratory behavior and reduced
physical activity in rats that is suggestive of fatigue.71 Animals that completely lack the
enzymes to make sulfatides and a related class of lipids, cerebrosides, progressively suffer
from growth retardation, loss of locomotor activity, weak legs and seizures.72
These observations suggest that deficiencies in vitamin K, especially vitamin K2, could result
in fatigue and learning difficulties in humans, and that rare, extreme deficiencies of vitamin
K2 in the brain could result in seizures. If this is the case, it would explain why Price observed
tooth decay, bone fracture, learning difficulties and seizures to share a common cause and a
common solution.
Other Roles of Vitamin K2
Our understanding of the K vitamins is rapidly expanding and we are likely to discover many
new roles for them as the twenty-first century progresses.
The highest concentration of vitamin K2 exists in the salivary glands and the pancreas. These
organs exhibit an overwhelming preference for K2 over K1 and retain high amounts of the
vitamin even when animals consume a vitamin K-deficient diet.15 The high presence of the
vitamin in both of these organs suggests a role in activating digestive enzymes, although its
apparent role in the regulation of blood sugar could explain its presence in the pancreas.76 The
testes of male rats also exhibit a high preference for and retention of vitamin K2,16 and human
11
sperm possess a vitamin K-dependent protein with an unknown function.77 The kidneys
likewise accumulate large amounts of vitamin K269 and secrete vitamin K-dependent proteins
that inhibit the formation of calcium salts. Patients with kidney stones secrete this protein in
its inactive form, which is between four and twenty times less effective than its active form at
inhibiting the growth of calcium oxalate crystals, suggesting that vitamin K2 deficiency is a
major cause of kidney stones.77
The use of Warfarin during pregnancy produces developmental malformations of the face; as
the nasal cartilage calcifies, growth of the nose comes to an early end, resulting in a stubby
appearance.78 Vitamin K2 therefore most certainly played a role in the development of
beautiful faces with broad features that Price observed among primitive peoples.
A number of cell experiments have shown that vitamin K2 has powerful anti-carcinogenic
properties that may make it useful in preventing or treating cancer in humans.79
Researchers have recently discovered a whole new class of vitamin K-dependent proteins
called transmembrane Gla (TMG) proteins. Their functions are unknown.33
The K vitamins perform all of their well understood roles in the part of the cell responsible for
the modification of proteins. Only a portion of the vitamin K within a cell exists in this area,
however. Even more exists in the inner membrane of the mitochondria where the cell
produces its energy.45 The greatest concentration exists in the nucleus, which possesses a
receptor for vitamin K that may be involved in regulating the expression of genes.44 Vitamin
K2 has a greater affinity than vitamin K1 for both the mitochondrial membrane and the nuclear
receptor. We presently know virtually nothing about these functions of the K vitamins and the
plot will only thicken as the story unfolds.
Vitamin K2 in Foods
Figure 4 shows the distribution of vitamin K2 in selected foods. Precise values for the organ
meats that would be richest in K2 are not available. The pancreas and salivary glands would
be richest; reproductive organs, brains, cartilage and possibly kidneys would also be very rich;
finally, bone would be richer than muscle meat.15,16,69 Analyses of fish eggs, which Price
found to be rich in Activator X, are not available.
Commercial butter is only a moderate source of vitamin K2. After analyzing over 20,000
samples of butter sent to him from around the world, however, Price found that the Activator
X concentration varied 50-fold. Vitamin K-rich cereal grasses, especially wheat grass, and
alfalfa in a lush green state of growth produced the highest amounts of Activator X, but the
soil in which the pasture was grown also profoundly influenced the quality of the butter. The
concentrations were lowest in the eastern and far western states where the soil had been tilled
the longest, and were highest in Deaf Smith County, Texas, where excavations proved the
roots of the wheat grass to pass down six feet or more through three feet of top soil into
deposits of glacial pebbles cemented together with calcium carbonate. It was this amazingly
vitamin-rich butter that had such dramatic curative properties when combined with highvitamin cod liver oil and nutrient-dense meals of whole milk, whole grains, organ meats, bone
broths, fruits and vegetables.
For over 50 years after Price described his discovery of Activator X, the medical and
nutritional communities saw vitamin K merely as a requirement for blood clotting. The poor
12
understanding of the functions of the K vitamins within the body and the apparent lack of any
relationship between Price's chemical test and the structure of any known vitamin made it
impossible to determine the identity of this mysterious substance. We now know, however,
that vitamin K2 and Activator X are one and the same. Like Price's X factor, vitamin K2 is
synthesized by animal bodies from its precursor in rapidly growing grass. Cereal grasses and
alfalfa are rich in this precursor, and these plants accumulate it in direct proportion to their
photosynthetic activity. It is critical to the ability of teeth and bones to lay down mineralized
tissue, and to the prevention of degenerative diseases of the cardiovascular and nervous
systems. It is the key factor that acts in synergy with vitamins A and D: these vitamins
command cells to make proteins, but vitamin K brings these proteins to life. It is an
"activator," then, in the truest sense of the word, and it is therefore fitting that we knew it for
so many decades simply as "Activator X."
Thank you to Michael Eiseike, a health researcher from Hokkaido Japan, for originally
bringing the Rotterdam Study to our attention and suggesting that vitamin K2 may be the X
Factor of Weston Price; and also to David Wetzel of Green Pasture Products for his input
and advice.
Figures
Figure 1: The Structure of K Vitamins and Their Chemical Behavior
Single lines represent single bonds between carbon atoms; double lines represent double
bonds between carbon atoms. Hydrogen atoms are attached to most of the carbons but are not
shown.
a.
Vitamin K1. The side chain extending to the right of the molecule is monounsaturated.
b.
Vitamin K2. The nucleus, composed of two ring structures, is the same as that of vitamin K1.
The side chain, however, is polyunsaturated rather than monounsaturated.
c.
13
Either K vitamin would be expected to react with hydriodic acid (HI) by absorbing hydrogen
atoms and liberating diatomic iodine (I2). The side chain is abbreviated by the letter "R."
d.
If the mixture of the vitamin K and hydriodic acid is combined with a starch indictor, the
diatomic iodine liberated by the reaction would turn the starch blue.
Figure 2. Corresponding Characteristics of Activator X and Vitamin K2
Activator X
Vitamin K2
Found in the butterfat of mammalian milk, the Found in the butterfat of mammalian milk and
eggs of fishes, and the organs and fats of
the organs and fats of animals. Analyses of
animals.
fish eggs are not available.
Synthesized by animal tissues, including the mammary
glands, from a precursor in rapidly growing, green grass.
Synthesized by animal tissues, including the mammary
glands, from vitamin K1, which is found in association
with the chlorophyll of green plants in proportion to their
photosynthetic activity.
The content of this vitamin in butterfat is proportional to
the richness of its yellow or orange color.
Its precursor is directly associated with beta-carotene,
which imparts a yellow or orange color to butterfat.
Liberates diatomic iodine from hydriodic acid during
chemical testing.
Liberates diatomic iodine from hydriodic acid during
chemical testing.
Acts synergistically with vitamins A and D.
Activates proteins that cells are signaled to produce by
vitamins A and D.
Plays an important role in reproduction.
Synthesized by the reproductive organs in large amounts
from vitamin K1 and preferentially retained by these
organs on a vitamin K-deficient diet. Sperm possess a K2dependent protein of unknown function.
Plays a role in infant growth.
Contributes to infant and childhood growth by preventing
the premature calcification of the cartilaginous growth
zones of bones.
Plays an essential role in mineral utilization and is
necessary for the control of dental caries.
Activates proteins responsible for the deposition of
calcium and phosphorus salts in bones and teeth and the
protection of soft tissues from calcification.
Increases mineral content and decreases bacterial count
of saliva.
Is found in the second highest concentration in the
salivary glands, and is present in saliva.
Intake is inversely associated with heart disease.
Protects against the calcification and inflammation of
blood vessels and the accumulation of atherosclerotic
plaque.
Increases learning capacity.
The brain contains one of the highest concentrations of
vitamin K2, where it is involved in the synthesis of the
myelin sheath of nerve cells, which contributes to learning
capacity.
Resolved chronic fatigue in one boy.
Deficiency induces fatigue in laboratory animals.
14
Resolved seizures in one boy.
Involved in the synthesis of lipids called sulfatides in the
brain, an absence of which induces seizures in laboratory
animals.
Figure 3. Vitamin K-Dependent Carboxylation
a.) A carbon dioxide molecule
b.) a carboxyl group
c.) Vitamin K-dependent carboxylation
The vitamin K-dependent carboxylase rearranges the chemical bonds within carbon dioxide
molecules. Carboxyl groups contain carbon and oxygen atoms and carry a charge of negative
one. Calcium carries a charge of positive two. The side chains of the amino acid glutamate
normally carry one carboxyl group; the vitamin K-dependent addition of a second carboxyl
group gives these side chains a charge of negative two and thus allows them to bind to
calcium, which has the equal and opposite charge. This process transforms glutamate into γcarboxyglutamate, abbreviated Gla. For this reason, many vitamin K-dependent proteins, such
as matrix Gla protein (MGP), contain "Gla" in their name.
Figure 4: Vitamin K2 Contents of Selected Foods22, 26
The percentage of vitamin K2 present as MK-4 represents that synthesized by animal tissues,
while the remainder represents that synthesized by bacteria during fermentation.
FOOD
VITAMIN K2 (MCG/100G)
Natto
1103.4
(0% MK-4)
Goose Liver Paste
369.0
(100% MK-4)
Hard Cheeses
76.3
(6% MK-4)
Soft Cheeses
56.5
(6.5% MK-4)
Egg Yolk (Netherlands)
32.1
(98% MK-4)
Goose Leg
31.0
(100% MK-4)
Curd Cheeses
24.8
(1.6% MK-4)
Egg Yolk (United States)
15.5
(100% MK-4)
Butter
15.0
(100% MK-4)
Chicken Liver
14.1
(100% MK-4)
15
Salami
9.0
(100% MK-4)
Chicken Breast
8.9
(100% MK-4)
Chicken Leg
8.5
(100% MK-4)
Ground Beef (Medium Fat) 8.1
(100% MK-4)
Bacon
5.6
(100% MK-4)
Calf Liver
5.0
(100% MK-4)
Sauerkraut
4.8
(8% MK-4)
Whole Milk
1.0
(100% MK-4)
2% Milk
0.5
(100% MK-4)
Salmon
0.5
(100% MK-4)
Mackerel
0.4
(100% MK-4)
Egg White
0.4
(100% MK-4)
Skim Milk
0.0
Fat-Free Meats
0.0
SIDEBARS
The Activator X Test
The chemical test that Price eventually came to use for the quantification of Activator X in
foods was originally suggested as an indirect test for vitamin D by Lester Yoder of the
Agricultural Experiment Station of Iowa State College in 1926.8 The basic principle of the
test, called iodometric determination, was most commonly utilized in the United States for
detecting the presence of organic peroxides.9 Since peroxides are capable of oxidizing ionic
iodide to diatomic iodine, researchers can detect them by combining the test substance with
hydriodic acid and a starch indicator. Hydriodic acid releases iodide ions into a solution. If
peroxides are present, they convert these iodide ions to diatomic iodine, which then turns the
starch blue or purple.
This is somewhat similar to the amylase test that is used as a demonstration in many high
school or college biology classes. In that test, however, preformed iodine is used; in the
absence of amylase, the iodine turns the starch blue, while in the presence of amylase, the
starch is broken down into sugar and the color change does not occur.
At the time, the only way to test a food for vitamin D was to feed it to rats on a mineraldeficient diet, kill the rats, and analyze the mineral content of their bones. The richer the food
was in vitamin D, the more it would stimulate absorption of the small amounts of calcium and
phosphorus in the diet and the higher the bone mineral content would be. Yoder suggested,
however, that there was a general correlation between the ability of an oil to peroxidize
(become rancid) and its vitamin D content, and advocated testing an oil's ability to oxidize
16
iodide as an indirect indicator of its level of vitamin D. Having no other convenient chemical
test, Price adopted this as his test for vitamin D.
The test was far from perfect. Yoder found peroxidation in substances with no vitamin D
activity such as turpentine, a thirteen-year-old sample of cholesterol, and an aged sample of
mineral oil. He further found that irradiating foods to the point at which their vitamin D
activity was destroyed actually increased their score on the test.8
As Price used this test on over 20,000 samples of dairy foods sent to him from around the
world, he realized that the physiological effects that correlated with a food's ranking were
different from those attributable to isolated vitamin D, and began using the term "Activator
X" to describe the nutritional substance that the test was measuring. He observed that the
vitamin content of these butter samples varied fifty-fold, and that the samples richest in
Activator X were the most potent for controlling dental caries. Clearly, Price's test was
detecting something besides rancid oils.
While researchers who published in English language journals traditionally used this test to
detect peroxides, researchers publishing in Russian and German language journals had been
using it to detect the synthetic compound benzoquinone all along.10,11 Benzoquinone belongs
to a class of chemicals called quinones that includes biological molecules such as coenzyme
Q10 and the K vitamins. These quinones possess oxygen-containing ring structures whose
oxygens will steal electrons and hydrogen ions from hydriodic acid and thereby oxidize ionic
iodide to diatomic iodine, causing the starch to become a bluish purple color (see Figure 1).
In the 1970s, researchers from Britain and Denmark were debating whether or not healthy rat
tissues contained lipid peroxides. The British researchers used the iodometric method to
determine peroxide levels and argued that healthy rat tissues did contain peroxides, while the
Danish researchers used a different method and argued that they did not. In a 1972 paper
published in the British Journal of Nutrition, the Danish researchers demonstrated that the
iodometric method was not showing the existence of peroxides in the rat tissues, but rather the
existence of coenzyme Q10 and probably other quinones.12
Price's test, therefore, was not specific to any one particular chemical compound. When used
for fresh oils, however, it would be able to detect a number of nutrients that include coenzyme
Q10 and the K vitamins. As shown in this article, it is the K vitamins that we should expect to
vary in direct proportion to the amount of richly green grass in the diet of the animals, while
the physiological effects Price identified with Activator X are specifically attributable to
vitamin K2.
Interactions between Vitamins A, D, and K2
SOFT TISSUE CALCIFICATION AND VITAMIN D TOXICITY
(Hypothesis)
Vitamin D
Vitamin K
Vitamin A
Fulfills demand for Vitamin K
Exerts Vitamin K sparing
effect
Increased demand
May protect by other
for Vitamin K
unknown mechanisms
17
Relative deficiency
of Vitamin K
Soft tissue calcification
Bone loss, growth retardation
Nervous system damage
BONES & TEETH
Vitamin A
Vitamin D
Vitamin A
Matrix Gla Protein
Vitamin D
Osteocalcin
Vitamin K
Activated Matrix Gla Protein
Activated Osteocalcin
Deposition of Minerals
Organization of Minerals
Vitamin A
Synthesis of Growth Factors
and Growth Factor Receptors
GROWTH
Vitamin D
Absorption of Minerals
Vitamin K
Prevention of the
Calcification of Growth
Cartilage
OPTIMAL GROWTH &
DEVELOPMENT
Strong Bones
Straight Teeth
Good Proportions
Wide Facial Development
Long Straight Nose
Is Vitamin K2 an Essential Nutrient?
Vitamins K1 and K2 are both effective cofactors for the enzyme that activates vitamin Kdependent proteins,23 but the liver preferentially uses vitamin K1 to activate clotting factors
while most other tissues preferentially use vitamin K2 to activate the other vitamin Kdependent proteins.21 Although animals can convert vitamin K1 to vitamin K2,14 there are a
number of lines of evidence strongly suggesting that humans require preformed K2 in the diet
to obtain optimal health.
Humans appear to have a finite ability to absorb vitamin K1 from plant foods. In the United
States, where the mean intake of vitamin K1 is less than 150 micrograms per day, blood levels
increase with increasing dietary intake until the latter reaches two hundred micrograms per
day, after which they plateau. In the Netherlands, where the mean intake of vitamin K1 is
much higher (250 micrograms per day), plasma levels of vitamin K1 have no relationship to
dietary intake at all.24 These results suggest that humans do not possess the ability to absorb
18
much more than 200 micrograms of vitamin K1 per day from vegetables.
This interpretation is also supported by feeding experiments. Whereas the absorption of
vitamin K2 from natto, a fermented soy food, is nearly complete, the absorption of vitamin K1
from servings of green vegetables ranging from two hundred to four hundred grams consumed
without added fat is only between five and ten percent. The absorption of similarly sized
servings of vegetables with added fat is still only between ten and fifteen percent.25-26 By
contrast, smaller servings are absorbed more efficiently. For example, the absorption from a
150-gram serving of spinach is 17 percent and the absorption from a 50-gram serving of
spinach is 28 percent.27 These results show that our absorption of the vitamin declines as the
amount we consume increases and strengthens the interpretation that we might only be able to
absorb about 200 micrograms per day. When study subjects consume a highly absorbable
pharmacological preparation of vitamin K1, a dose of 1000 micrograms per day is required to
maximize the activation of proteins important to bone metabolism.28 If we can only absorb
one-fifth of this amount from vegetables, we cannot support our skeletal system with vitamin
K1 regardless of how efficiently we may be able to convert it to vitamin K2.
The ability to convert K1 to K2 varies widely between species and breeds of animals. The
German researchers who first reported this conversion found that rats made it poorly
compared to birds and that pigeons made it most efficiently.14 Every tissue tested in male
Wistar rats is capable of making the conversion,15 whereas the liver, kidneys and heart of
male Lewis rats will preferentially accumulate preformed K2, but, unlike the pancreas and
testes of these same animals, will not synthesize it from K1.16 The K2 content of human breast
milk increases when mothers consume pharmacological preparations of K1, but the K2 content
of their blood does not;17 since the conversion takes place in the target tissues rather than the
blood, however, we do not know how efficiently other human tissues make this conversion.
Vitamins K1 and K2 share a common ring-structured nucleus but possess different types of
side chains. The first step in the conversion of K1 to K2 appears to be the cleavage of its side
chain in either the liver or the gastrointestinal tract, yielding a toxic oxidizing agent called
menadione; much of this metabolite is detoxified by the liver and excreted in the urine, while
the remaining portion can be used to synthesize K2 in tissues.29 After this cleavage takes
place, menadione must be transported to its target tissues where cellular enzymes can add a
side chain to it, completing the transformation to K2. Because they are transported in different
types of lipoproteins, vitamin K1 is primarily sent to the liver, whereas vitamin K2 is primarily
sent to the other tissues;30 we know very little, however, about the transport of menadione in
the blood. We also know very little about the rate at which our cells are capable of adding side
chains to these molecules; presumably, if the supply of menadione exceeds the rate at which
the cell can add these side chains, the menadione will exert toxic effects and cause oxidative
damage within the cell. Preliminary evidence indicates that doses of 1000 micrograms per day
of supplemental K1 may contribute to periodontal disease,31 suggesting that our bodies'
resistance to absorbing this much K1 from vegetables may serve an important purpose.
The clearest demonstration that humans require dietary preformed vitamin K2 for optimal
health is that epidemiological and intervention studies both show its superiority over K1.
Intake of vitamin K2, for example, is inversely associated with heart disease in humans while
intake of vitamin K1 is not,20 and vitamin K2 is at least three times more effective than
vitamin K1 at activating proteins related to skeletal metabolism.32 This nutritional superiority
makes it clear why the primitive groups that Weston Price studied expended so much effort
procuring foods rich in vitamin K2 like the organs and fats of animals and the deeply colored
19
orange butter from animals grazing on rich pastures.
The Vitamin K-Dependent Carboxylase
Most known functions of the K vitamins are mediated by the vitamin K-dependent
carboxylase. The carboxylase is an enzyme bound to the membrane of the endoplasmic
reticulum, a cellular organelle involved in the synthesis and modification of proteins. It uses
vitamin K as a cofactor to add carboxyl groups to the side chains of the amino acid glutamate
within certain vitamin K-dependent proteins (see Figure 3). This gives them a negative
charge, allowing them to bind to calcium, which carries a positive charge.40
Vitamin K-dependent proteins must be carboxylated before they leave the cell or insert
themselves into its membrane. They may contain anywhere from three to thirteen glutamate
residues (amino acids are called "residues" when they are bound up within proteins) that must
be carboxylated; the carboxylase binds to them only once, however, and carboxylates each of
these before it releases the protein. On the other hand, vitamin K can only be used for the
carboxylation of a single glutamate residue and the carboxylase must release it after each
carboxylation and allow it to be recycled and returned. A different enzyme, vitamin K
oxidoreductase, recycles the vitamin; this enzyme is the target of the anticoagulant drug
Warfarin and its relatives.40 Since Warfarin targets the recycling of vitamin K rather than the
vitamin K-dependent coagulation proteins themselves, it not only acts as an anticoagulant, but
also causes arterial and aortic valve calcification in both rats21 and humans41,42 and inhibits the
mineralization of bone matrix.35
The distribution of the carboxylase among species and among tissues within an organism can
help us understand its significance and that of its cofactor, vitamin K. With the exception of
some microorganisms that have "stolen" the enzyme by incorporating the genetic material of
other species,43 the carboxylase is present only in multicellular animals, underscoring its
importance to intercellular communication. In the growing embryo, it is first expressed in
skeletal and nervous tissue; vitamin K is therefore almost certainly essential to the
development of the skeletal and nervous systems from their very beginnings.40
Vitamin K's activity as a cofactor for the carboxylase may only be the tip of the iceberg. In
osteoblasts, the cells responsible for bone growth, the greatest concentration of vitamin K2
exists in the nucleus where the genetic material is; the second greatest concentration exists in
the mitochondria, the so-called "power house" of the cell; finally, only the third greatest
concentration exists in the endoplasmic reticulum where the carboxylase is found.44 We do
not currently have enough information to understand the role of the K vitamins in the
mitochondria or the nucleus. Osteoblasts possess a nuclear receptor for vitamin K2, suggesting
it has a role as a nuclear hormone. Vitamin K2 has a higher affinity than vitamin K1 both for
the nuclear receptor44 and for the mitochondrial membrane.45 There is also evidence that
vitamin K2 plays a role as an antioxidant within the cells that synthesize the myelin sheath,
which forms the electrical insulation of nerves.46 Although it took until the 1970s to define the
function of vitamin K as a cofactor for the carboxylase enzyme, the twenty-first century may
well ring in a new revolution in our understanding of this amazing vitamin with the
recognition that it is, to modify a phrase coined by Tufts University's Dr. Sarah Booth, "not
just for the carboxylase anymore."
20
Vitamin K2 and the Brain: A Closer Look
The concentration of vitamin K2 is higher in myelinated regions than in non-myelinated
regions of the brain (myelin is the sheath that forms the electrical insulation of neurons) and it
is correlated with the presence of important lipids such as sphingomyelin and sulfatides. The
small amount of K1, by contrast, is distributed more randomly,73 suggesting that it may not be
as functionally important. These lipids are part of a broader class of compounds called
sphingolipids that play essential roles in the brain as structural constituents of membranes,
signaling factors, and promoters of cell survival. Vitamin K2 supports the activity of the
enzyme that catalyzes the initial reaction for the production of all sphingolipids as well as the
enzyme that catalyzes the final step in the synthesis of sulfatides. Warfarin or dietary vitamin
K deficiency cause marked decreases in the activities of these enzymes and of the levels of
sulfatides in the brains of rats and mice, while the administration of either vitamin K1 or K2
restores them.46
In addition to the production of sulfatides and other sphingolipids, vitamin K2 plays at least
two other important roles in the brain. The vitamin K-dependent protein gas6 promotes the
survival of brain cells,74 and K vitamins, by an unknown mechanism, completely protect
against the free radical-mediated death of the cells that synthesize myelin. Both an excess of
glutamate and a deficiency of cystine can cause this type of cell death. Although K1 and K2
protect against glutamate toxicity equally, K2 is fifteen times more effective than K1 at
counteracting the harmful effects of cystine depletion. Oxidative stress in the vulnerable
infant brain can cause mental retardation, seizures, and cerebral palsy. Adequate intake of
vitamin K2 during infancy may therefore protect against these diseases.75
Bacterial Production of Vitamin K2
"Vitamin K2" actually refers to a group of compounds called menaquinones. While vitamins
K1 and K2 have different types of side chains, the side chains of the various menaquinones
within the K2 group are all of the same type but are of varying lengths. Each of these forms is
abbreviated MK-n, where "n" is a number that denotes the length of the side chain. Animal
tissues exclusively synthesize MK-4, but many anaerobic bacteria synthesize other
menaquinones, which they use for energy production much in the way that plants use vitamin
K1.80 We can therefore obtain vitamin K2 by absorbing that which is produced by our
intestinal flora or by eating fermented foods, in addition to eating animal foods which contain
vitamin K2 synthesized from vitamin K1 found in grass.
Lactic acid bacteria mostly produce MK-7 through MK-10,18 while MK-10 and MK-11
accumulate in the human liver over time, presumably originating from bacterial production in
the gut.81 It was once thought that intestinal bacteria were a major contributor to vitamin K
status: the menaquinone content of stools is high, antibiotics have been associated with
defects in blood clotting that resolve with vitamin K supplementation, and autopsies show that
the great majority of vitamin K in the liver is present as "higher" menaquinones of bacterial
origin. The balance of the evidence, however, challenges this view. Most of the menaquinones
produced in the intestine are embedded within bacterial membranes and unavailable for
absorption. Antibiotics produce vitamin K-responsive clotting defects not by reducing the
intestinal production of K vitamins, but by inhibiting the enzyme within the human body that
recycles them. Finally, the liver appears to accumulate higher menaquinones not because it is
21
supplied with them abundantly but because it does not use them efficiently. Intestinal
production of menaquinones therefore likely makes some contribution to vitamin K status, but
one that is very small.80
Fermented foods such as sauerkraut, cheese, and natto, a soy dish popular in Eastern Japan,
contain substantial amounts of vitamin K2. Natto, in fact, contains the highest amount of any
food measured; nearly all of it is present as MK-7.26 MK-7 is highly effective: one recent
study showed that it increased the percentage of activated osteocalcin in humans three times
more powerfully than did vitamin K1.32 There are no studies available, however, comparing
the efficacy of MK-7 to that of the MK-4 found in animal products. MK-9, and presumably
MK-7, stays in the blood for a longer period of time than does MK-4, but this appears to be
because tissues take up MK-4 much more rapidly.30 Whether the rapid uptake of MK-4 or the
longer time spent in the blood by bacterial menaquinones have particular benefits or
drawbacks is unclear. Future research will have to clarify whether the vitamin K2 synthesized
by animal tissues and by bacteria are interchangeable, whether one is superior to the other, or
whether each presents its own unique value to our health.
Supplementing with Vitamin K2
The best sources of vitamin K2 are fermented foods and grass-fed animal fats. These foods
contain a wide array of nutrients that may act synergistically with vitamin K2 in ways we do
not yet understand. Price 's vitamin-rich butter and butter oil concentrate provided not only
vitamin K2 but also vitamin E, vitamin A, vitamin D, conjugated linoleic acid (CLA) and
other nutrients. Nevertheless, some people may wish to supplement with vitamin K2 if they do
not have access to high-quality food, wish to use a higher dose to treat a health condition, or
want extra insurance.
Two forms of vitamin K2 supplements are commercially available: menaquinone-4 (MK-4),
also called menatetrenone, and menaquinone-7 (MK-7). MK-4 is a synthetic product that is
believed to be chemically and physiologically identical to the vitamin K2 found in animal fats.
This form has been used in most of the animal experiments and in the Japanese osteoporosis
studies. Although synthetic, it is effective, and there is no known toxicity. MK-7 is a natural
extract of natto, a fermented soy food popular in Eastern Japan. MK-4 is much less expensive
than MK-7, but no studies have yet compared the efficacy of these two forms.
Menaquinone-4 Supplements: Thorne Research and Carlson Laboratories both offer costeffective MK-4 supplements. Thorne's product is a liquid supplement. The MK-4 is dissolved
in a medium-chain triglyceride base (the fats found in coconut oil) with mixed tocopherols
(vitamin E). Carlson's product is less expensive than Thorne's, but comes in dry capsules
primarily composed of cellulose and other fillers, and allows the user less control over the
dose.
Menaquinone-7 Supplements: Jarrow Formulas and Source Naturals both offer costeffective MK-7 supplements. Source Naturals' product is less expensive, but Jarrow's contains
fewer additives and certifies that the soy used to make the product is not genetically modified.
Vitamin K2 supplements interfere with the activity of oral anticoagulants such as warfarin.
Patients who are using warfarin should only use vitamin K2 supplements with the knowledge
of the prescribing physician.
22
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Follow Up Questions and Answers
Question: How much K2 is recommended for adults and for children?
Answer: Unfortunately we do not have any solid numbers on the optimal or minimum intake
of K vitamins, neither from modern scientific analysis nor from what people consumed in
optimal traditional diets. However, we do know that virtually all adults have some degree of
deficiency, whether this is very small or very substantial, and a recent study suggests that
children are much more likely to be deficient, so children may actually need more because
they are growing. The best thing to do would be to eat from the foods richest in vitamin K2:
natto, cheese or goose liver, at least once a week and to eat from the other relatively rich
foods—grass-fed butter, animal fats and fermented foods—on a daily basis. If you choose to
take any of the supplements listed in the article in addition to this, there is currently no reason
to believe that it is necessary to take more than the minimum dose (one drop of Thorne or one
capsule of Jarrow). In the years ahead, we should see much more definitive information
coming out on this, and hopefully we will also see some research reopen the questions that
Price had raised about the agricultural practices that lead to the highest levels of Activator X
in foods.
Question: What is the appropriate dose of vitamin K2 for maintenance and therapeutic
purposes?
Answer: We do not have adequate information on dosage requirements for vitamin K2. I
would think that for maintenance one should shoot for 100 mcg minimum, possibly more for
children, but we will have to wait for further research to quantify this. There are unpublished
anecdotes according to which some people have found up to 5-10 milligrams useful for
treating specific conditions, such as autism or spider veins. At present, this is a matter that the
individual must settle through experimentation.
Question: Do we know the levels of vitamin K2 in the primitive societies studied by Dr. Price?
25
Answer: We have no quantitative information on K2 as K2 or as Activator X in primitive
societies or in Price's practice because Price did not have a means of quantifying the levels by
mass—for example, how many micrograms were contained in a given food sample. Price
could only compare different foods based on the intensity of the blue color yielded by the test,
which he then compared to standards made from numerous different dilutions of a blue dye.
So Price could say that one food was a richer or poorer source than another, but he could not
determine the precise amount contained within the food.
Question: Is the K2 found in animal products or fermented foods affected by cooking?
Answer: I have yet to see any hard data on cooking losses, but everything I have read
indicates that vitamin K is very heat-stable (though it can apparently incur losses from
exposure to light).
Question: Is the Wulzen anti-arthritis factor in butter a separate compound from K2?
Answer: I do not know whether the Wulzen factor is a separate compound; however, others
have suggested that they are separate because Wulzen found this factor to be destroyed by
pasteurization, whereas Price and maybe others found activator X to be heat-stable.
Question: Fermented foods are said to be good sources of K2 but in your article you say that
most of the vitamin K2 produced by bacteria in the gut is now believed to be embedded in the
bacterial membranes and unavailable for absorption. One might think therefore that the
vitamin K2 produced in fermented foods is similarly unavailable. Are the bacteria in
fermented foods different? Does stomach digestion free up the K2?
Answer: Whether it is because some bacteria secrete the K2 or because the acidic digestion of
the stomach ruptures the membranes I do not know, but the absorption of K2 from natto is
near complete.
Question: Does yogurt contain vitamin K2?
Answer: Yogurt has roughly the same amount of K2 as milk, with just a tiny bit produced.
This is probably because commercial yogurt is only fermented for four hours, whereas hard
cheese is fermented for at least two months.
Question: Can you calculate how much K2 is in commercial versus grass-fed butter?
Answer: I do not think this can be calculated. The primary confounder is that commercial
butter comes from cows in confinement operations fed massive amounts of menadione, a
portion of which can be converted into K2. We have no idea at what rate this is turned into K2
and how it compares to K1 from grass as a precursor to K2, so we have no baseline from
which to calculate.
Question: I'd like to use natto as a source of K2, but I have an allergy to yeast. Do you know
which microorganisms ferment soy to create natto, and whether yeast is used in other parts of
the process?
Answer: Natto is fermented with Bacillus subtilus, subspecies natto. Yeast is not essential to
the process as far as I know, but I do not know whether the cultures tend to pick up yeast or
26
whether for some reason some products may also deliberately use yeast. You may want to
inquire with a specific manufacturer or from whomever you buy the culture if you choose to
make your own.
Editor's note: Natto is definitely an acquired taste, one usually not acceptable to westerners.
This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly
magazine of the Weston A. Price Foundation, Spring 2007.
About the Author
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mK4 VS mk7
written by Kris Johnson, Mar 09 2014
Dr Kate's book is most interesting
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K4 vs K7
written by Kris Johnson, Mar 09 2014
According to Kate Rheaume-Bleue in 'VitaminK2 and the Calcium Paradox' MK4 has a shorter half life in the body, so
you need to take it 3 times per day, whereas MK7 lasts for many hours, so once a day is fine. MK7 recommended dose
is also much smaller, than MK4, for some reason - 120 micrograms, vs 4,500 micrograms for MK4
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MK4 or MK7?
written by Jon Nelson, Mar 04 2014
You can find people who advocate for MK7 and others for MK4. We're lacking comparative studies, so we just have to
go with what (little) we know now. I've seen claims that MK7 is better because it raises serum levels quicker and for
longer and with much lower dosage. I've seen counter claims that maybe the MK4 is more quickly going to work in
tissues and not floating around in the blood and that it might be quickly activating proteins and that effect lasts a while
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even if it doesn't show up in the blood. I've seen claims that MK4 was studied in Japan for osteoporosis and therefore
we can't say that MK7 would have the same effect, but this ignores the fact that bone fractures in Japan are negatively
correlated with natto consumption (MK7). I've seen claims that some MK7 is converted to MK4 in the body. Until the
studies are done, I think we need to conclude that we don't get enough K2 and we need to get more and they are both
very good, perhaps in some different but also overlapping ways. My solution is to eat my home made natto with most
meals and to occasionally supplement with Super K from Life Extension. It has MK4, MK7 and K1.
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MK 4 or MK7?
written by Jen McCarthy, Feb 17 2014
Thank you for this wonderful article. I'm still confused though as to whether we should be trying to obtain MK 4
Vitamin K2, or will any K2 be as potent? If anyone could clear up that confusion, I'd greatly appreciate it!
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Benefit could also be bacteria/enzymes
written by Jakob, Oct 01 2013
I think it may very well turn out that the benefits of cheese and natto is not so much the MK-7 as a variety of other
components produced by the bacteria, like enzymes, or possibly their ability to adjust intestinal flora to a more
desirable one (atherosclerosis may also possibly be caused by bacteria and improperly digested foods that enters the
body as a result of leaky gut and malabsorption).
It is not clear how effective isolate MK-7 is, one study from Norway showed it had no effect (200 mcg/day) on
osteoporosis after 1 year of supplementation.
I just saw this study suggesting Kefir could be beneficial for atherosclerosis:
http://www.athero.org/commentaries/comm1086.asp But there´s not much K2 in kefir.
Over the years a variety of components (not the K2) has been identified in natto to allegedly reduce atherosclerosis,
one of those is sold as the supplement nattokinase (an enzyme that is supposed to break down plaque in arteries).
In the end we may not really need any supplements, except possibly vitamin D3 for people living far north that doesn´t
eat their traditional high marine food diet.
Most nutrients are simply available in a good nourishing traditional diet. But I think a focus on the digestibility of foods
is essential. This applies to enzymes, so for example eating soft boiled eggs will preserve a ton of enzymes in the yolk,
raw honey can provide huge quantities of amylase to break down starches, and fermented foods like kefir will also
already have produced various enzymes, ditto for sauerkraut and other fermented foods. Sourdough bread is also easy
to digest.
Fats, sugar, starches may cause problems with inadequate lecithin/choline and acids. So one would want to eat
avocado as guacemole (with lemon juice/vinegar), olive oil dressing mixed with vinegar. Etc.
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written by Jon Nelson, Sep 28 2013
Natto is a wonderful fermented food. There are hundreds of years of history of its successful use in Japan. It is easy
and inexpensive to make, but the big hurdle it has outside Japan is it's taste and to a lesser extent its texture.
Traditional Japanese taste has preferred strong smelling and tasting natto. More recently their preference has been
shifting to more mild tasting natto. The ammonia smell is the result of which strain of natto bacteria is used and of
partial protein breakdown and probably is not important for health benefits. When you make your own natto you can
chose organic soy beans or many other beans. While soy beans are ideal, there are ways to feed the natto a little
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something extra. I have mixed biotin and sugar with the inoculant with good results. I mostly use navy beans, but also
like to make a garbanzo natto humus that most people find as good as any humus. I moderate a Yahoo Group on natto
that serves as a repository for information on how to make natto, alternative beans to use, recipes, how to get used to
the taste and a place to ask questions. Unfortunately Yahoo has recently changed their format, making it harder to use.
The URL for the group is:
groups.yahoo.com/neo/groups/nattosupport/info (I've left the http// off the front)
If you are not familiar with the new Yahoo Neo format, you will need to click on 'Conversations' to see the messages.
My belief is that most of us should be eating natto and I've found the more I eat the more I like it.
/Jon
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written by jack miller, Sep 11 2013
I just added some natto to my chilli and its really not so bad. It could easily go into winter soup or stew.
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natto flavour
written by jack miller, Sep 11 2013
I just made some chilli and added some natto for the first time. It barely made a dent in the flavour so I added a bunch
more. It adds an earthy flavour and is not horrible.
From now on I'll simply put a dash in my soup or stew and maybe even screen out the soy beans.
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+0
Mr.
written by Heinz Pflieger, Jun 18 2013
As a WAPF member I read as much as I possibly can. Well aware of the good stuff written by Chris Masterjohn.
Although I have embarked on a daily exercise program and nutritional program and have my Osteoarthritis pretty well
under control it seems, after my 5 year daily effort - I would love to know: Once calcium deposits have developed
around the bone openings in the spine and other soft tissue areas; does the right nutrition and K2 lead eventually to a
reduction of these calcium deposits?
Thanks kindly, Heinz.
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+6
Why Goose Liver?
written by Jeremy Burchett, May 11 2013
Why is goose liver so high in K2? And is beef liver not high enough in K2 to make the list? I ask because goose liver is
hard to find (for most people) but grass fed beef liver and pastured chicken liver is not. I guess I'll have to find goose
liver. Oh and People!... Eat your Natto! for the benefit of your body!... yes it tastes like socks but you get used to it and
soon will crave it. Its my first day on it and I instantly feel an effect, just like my first day on Cod liver oil and high vit.
butter oil.
Let's find those sacred foods and eat them!
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+0
Some more confusion about K2...
written by Theonat, Mar 17 2013
I am currently reading the 2012 book "Vitamin K2 and the Calcium Paradox." In it the author references this very article
a couple times. However, she claims certain things about Vitamin K2 which seems wrong or contradictive.
1) She claims neither K1 nor K2 can be stored. Is that true? I thought they were stored in the liver, pancreas, brain, and
other places?
2) She says that the enzyme used to recycle K1 does NOT recycle K2, and thus warfarin would have no effect on K2.
3) She claims that MK-7 is much more effective than MK-4 because 120mcg of MK-7 reaps the same amount of benefits
as 4,500mcg of MK-4.
4) Her graphic illustration of the MK-4 and MK-7 molecules seems... odd. I can't quite put my finger on it, but I think it's
a mistake. The two-ring structure is angled differently on MK-7, and she writes H3C where CH3 should be placed. It's
hard to explain, but her illustration is on page 66. Can someone else verify this? Is her graphic wrong? I cannot find
this graphic anywhere else on the internet.
The confusion does not stop at Vitamin K, either. Earlier in the book she admits that the lipid hypothesis (saturated fat
/ cholesterol) is outdated and incorrect. However, later in the book she claims pastured animal foods are healthier
because they contain LESS saturated fat and cholesterol. Huh? I guess the propaganda is so strong that nutritionists
don't even realize when they perpetuate it. She does this "flip flop" again in later chapters.
Are these true mistakes on her part, or has new research shown otherwise? She does cite references and doesn't pull
stuff out of nowhere. She seems well verse and appears to be a good researcher. After all, she references Chris
Masterjohn a couple of times.
So what I'm saying is that the more I read about nutrition (vitamin K2 in particular), the more confused I become. Can
any of you, including Chris, help clear this up for me? It would mean a lot to me.
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+8
K1 conversion into K2 in fermented foods
written by David J, Feb 17 2013
Is all the vitamin K1 content in cabbage converted into vitamin K2 in sauerkraut (and the same for all other fermented
foods) or is the vitamin K1 content still present in sauerkraut?
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+1
K2 and warfarin
written by Kris Johnson, Dec 14 2012
It is my understanding that it is easier to adjust warfarin dose when you are consuming a steady amount of vitamin K1
from greens, etc. Vitamin K2 has a weak effect on blood clotting. Unfortunately your doctor may not know anything
about the benefits of K2, so it might help to bring in this article. You need those grass-fed animal products to get your
K2.
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+2
To clot or not to clot
written by Bella, Nov 17 2012
30
I am taking the Blue Ice Royal butter oil with a view to keeping calcium out of my arteries, but recently had 2 long
episodes of rapid atrial fibrillation, and there is warferin in my future, I can see it in my doctor's eyes! I am looking at
nattokinase instead, but I want to understand about the differences between K1 and K2 as you describe them here.
K1 is involved in clotting ( I should note) and K2 is more to do with calcium. We make K2 from K1. You don't say the
dynamic goes the other way, but you do say that people on warferin should not take K2, at least make doctor aware so
he can put your warferin dose up, I expect! So on the one hand K2 doesn't seem to be a clotting no no, but on the other
it does, Which is it please? If both, what is the mechanism? Can I keep taking the k2 even though I am now officially at
risk of stroke because my heart might produce clots.
Thank you!
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+5
...
written by Polly Kraemer, May 06 2012
Have you heard of Nature's Pasture high vitamin butter oil/cod liver oil blend? That is what I take. Is this an appropriate
supplement for the k1 and k2? Xfactor.
How many a day? I have many many health problems that no traditional doctor seems to know what to do.
Please help
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+9
MD
written by Stanley Lang, Apr 09 2012
Do you know if organic apple cider vinegar has K2 and if so how much?
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+12
X Factor
written by Claus, Jan 30 2012
It will be interesting to follow the X Factor this year :-)
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+0
K1 and Diabetes, Strontium & D3
written by Ted Birnbaum, Dec 02 2011
I normally take 100 micrograms of K1 every other day. I decided to stop it completely to see its effect. After 4.5 days of
no K1, my sleep was interrupted about every 2 hours by the need to urinate. And each time I awoke my mouth was
unusually dry (parched) and thirsty. I also had a bad (as in unable to put socks on or tie shoes without bad pain) ache
in my left hip which REFUSED TO HEAL. I took many supplements which usually speed healing for me, with no effect.
During the daytime, I also noticed an increased need to urinate & drink water. My weight has also been on the decline,
going from 157 to 147 over the last 6 months...although there were probably additional reasons for that. Prior to this
experience there was another brief interval when I had increased frequency of nightly urination....when I was taking
antibiotics for my teeth. That must have lowered my good intestinal bacteria count...which produces K1. After 2 nights
of high frequency urination, I took 200 micrograms of K1 and also had a serving of good yogurt. That nite I slept 5.5
hours before awakening and needing to urinate (about normal for me)...& slept well afterwards. My mouth was also not
parched like the previous nites. During the daytime I also noticed significant healing of my left hip and less need to
urinate or drink water. I again took 100 micrograms of K1 and didn't have to urinate excessively. K1 is much cheaper
31
than K2 & that's why I am using it, & I was hoping my body would convert some of the K1 to K2. I am male, 63 years old
with an ideal weight of 148? and usually do not suffer from an excessive need to urinate. After reading your very
revealing article, I may buy some K2. I have also used strontium citrate & believe it helped my teeth...but found
strontium in EXCESS could hurt my sleep, heart beat & even the teeth in extreme excess. All those areas require a
good mineral balance in the blood and could be hurt by excessive movement of calcium from the blood to the teeth &
bones. I wonder if K2 will exhibit the same effect. I also observed that vitamin D3 works in opposition to strontium. I've
had trouble with D3..hurting my sleep..wonder if that will be cured by K2 in light of this article
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+7
...
written by Donna, Jun 24 2011
Wow!!!! this was an awesome article and so informative. I have Osteoporosis and am taking a combo of D3&K2 along
with Strontium Citrate and other bone supplements. Have you heard of Strontium Citrate for bones?
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...
written by Brandon Berg, May 18 2011
Other way around, Marcus. Natto is a Japanese compound word whose components are natsu (storage) and to (bean).
Soybeans kept in storage for a long time, i.e., fermented. The subspecies of bacteria is named for the food in which it
is found.
And I agree with Chris that it's definitely an acquired taste. I tried it once at a sushi restaurant several years ago and
thought it was pretty terrible. In light of this information, I may have to head down to Chinatown and give it another try.
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+1
VitaminK2 or VitaminK4?
written by Lisa, Mar 27 2011
I have read your article and I would like to take supplements of vitamin K2 (that are mentioned in your article) as I take
calcium supplements,
it seems that the one derived from Natto one is the best
However, as Dr Mercola states, all soy products, especially the fermented ones, are highly goitrogenic, and I have
some hypothyroid conditions
So my question is, would that be the same if I use the Vitamin K2 ( MK4) instead than the MK7? As it seems that the
MK4 is not derived from soy, do you know if it is equally efficient?
Thanks
Lisa
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...
written by Tony Rutz, Jan 05 2011
Do you know if K2 supplementation been shown to reverse aortic stenosis?
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Warfarin and Vitamin K2
written by PhilM, Dec 16 2010
Chris,
Wow! What an information rich article this is! I am still trying to digest the details.
Does eating foods rich in K2 (natto especially) affect anti-coagulation? I am especially curious on how K2 differs from
K1 in this respect.
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Natto question
written by Marcus, Dec 04 2010
Judging from the last answer to the last question, am I to understand that Natto is named after the bacteria it is
produced by?
Marcus
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High Vitamin Butter Oil
written by jimmyv, Aug 27 2010
If High Vitamin Butter Oil is known to contain the richest source of Activator X, does this mean that it is rich in K2? In
the article above, the 'comparison' reference makes it seem like the butter oil is a great substitution for K2, since it
provides very similar benefits. Am I way off on this? Is K2 and Green Pastures Butter Oil one in the same? Also, if it is
still undetermined how much K2 is the right amount, how do we know that taking the recommended doses of CLO
combined with HVBO contains a safe and sufficient amount of D and A and K2 to provide all the benefits referenced
above?
Thanks!
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Will K2 interfere with Aspirin
written by rashmie, May 15 2010
Hello,
This is a very informative article. It can be revolutionary to know that Vitamin K1 and K2 perform specific functions.
That, K1 primarily fulfills the blood clotting functionality while K2 activates the protein that allows calcium to stay
where it should - in the bones, rather than on soft tissues.
If K2 has this specific function of directing calcium to the bones, then can I safely supplement my mother with K2
who's recently undergone a Bental surgery (replacement of the aorta and valves) and she was on Warfarin initially for 2
months and now is removed from that but is put on Aspirin? My mother has severe bone problems, has Osteopenia
and is really deficient in D3.
Your input will be much appreciated. Mym mom is really suffering with all sorts of pain all over her body.
Thanks much.
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+8
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Vit. K2
written by Colleen Mulvihill, May 10 2010
I have been having a hard time digesting food, problems thinking,nerve problems, heart palpatations, breathing
problems. I know I am low in Vit K2 per homopathic. Could this be the cause. I was on Warafarin for about 1 year
because I had a blood clot in my leg. Since I have taken Warfarin, I have had so may symptoms...extreme tiredness,
confusion and so much more. What would you recommend? I never feel well. Is there a standard blood test for Vit. K2
Thank you,
Colleen
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...
written by Tim Zuffi, Apr 13 2010
I have read the scientific papers showing the connections of vitamin K2 insufficiency/deficiency to osteoporosis,
calcium deposits in the arteries and cartilage etc. I found this paper (http://bloodjournal.hematology...type=HWCIT)
particularly impressive because it shows how increasing the consumption of vitamin K2 seems to reverse arterial
calcification. What I would like to know is if anyone is doing a similar study with either people with osteophytes/bone
spurs or with osteoarthritis, given that these diseases seem to be other manifestations of shuttling calcium to all the
wrong places.
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+9
i have osteoporosis and i want to change that
written by joellenoelle, Feb 25 2010
informative article. I can't belive my dr wants me to take dangerous osteoporosis drugs when all i really may need is
some healthy eating habits and some vitK2
a must read for usre
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+2
Kidney Stones and K2
written by Don, Feb 16 2010
I have suffered from kidney stones that I am unable to pass without surgical intervention. To think that it might be a
lack of vitamin K2 all along is encouraging. There are so many theories about the cause of Kidney Stones including too
much calcium, oxalate,cadmium, fluoride... it has my head spinning. I always found the idea of avoiding the list of 200
oxalate containing foods recommended by my local hospital's website could do more harm than good as many are
nutritious.
Anyone suffering from a Calcium/oxalate kidney stone please try drinking the undiluted juice of several lemons and/or
Apple Cider Vinegar mixed with a small amount of water. I had 2 Kidney stones that disappeared minutes after I drank
these substances. Please don't believe me, try it yourself!
34
Cure for Cancer: Activator X May Be the
Missing Link
Posted on January 8, 2010 by Chris Masterjohn
Originally published on April 30, 2009.
In the spring of 2007, Wise Traditions carried my article, “On the Trail of the Elusive X
Factor,” in which I argued that the vitamin-like compound that Weston Price dubbed
“Activator X” in the 1945 edition of Nutrition and Physical Degeneration was the very same
nutrient researchers now call “vitamin K2.” Vitamin K2 is abundant in grass-fed animal fats
and fermented foods, and promotes broad facial structure, healthy bones and teeth, a properly
functioning nervous system, and robust cardiovascular health.
An accumulating body of research suggests that vitamin K2 may also protect against cancer.
A 2004 study published in the Journal of the American Medical Association showed that 45
milligrams per day (mg/day) of vitamin K2 in the MK-4 form could reduce the risk of liver
cancer by 80 percent in twenty women with viral cirrhosis compared to twenty controls who
received no treatment. Statistical adjustments for other factors that could affect the risk of
cancer suggested that vitamin K2 could reduce this risk by just under 90 percent.
The women were randomly allotted to a treatment or control group, but the study was neither
placebo-controlled nor double-blind, and it used a dose of vitamin K2 that is impossible to get
from food. It therefore left open the question of whether vitamin K2-rich foods such as grassfed liver, butter, cheese, and egg yolks could reduce the risk of cancer.
New research from the Heidelberg cohort of the European Prospective Investigation Into
Cancer and Nutrition (EPIC-Heidelberg) suggests that vitamin K2 in amounts obtainable from
natural foods does in fact protect against cancer. Analyses conducted in the Dutch
PROSPECT cohort of this study expanded earlier findings of The Rotterdam Study by
showing that vitamin K2, but not vitamin K1, is associated with a reduced risk of coronary
calcification and heart disease. Analyses conducted in the German Heidelberg cohort of the
study similarly found that vitamin K2, but not vitamin K1, is associated with a reduced risk of
advanced prostate cancer. People who consumed more than 46 micrograms per day (mcg/day)
at the beginning of the study were only half as likely to develop advanced prostate cancer
over the following nine years as people who consumed less than 26 mcg/day.
The investigators also examined the relationship between undercarboxylated osteocalcin and
the risk of adavanced prostate cancer. Osteocalcin is a protein made by bone, a small portion
of which slips out into the blood. Vitamin K is required to “carboxylate” the protein, which is
a form of activation that gives the protein the ability to bind calcium. When the vitamin K
level of bone decreases, the amount of deformed, inactive, “undercarboxylated” osteocalcin in
the blood increases. The percentage of serum osteocalcin that is in its activated state, then, is
an indicator of the vitamin K status of bone and probably the extra-hepatic (non-liver) tissues
in general. This is influenced to some degree by vitamin K1 status, but is influenced to a
much greater extent by vitamin K2 status.
35
In the EPIC-Heidelberg cohort, in which the percentage of osteocalcin that is in its active
form ranged from 80 to 89 percent, a 0.1-unit increase in the ratio of inactive to active
osteocalcin was associated with a 38 percent increase in the risk of advanced prostate cancer.
There are three major insights we can obtain from the EPIC-Heidelberg data: first, vitamin K2
from foods may be much more powerful than synthetic vitamin K2 from supplements;
second, vitamin K2 may protect against cancer through mechanisms that are independent
from its classical role in protein carboxylation; and third, many segments of the population,
especially growing children and postmenopausal women, are dangerously deficient in the allimportant activator X.
Vitamin K2: Are Foods More Powerful Than Supplements?
In Japanese postmenopausal women, 1.5 milligrams per day (mg/day) of vitamin K2 in the
MK-4 form is required to raise the percentage of serum osteocalcin that is in its active form
from about 70 percent to just over 80 percent. This is a similar increase to the increase from
80 to 89 percent in the EPIC-Heidelberg cohort that was associated with about one-third
lower risk of advanced prostate cancer, whereas a mere 20 mcg/day increase in vitamin K2
intake was associated with an even larger fifty percent decrease in risk. This 20 mcg/day dose
is 75 times less than 1.5 mg/day.
Any attempt to explain this discrepancy is speculative. There are several reasons that could
account for this difference. Postemenopausal women may have a higher vitamin K
requirement than other members of the population. Supplemental MK-4 could be less
effective at activating osteocalcin than other forms of vitamin K. The MK-7 form of vitamin
K2 is three times more effective at activating serum osteocalcin than synthetic vitamin K1,
but no one has yet compared either of these forms to MK-4. Any comparison between MK-7
and MK-4 would be confounded by the fact that MK-7 supplements are isolated from natural
food sources while MK-4 supplements are synthetic. This brings us to the third possibility,
that natural food sources of MK-4 are more powerful than synthetic MK-4 supplements. This
is a possibility that cannot be ignored. Ultimately, we would like to see trials using K2-rich
foods such as grass-fed liver, butter, cheese, egg yolks, and fermented foods such as natto, to
increase the activation of osteocalcin or decrease the risk of prostate cancer.
Do the Unique Actions of MK-4 Protect Against Cancer?
Another reason the negative correlation between vitamin K2 intake and advanced prostate
cancer may be stronger than the negative correlation with serum osteocalcin may be that the
unique actions of MK-4 are responsible for the protective effect. Any vitamin K that reaches
bone tissue will contribute to osteocalcin activation, but only a portion of the MK-7, K1, and
other forms of vitamin K that reach the tissue will be converted to MK-4.
Recent experiments in isolated cells have shown that MK-4, but not MK-7 or vitamin K1,
regulates gene expression like its partner vitamins A and D. By binding to its nuclear receptor,
called the SXR, or by activating an enzyme called protein kinase A, MK-4 regulates the
expression of dozens of genes, some of which are involved in regulating cellular growth and
proliferation, two processes important in the development of cancer.
Both vitamin K1 and vitamin K2 in the MK-4 form inhibit the growth and proliferation of
isolated cancer cells, but the concentrations required for K2 to be effective are five times
lower than the concentrations required for K1 to be effective.
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Since many animal cells can convert vitamin K1 to MK-4, this raises the possibility that any
protective effect of vitamin K1 may be due to the portion of it that is converted to MK-4.
Since vitamin K1 is preferentially delivered to the liver rather than to other tissues, this may
be why vitamin K1 at doses found in the diet offers little if any protection against cancer.
The Widespread Deficiency of Activator X
Virtually everyone who does not supplement with vitamin K has at least some of their serum
osteocalcin in the defective, undercarboxylated form. This suggests that most people have
suboptimal vitamin K2 status, but it could always be argued that there is no need to have all
of the osteocalcin activated.
The EPIC-Heidelberg study makes clear that 10-20 percent of serum osteocalcin in its
inactive form indicates a state of deficiency.
Wisconsin adults have between 2 and 15 percent of their serum osteocalcin in its inactive
form. The numbers for growing chilren, however, are much worse. Osteocalcin levels are
much higher in children because the activty of growing bone is much higher. Consequently,
the demand for vitamin K2 is much higher. In 11-year-old and 12-year-old Danish girls,
undercarboxylated osteocalcin levels reach almost 60 percent. Over half the girls have levels
over 20 percent. In children of ages 8 through 14 in Amsterdam, undercarboxylated
osteocalcin ranged from 11 to 83 percent and increased during puberty. A small study in The
Netherlands found average levels of 43 percent in adults and 67 percent in children,
increasing during puberty from 64 percent to 73 percent.
Children are not at risk for most cancers, but the structure of our bodies becomes fixed in
many ways during our growth and development, and the widespread severe deficiency of
activator X during this period is likely to compromise long-term health for decades, even
though demand for the vitamin will decline during adulthood.
Postmenopausal women, however, are at risk for developing cancer, and the numers are
almost as frightening in this population as they are in children. In postmenopausal American
women in the Framingham Offspring Study, for example, which did not account for whether
anyone was supplementing with vitamin K, undercarboxylated osteocalcin ranged from zero
to 91 percent, and averaged 17 percent.
One wonders whether vitamin K2 intake is associated with a reduced risk of breast cancer in
the same way it is associated with a reduced risk of prostate cancer.
Interpreting Uncertainty Through the Lens of Traditional Diets
Correlation never implies causation. The mere fact that vitamin K2 intake and vitamin K
status is associated with a reduced risk of prostate cancer does not in and of itself imply that
vitamin K protects against prostate cancer. The fact that cell experiments and a human trial
using large doses of vitamin K2 both show an anticarcinogenic effect of the vitamin, however,
strengthens the hypothesis that foods rich in K2 do in fact protect against cancer.
Moreover, traditional diets were rich in vitamin K2 and appeared to afford protection against
cancer. When Weston Price visited the Torres Strait Islands north of Austrailia, he spoke to a
doctor who had suspected only one case of cancer and operated on none among more than
37
4,000 natives eating their traditional diet, but had operated on dozens of whites eating diets of
refined foods living in the same area.
It should be humbling to us that these natives did not have any of the money, research
methods, or medical equipment that we have, yet were far more successful at protecting
themselves against cancer and other degenerative diseases than we are. What they did have
was traditional wisdom accumulated over the ages — something to which our society offers
little respect but nevertheless confirms over and over again with the tools of modern science.
Those of us in the know can get ahead of the game by deferring to traditional wisdom here
and now, and thus obtain protection from modern disease and support for longevity and
vibrant health.
Undercarboxylated Osteocalcin: Marker of
Vitamin K Deficiency
Weston A. Price Foundation
http://www.westonaprice.org/blogs/cmasterjohn/2013/07/17/undercarboxylated-osteocalcin-marker-of-vitamin-kdeficiency-or-booster-of-insulin-signaling-and-testosterone/
Undercarboxylated Osteocalcin: Marker of
Vitamin K Deficiency, or Booster of Insulin
Signaling and Testosterone?
Posted on July 17, 2013 by Chris Masterjohn
Osteocalcin is a vitamin K-dependent protein that our bones produce. The job of vitamin K is
to activate this protein by adding carbon dioxide to it, which in scientific jargon we call
“carboxylation.” Vitamin K researchers widely regard the ratio of undercarboxylated to
carboxylated or total osteocalcin as a marker of inadequate vitamin K status. Evidence has
accumulated over the last half decade, however, that undercarboxylated osteocalcin may
38
stimulate the production of insulin and testosterone, while simultaneously enhancing insulin
sensitivity, and by doing so, make us lean and fertile.
Is undercarboxylated osteocalcin a good thing or a bad thing? Could this represent a downside
to getting enough vitamin K, particularly vitamin K2, the form that most effectively reaches
our bones? I’ll tackle these questions in this post as I critically review the literature on
undercarboxylated osteocalcin’s role as an insulin- and testosterone-boosting hormone.
Widespread Deficiency of Vitamin K2?
In my Spring, 2007 article, “On the Trail of the Elusive X-Factor: A Sixty-Two-Year-Old
Mystery Finally Solved,” I followed the convention of the vitamin K research community by
using the proportion of osteocalcin in its undercarboxylated form — which I then called
“inactive,” a term that now seems inappropriate — as a marker of inadequate vitamin K
status. More specifically, it indicates deficient vitamin K status of bone, and since vitamin K2
reaches bone more effectively than K1, it is in a certain sense more a marker of K2 deficiency.
I supported this by pointing out that people with the highest proportion of osteocalcin in this
form have a five-fold greater risk of fracture. Vitamin K2 supplementation, moreover,
improves the activation of osteocalcin, and in a series of Japanese trials it reduced fracture
risk by 80 percent. These data offer strong support for using undercarboxylated osteocalcin as
a marker of vitamin K deficiency in bone tissue.
In a 2010 blog post, I argued that “10-20 percent of serum osteocalcin in its inactive form
indicates a state of deficiency” on the basis that within this range small improvements in the
proportion of osteocalcin that is carboxylated are associated with large decreases in the risk of
advanced prostate cancer. I further argued that there is “widespread deficiency” of vitamin K2
in children, based on studies showing that the proportion of osteocalcin that is inactive is
remarkably high in children, considerably higher than 10-20 percent, and increases during
puberty, reaching in some children as high as 83 percent.
Our bone-building cells, osteoblasts, produce osteocalcin. As a result, we make more
osteocalcin when we are building more bone. Childhood is a period of rapid bone growth,
especially adolescence, during which bone mass approximately doubles (1). This would seem
to offer a very simple and elegant explanation of why the proportion of undercarboxylated
osteocalcin is so high during childhood and especially during puberty: when bones are
growing, the production of osteocalcin, and thus the demand for vitamin K, is very high; if the
intake of vitamin K, especially vitamin K2, is low, then a large proportion of this osteocalcin
will be undercarboxylated. According to this paradigm, undercarboxylated osteocalcin reflects
widespread deficiency of vitamin K2 in growing children.
Undercarboxylated Osteocalcin: A
Beneficial Insulin- and TestosteroneBoosting Hormone?
39
Beginning in 2007, however, a body of literature began to emerge suggesting that
undercarboxylated osteocalcin plays an important physiological role as an insulin-stimulating,
insulin-sensitizing, testosterone-boosting hormone — at least in mice, anyway. These
findings, if they can be generalized to humans, have the potential to throw a major monkey
wrench into the standard interpretation of undercarboxylated osteocalcin as a marker of
vitamin K deficiency.
Undercarboxylated Osteocalcin, Insulin, and Energy
Balance
In 2007, Lee and colleagues from the labs of Gerard Karsenty and Patricia Ducy at Columbia
University published a study (2) showing that mice engineered to lack the osteocalcin gene
were fat, had elevated blood glucose, burned energy at a lower rate, and were both deficient in
and insensitive to insulin.
Incubating fat cells with osteoblasts caused them to produce adiponectin, an insulinsensitizing hormone, and incubating pancreatic cells with osteoblasts caused them to produce
insulin itself. Osteoblasts were only effective, however, if they produced osteocalcin;
osteoblasts taken from the mice with a deletion in the gene had no effect. Actually, osteoblasts
themselves weren’t needed. Just incubating the cells with osteocalcin worked fine.
But here’s the catch: treating the osteoblasts with warfarin, which reduces the carboxylation
of osteocalcin by interfering with vitamin K metabolism, actually increased the effect. In fact,
when the investigators compared purely carboxylated osteocalcin to purely uncarboxylated
osteocalcin, only the uncarboxylated form was effective. Giving the live, osteocalcin-deficient
mice uncarboxylated osteocalcin, moreover, improved their glucose tolerance and insulin
secretion.
We should note here that the osteocalcin the investigators used wasn’t just
“undercarboxylated” as it tends to occur in humans and live animals (meaning it has some
carbon dioxide added to it, but less than it should), but totally “uncarboxylated” because they
genetically engineered bacteria to make it, and these bacteria were among the vast majority of
microorganisms that lack the vitamin K-dependent enzyme responsible for carboxylation.
The same group published a second study early the following year (3) showing that these
phenomena held true not just in genetically engineered mice but even in wild-type mice.
Subcutaneous infusion of uncarboxylated osteocalcin protected mice against the damaging
metabolic effects of both highly purified, industrial, high-fat rodent diets as well as damage to
the hypothalamus, a key part of the brain that contributes to the regulation of energy balance.*
Undercarboxylated Osteocalcin, Testosterone, and
Fertility
In 2011, the Karsenty and Ducy labs, along with several other collaborators, published a
landmark paper expanding their findings from energy metabolism to male fertility (4). In male
mice, experiments involving deletion of the osteocalcin gene or administration of
uncarboxylated osteocalcin showed that undercarboxylated or uncarboxylated osteocalcin
increases production of testosterone, the size and weight of testes, and both the frequency and
size of sired litters.
40
Mice lacking osteocalcin also had an excess of luteinizing hormone (LH), a pituitary hormone
responsible for increasing testosterone production. The excess of LH seems to be an attempt
to compensate for the lack of testosterone, but it obviously isn’t effective at restoring
testosterone to normal.
In female mice, by contrast, the protein had no effect on fertility or on production of estrogen
and progesterone. The paper makes no mention of female testosterone or male estrogen and
progesterone.
The investigators also identified a protein that may act as a receptor for undercarboxylated
osteocalcin, present in testes but not ovaries, which would explain why the effect seems to
apply to male mice but not females.
The Critical Role of Bone Resorption
Additional studies from the Karsenty lab and various collaborators showed that genetically
altering or pharmaceutically treating the mice to increase or decrease the rate of bone
resorption controlled the release of undercarboxylated osteocalcin into circulation and its
subsequent effects on energy balance and testosterone (5, 6).
Bone growth and bone resorption are both parts of normal, everyday, healthy bone
metabolism. Bone resorption is the acidic dissolution and digestion of mineralized bone
matrix. It plays important roles in regulating the levels of minerals in the blood, mainly
calcium and phosphorus, and in allowing bone matrix to reorganize as needed to best fulfill
the demands of the body and environment.
While the vitamin K-dependent addition of carbon dioxide allows osteocalcin to accumulate
in the bone matrix, bone resorption creates an acidic environment that removes some of the
carbon dioxide and allows release of undercarboxylated osteocalcin into the blood. Removal
of carbon dioxide is known as “decarboxylation.” According to the paradigm Karsenty and
his collaborators have been presenting, this process allows the activation of osteocalcin to its
hormone form.
These authors follow the exact opposite usage that I have over the past six or seven years and
refer to undercarboxylated osteocalcin as the “active” form. For clarity, I may refer to this
form as “hormonally active.”
Sarah Booth and her colleagues at Tufts University have pointed out that when human
osteoclasts are cultured on bovine bone, only a small amount of osteocalcin is released and
enzymes subsequently digest most of it into fragments that are unlikely to act as hormones
(7).
The Karsenty lab’s data, however, is quite convincing that bone resorption releases functional,
hormonally active osteocalcin in mice. As mentioned above, genetic or pharmaceutical
interventions to increase or decrease bone resorption not only controlled the release of
undercarboxylated osteocalcin, but also produced the expected effects on energy metabolism
and testosterone. When the researchers mimicked the process outside of a live animal,
moreover, they verified the hormonal activity of the osteocalcin that was released.
41
Roles for Insulin and Leptin
In the initial paper reporting that mice lacking the osteocalcin gene were fat and in metabolic
disarray, the investigators also uncovered a role for the Esp gene: deleting it increased the
amount of undercarboxylated osteocalcin circulating and had the exact opposite metabolic
effects as deleting the osteocalcin gene. Subsequent experiments published by the same group
(5) showed that the protein encoded by this gene neutralizes the insulin receptor once it has
been activated. Although this gene isn’t active in humans, we have a different enzyme known
as PTP1B that fulfills the same function.
In the same paper (5), the researchers reported that, although insulin signaling in osteoblasts
promotes bone growth and ultimately leads to stronger bones, it also promotes bone
resorption. Bone growth involves the production of osteocalcin, its vitamin K-dependent
carboxylation, and its accumulation in bone matrix; bone resorption involves its
decarboxylation and release into circulation as a hormone. Insulin signaling in osteoblasts is
therefore a key pathway that promotes the release of circulating hormonally active
osteocalcin.
This group had also published a separate paper (8) showing that leptin, a hormone secreted by
fat tissue, acts on the brain to increase signaling of the sympathetic nervous system to
osteoblasts, which increases the activity of the Esp gene. This antagonizes insulin signaling in
osteoblasts, decreases bone resorption, and thereby decreases the circulating amount of
hormonally active osteocalcin.
This paper remarkably showed that, in mice, fat tissue, bone tissue, and the brain all
communicate with each other to regulate energy metabolism and fertility.**
This evidence suggests that a higher insulin-to-leptin ratio may promote bone resorption and
thereby promote the release of hormonally active osteocalcin. We should exercise caution
when generalizing from these studies, however, since even if this hormonal axis works
similarly in humans, simply measuring the concentrations of these hormones in the blood
does not necessarily provide adequate information about their signaling activity at the cellular
level where they are fulfilling their functions.
Of Mice, Men , and a Little Protein In Need
of a Job
So far, all of the direct experimental evidence supporting the hormonal role of osteocalcin is
in mice. The Karsenty lab and its collaborators argued that it would be unprecedented for this
work to have no implications for humans, but also admitted the need for direct evidence (4):
. . . there is no example yet of a molecule being a hormone in the mouse that has abruptly lost
this attribute in humans. This is, nevertheless, an aspect of osteocalcin that will need further
investigation in the future.
Mouse Osteocalcin Could Hypothetically Be Unique
42
In a critical review referenced above (7), Sarah Booth and colleagues pointed out that the
sequence of the mouse osteocalcin gene has less similarity to that of the human gene
compared to many other species. The way the gene is organized on chromosomes differs and
the way vitamin D regulates its expression also differs between mice and humans. Rats are
actually closer to humans than mice in these respects. While these points hardly refute a
hormonal role for osteocalcin in humans, they do support, in a very limited way, the
possibility that the function of osteocalcin could vary between species, which further
emphasizes the need to generate direct evidence for its hormonal role in humans.
If Osteocalcin Isn’t a Hormone, What on Earth Does It
Do?
On the other hand, if these newly discovered hormonal roles of osteocalcin hold across
species, this would help disperse some of the fog of mystery that has enveloped for so many
years the question of just what it is this protein actually does. As I pointed out back in 2007,
mice that lack the osteocalcin gene have no problems mineralizing their bones, but the bone
matrix is organized somewhat differently. I concluded that “this could mean that osteocalcin
is important to the functional quality of bone and the ability to regulate its shape,” but “could
mean” is a critical phrase in that sentence.
It was the Karsenty lab that carried out these studies back in the 1990s, the same lab that has
been promoting the paradigm that osteocalcin acts as an insulin- and testosterone-boosting
hormone. One of their early studies (9) suggested that mice with no osteocalcin gene actually
have better bone strength than normal mice. Their subsequent analysis (10) of these mutant
mice indicated the bone matrix seemed less “mature,” but the functional benefit of osteocalcin
remained elusive.
To go beyond “could mean” when the only clearly demonstrated function of the protein was
to reorganize bone in a way that decreases its strength would have been a stretch. Indeed,
although osteocalcin must logically have some beneficial role in the body, the question of just
what that role actually is was at that time extremely puzzling.
In retrospect, the figure in my 2007 article depicting the role of osteocalcin as “organization
of minerals” over-interpreted the evidence available back in 2006 when I was researching the
article. I was assuming that, if this was osteocalcin’s only known function, it must be
beneficial in some way even if its benefit was far from obvious.
When we consider that these mice have no obvious bone defects yet are fat, infertile, and
metabolically damaged, it would seem that in the mouse the primary role of osteocalcin is to
regulate energy metabolism and fertility rather than to do anything particular to bone.
And since in mice osteocalcin affects the production or activity of numerous other hormones
that affect bone metabolism, such as insulin, adiponectin, and testosterone, there is no reason
to assume that osteocalcin’s modest yet quite puzzling effects on bone are directly a result of
its accumulation in bone matrix. Indeed, the changes in the bones of osteocalcin-deficient
mice could simply be a relatively minor side effect of the disturbances in these other
hormones.
If undercarboxylated osteocalcin is not a hormone that regulates energy balance and fertility
in humans, we are back to square one with little understanding of its function. These mouse
43
studies, then, provide us with hope that we may be making progress towards solving the
enigma.
Limited Support From Epidemiological Evidence
There is a considerable amount of epidemiological evidence associating total osteocalcin with
energy metabolism in humans, but this sheds little light on the matter because the studies do
not look at undercarboxylated osteocalcin specifically (for example, 11, 12). This could
simply reflect an association between bone growth and overall health.
There is a growing body of favorable epidemiological evidence looking at undercarboxylated
osteocalcin, but because of the complex interactions between the cells and hormones
involved, these studies are difficult to interpret. Here are some examples:


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
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
Among just under 300 men and postmenopausal women with type 2 diabetes,
undercarboxylated and total osteocalcin were inversely related to fat mass and HbA1c,
a marker of poor glucose metabolism (13). Puzzlingly, the ratio of undercarboxylated
to total osteocalcin had the opposite association with fat mass in men but no
association in women, and the associations between undercarboxylated osteocalcin, fat
mass, and glucose metabolism lost statistical significance after adjustment for putative
confounders in women, but not in men.
Among just under 60 male subjects across a wide spectrum of body weights, morbidly
obese men had lower undercarboxylated osteocalcin than normal-weight men, and a
lower ratio of undercarboxylated to total osteocalcin (14). Among all the obese
subjects, undercarboxylated osteocalcin inversely correlated with waist circumference
and fasting glucose.
Among just over 60 overweight men, the ratio between undercarboxylated and
carboxylated osteocalcin, but not either individual form of the protein, correlated with
free testosterone, but not with total testosterone or other sex hormone-related measures
(15).
Among just over 50 healthy boys ranging in age from 7 to 21, both undercarboxylated
and total osteocalcin correlated with serum testosterone after adjusting for “bone age,”
an estimation of the maturity of a child’s skeleton (16). These authors did not report
correlations with the ratio between the two forms of osteocalcin.
Among just under 70 men with severe type 2 diabetes, undercarboxylated osteocalcin
did not correlate with testosterone until the authors statistically adjusted for markers of
bone and glucose metabolism, gonadal hormones, age, and body mass index (17).
After adjustment, undercarboxylated osteocalcin correlated positively with free
testosterone and inversely with luteinizing hormone. The ratio of undercarboxylated to
total osteocalcin was similarly correlated with testosterone, whereas total osteocalcin
itself was not.
Among just under 250 healthy postmenopausal women, by contrast, Cees Vermeer’s
Netherlands-based vitamin K research team found very different results: carboxylated
osteocalcin was inversely related with body weight, body mass index, hip and waist
circumference, and body fatness, whereas the ratio of undercarboxylated to
carboxylated osteocalcin had smaller positive associations with these parameters, and
our putative hormone, undercarboxylated osteocalcin, had no such associations (18).
These studies are difficult to interpret. The reasons are myriad:
44



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
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Undercarboxylated osteocalcin could reflect the insufficient carboxylation of the
protein, or could reflect its decarboxylation during bone resorption.
Insufficient carboxylation of the protein could, in turn, reflect a high rate of its
production during bone growth, inadequate vitamin K status, or most likely some
combination thereof.
The ratio of undercarboxylated to total osteocalcin could reflect poor vitamin K status,
but it could also reflect a greater rate of bone resorption compared to bone growth.
It is unclear whether the absolute amount of undercarboxylated osteocalcin or its ratio
to total osteocalcin would be the best measure of its hormonal activity because no one
to my knowledge has determined whether the carboxylated form interferes with the
hormonal activity of the undercarboxylated form.
Since all of the downstream targets of undercarboxylated osteocalcin, such as insulin,
adiponectin, and testosterone, affect bone metabolism, correlations between these
factors are riddled with chicken-and-egg questions.
To confuse matters further, some recent reports (14, 15) indicate that, in addition to
osteoblasts, pre-adipocytes in fat tissue produce osteocalcin, including
undercarboxylated osteocalcin. They produce more osteocalcin in response to
testosterone, but less osteocalcin as the fat tissue proliferates and the pre-adipocytes
turn into true fat cells. This adds another chicken-and-egg question to correlations
between osteocalcin and testosterone. It also adds a further layer of confusion: lower
undercarboxylated osteocalcin in obesity could reflect not only a fat-burning effect of
the putative hormone, but also a lower production of it by adipose tissue in people
with greater numbers of fat cells.
Overall, then, I would say the epidemiological evidence is, although somewhat conflicting in
some respects, generally consistent with a fat-burning and testosterone-boosting effect of
undercarboxylated osteocalcin in humans, but I would be reticent to claim the evidence is
more than slightly supportive.
Human Genetic Evidence
The strongest and most direct evidence to date that undercarboxylated osteocalcin acts as a
hormone in humans comes from human patients with genetic defects in the putative
osteocalcin receptor (6). The Karsenty lab and their collaborators analyzed the genetics of just
under 60 men with primary testicular failure presenting with low sperm count and high
luteinizing hormone (LH), but without any increase in testosterone resulting from the high
LH. Two of them (3.4%) had genetic defects in the putative osteocalcin receptor.
Although this genetic defect is present in 1.2% of African Americans and 0.02% of Europeans
who submitted DNA to the NHLBI Grand Opportunity Exome Sequencing Project, none of
the more than 900 healthy controls recruited by the Karsenty team had the defect. This
provides strong preliminary evidence that the defect is associated with and perhaps causes
testicular dysfunction that resembles the infertility seen in mice lacking the osteocalcin gene.
The patients with this defect resembled these mice in other ways as well. One had a large
waist circumference and excess body fatness as well as glucose intolerance, while the other
had a history of high blood glucose that he kept under control with daily exercise and strict
caloric restriction.
45
I refer to this receptor as a “putative” osteocalcin receptor because in test tube experiments it
binds to a variety of different compounds. The only compound for which there is thus far
clear evidence of receptor activation in live animals is undercarboxylated osteocalcin. Thus,
the resemblance of men with defects in the receptor to mice with defects in the osteocalcin
gene suggests that undercarboxylated osteocalcin is hormonally active in humans, but the
evidence is not conclusive.
Looking at the Totality of the Evidence
Adding up a bunch of inconclusive studies can never yield a conclusive result, but when we
view the hints of the hormonal role of undercarboxylated osteocalcin in humans from
epidemiological and genetic evidence in the context of the conclusive evidence for its
hormonal role in mice and in the context of the lack of any other compelling explanation for
the function of this protein in any species, we arrive at very strong hints that this protein is, in
fact, a hormone in humans.
While the evidence is not yet conclusive, I would hedge my bets that future evidence, as it
improves both in quantity and quality and pushes us towards a conclusion, will support rather
than refute the hormonal role of undercarboxylated osteocalcin in humans and across many
species.
Should We All Get Deficient in Vitamin K?
If we accept the probability that undercarboxylated osteocalcin has positive hormonal roles in
humans, as I do, this naturally leads us to consider the implications for vitamin K intake.
Since the function of vitamin K is, in part, to carboxylate osteocalcin, and since it decreases
circulating amounts of undercarboxylated osteocalcin, could obtaining an abundance of
vitamin K from foods or supplements be harmful?
On the one hand, the experiments I cited above showed that osteoblasts or their secretions
could elicit hormonal responses more effectively when made vitamin K-deficient with
warfarin.
On the other hand, the Karsenty team and its collaborators have consistently argued, with
strong evidence, that bone resorption is the trigger for release of hormonally active
osteocalcin into the bloodstream. If this paradigm is correct, one could argue that adequate
vitamin K is needed to ensure that osteocalcin is fully carboxylated as it is produced, allowing
it to accumulate in bone matrix, so that the presence of the undercarboxylated form in the
bloodstream accurately reflects the degree of bone resorption.
Vitamin K, moreover, is involved in much more than osteocalcin metabolism. As I pointed
out back in 2007, it not only supports strong bones and teeth, adequate growth, and the health
of the kidneys, brain, and heart, but it appears to support energy metabolism and fertility as
well, since it accumulates in the pancreas and testes and activates a protein of unknown
function in sperm.
Rats on vitamin K-deficient diets develop poor glucose tolerance (19). There is some weak
indication, conversely, that vitamin K2 supplementation in humans with poor status improves
46
glucose and insulin metabolism (20). Vitamin K1 or K2 supplementation in rats, moreover,
lowers body fatness (21) and vitamin K2 supplementation increases testosterone (22).
Clearly, the research on the hormonal role of undercarboxylated osteocalcin does not suggest
in any way that the road toward leanness and virility is paved by vitamin K deficiency.
Undercarboxylated Osteocalcin: Why So
High in Growing Children?
This brings us back to the original question: why are blood levels of undercarboxylated
osteocalcin so high in growing children? Is it a marker of vitamin K deficiency, or part of a
developmental program to boost anabolic hormones?
I believe a consideration of the developmental endocrine program launched during puberty (1)
indicates that the original interpretation of this protein as a marker of vitamin K deficiency is,
in this case, correct. During adolescence, bone growth predominates over bone resorption,
making bone resorption a rather untenable explanation for the presence of undercarboxylated
osteocalcin in blood. Sex hormones and growth hormone increase the activation of vitamin D
to its hormone form, calcitriol, which increases the production of osteocalcin, alongside
massive increases in bone growth. If the supply of vitamin K to bone tissue is inadequate to
meet the demand to carboxylate all this extra osteocalcin, it will be released into the
circulation in its undercarboxylated form.
The incidence of fracture increases in boys and girls between the ages of 10 and 14, and in 14year-old boys it reaches the same magnitude as in 53-year-old women. The author of a recent
review (1) suggested that fracture risk increases during adolescence because bone volume and
soft tissue mass grow so rapidly during this period that the process of mineralization can’t
keep up:
Adolescence may be a period of life during which the bones are relatively “thin” in
comparison with the mass of soft body tissue. The inability of the mineralization process to
keep pace with the growth in length of the long bones may be an inevitable consequence of
the magnitude of the sex steroid-driven growth spurt. Indeed, bone modelling at the epiphyses
and metaphyses may be so active that skeletal volume is expanding at a faster rate than the
mineralization process.
Inevitable? Probably not. If the large increases in undercarboxylated osteocalcin indicate an
inadequate supply of vitamin K to bone, then they likely also indicate an inadequate supply of
vitamin K to the cells of cartilage and blood vessels, which make matrix Gla protein, one of
the most important proteins known to support bone mineralization (even if it may do so
indirectly).
Cees Vermeer’s group published an epidemiological study consistent with this concept (23).
Among over 300 children between the ages of 8 and 14, the ratio of undercarboxylated to
carboxylated osteocalcin was positively associated with testosterone in boys and estrogen in
girls, but inversely associated with bone mineral content.
The association with sex hormones is inconsistent with the mouse studies on the hormonal
role of osteocalcin: it produces testosterone in male mice but has no effect on estrogen in
47
female mice. Yet it is perfectly consistent with the hormonal program launched during
adolescence (1), wherein both testosterone and estrogen play roles in increasing bone growth
and osteocalcin production. The inverse association between undercarboxylated osteocalcin
and bone mineral content is consistent with a supply of vitamin K too scant to support the
mineralization process.
Conclusion? Back to Bone Resorption…
Is vitamin K completely off the hook? Not necessarily. Certain genetics, an excessively high
ratio of calcium to phosphorus in the diet, statins, osteoporosis drugs, and a variety of highdose nutritional supplements, possibly including vitamin K, could interfere with the process
of bone resorption. Such conditions could suppress the normal release of hormonally active
osteocalcin, and adding vitamin K into the mix could conceivably aggravate the situation.
In a future post, I’ll attempt to fill in the rest of this story by making sense of the hormonal
and nutritional regulation of bone resorption, and its role in regulating the circulation of
hormonally active osteocalcin.
I think the evidence is clear, however, that when all systems are otherwise working properly,
adequate vitamin K supports proper glucose metabolism, energy balance, and fertility. I
would feel very confident hedging my bets that more vitamin K for growing children would
mean better bone development and a lower risk of fracture.
This is consistent with Weston Price’s emphasis on the extraordinary skeletal and dental
health and the beautiful, broad, well developed faces of individuals consuming their
traditional ancestral diets, free of refined foods and rich in fat-soluble vitamins.
Read more about the author, Chris Masterjohn, PhD, here.
Notes
* Oddly enough, however, the experiments with fresh pancreatic islets and fat cells taken
from the mice suggested that the positive effects of uncarboxylated osteocalcin on insulin
only occurred at concentrations extremely low compared to those of undercarboxylated
osteocalcin normally present in mice, while the effects on adiponectin and energy expenditure
only occurred at normal to high concentrations. Similarly, in the later experiment concerning
fertility, only small doses of uncarboxylated osteocalcin enhanced testosterone production.
Larger doses abolished the effect.
I chose to relegate this to the “notes” section because some of the in vivo evidence from these
studies seems to indicate that osteocalcin has hormonal effects on all these parameters across
a wide range. For example, both increasing or decreasing the rate of bone resorption affects
energy balance and testosterone, apparently via undercarboxylated osteocalcin, showing that
departures from “normal” in both directions are effective, and thus that “normal” is within the
effective range. In general this is true for a variety of other loss-of-function and gain-offunction genetic experiments reported in these papers that alter the biochemical pathways
discussed. Overall, though, I think these findings related to dose need more attention in future
research. [Back to Main Text]
48
** Fat tissue produces another factor involved, adiponectin (24). While leptin levels increase
with body fatness, adiponectin levels decrease. Although adiponectin’s signaling pathways
are generally thought to be distinct from those of insulin, in this case it acts through the same
signaling pathway as insulin in both osteoblasts and in the brain. Paradoxically, its actions in
osteoblasts promote bone resorption while its actions in the brain decrease bone resorption.
The net effect of deleting the adiponectin gene in mice is to produce higher bone mass in
young mice and lower bone mass in older mice. It would thus seem that the short-term effect
of adiponectin is to promote bone resorption while its long-term effect is to inhibit bone
resorption, but ultimately the implications of these diametrically opposed roles are unclear.
[Back to Main Text]
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17 Responses to Undercarboxylated Osteocalcin: Marker of Vitamin K
Deficiency, or Booster of Insulin Signaling and Testosterone?
1.
George Henderson says:
July 17, 2013 at 10:50 pm
Interestingly, vitamin E elevated undercarboxlated prothrombin, but not osteocalcin,
in this human study http://www.ncbi.nlm.nih.gov/pubmed/15213041
if tocopherol does protect undercarboxylated osteocalcin in rodents, this might explain
why it is a fertility factor.
There are no animal studies in Pubmed and just one other relevant human study:
http://www.ncbi.nlm.nih.gov/pubmed/12032162
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An Ancestral Perspective on Vitamin D Status, Part 2: Why Low 25(OH)D Could Indicate a Deficiency of Calcium
Instead of Vitamin D →
51
An Ancestral Perspective on Vitamin D
Status, Part 1: Problems With the “Naked
Ape” Hypothesis of Optimal Serum
25(OH)D
Posted on December 18, 2013 by Chris Masterjohn
It has become increasingly common for health enthusiasts and now even typical patients in
the doctor’s office to have a lab estimate their vitamin D status by measuring serum 25hydroxyvitamin D, abbreviated 25(OH)D, and use vitamin D supplements to bring this value
into the “sufficient” range. While even this basic practice is problematic, the extraordinary
influence of what I like to call the “naked ape hypothesis of optimal serum 25(OH)D” has
created a paradigm wherein “deficiency” and “insufficiency” are together seen as the norm,
and 25(OH)D levels that may actually be quite dangerous — especially when not adequately
balanced by other nutrients in the diet — are specifically sought out as a panacea.
Indeed, this paradigm heavily influenced some of my early articles on the fat-soluble
vitamins, such as my 2006 article “From Seafood to Sunshine: A New Understanding of
Vitamin D Safety,” where I contributed original ideas about the interactions between the fatsoluble vitamins, but essentially took the popular ideas advocating high levels of serum
25(OH)D for granted. I now believe my rush to embrace the latter paradigm was quite hasty
and that it deserves the same critical attention that I have put into my ideas about vitamin
interactions.
In this series, I will argue that we should emphasize serum 25(OH)D much less and
emphasize the nutrient density and nutrient balance of the overall diet and lifestyle much
more. I will also offer some practical guidelines for interpreting 25(OH)D in a more nuanced
and sophisticated way.
I’d like to begin by pointing out some not-so-obvious and yet profound problems with the
“naked ape hypothesis of serum 25(OH)D.” For simplicity, I may refer to this hypothesis
simply as the “naked ape hypothesis” through the remainder of this post.
If you’re anxious for the bottom line, you can watch the video summary. If you’d like to head
straight into meat of the post, you can find it below.
The “Naked Ape Hypothesis” Defined
The naked ape hypothesis essentially holds that the requirement for a certain 25(OH)D
concentration circulating in serum was fixed into our genome during some critical prehistoric
window wherein humans exposed themselves to maximal levels of sunshine, that this level
can be estimated by examining humans with maximal sun exposure today, that we should
presume this level to be safe and optimal, and that the burden of evidence lies on anyone
suggesting otherwise.
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Dr. Reinhold Vieth has most commonly and popularly articulated the hypothesis using the
phrase “naked ape” to describe our prehistoric ancestors. Here is a quote, for example, from a
book chapter he co-authored with Dr. Gloria Sidhom in 2010 (1):
During the evolution of our species, requirements for vitamin D were satisfied by the life
of the naked ape in the environment for which its genome was optimized through
natural selection. The horn of Africa was the original, natural environment for the species,
Homo sapiens. Our genome, our physiology, and hence our vitamin D requirement are not
thought to have changed in the past 100,000 years. . . . Since early human evolution occurred
under UV-rich conditions, typical 25(OH)D concentrations were surely higher than 100
nmol/L [40 ng/mL]. Levels like this are now seen in lifeguards, farmers, or people who sun
tan. . . . Since our genome was selected under these conditions through evolution, it should be
evident that our biology was optimized for a vitamin D supply that is far higher than we
currently regard as normal.
Dr. Vieth articulated the same hypothesis in an incredibly popular and influential 1999 article
(2) wherein he provided specific data supporting the high serum 25(OH)D levels referred to in
the quote above. As of this writing, Google Scholar estimates that this paper has been cited a
whopping 1,169 times. When I made similar points in my 2013 Ancestral Health Symposium
presentation in Atlanta this past August, Google Scholar estimated it had been cited 1,126
times, suggesting it may have been cited in 43 additional papers just in the last four months.
In the paper, Vieth articulated the hypothesis in a similar way to that quoted above:
Many arguments favoring higher intakes of calcium and other nutrients have been based on
evidence about the diets of prehistoric humans. Likewise, the circulating 25-hydroxyvitamin
D concentrations of early humans were surely far higher than what is now regarded as normal.
Humans evolved as naked apes in tropical Africa. The full body surface of our ancestors
was exposed to the sun almost daily. . . . Serum 25(OH)D concentrations of people living or
working in sun-rich environments are summarized in Table 1.
And here is the data from Table 1, with the 25(OH)D values converted from nmol/L to ng/mL
to make them comparable to the values Americans get back from clinical labs (my apologies
to my international readership for this bias; click to enlarge):
While Dr. Vieth often refers to prehistoric
humans as “naked apes,” others promote the same hypothesis without necessarily invoking
that specific phrase. In a preliminary criticism of the 2010 vitamin D recommendations from
the Institute of Medicine, Dr. Robert Heaney articulated the hypothesis as follows (3):
. . . I believe that the presumption of adequacy should rest with vitamin D intakes needed to
achieve the serum 25(OH)D values (i.e., 40–60 ng/mL) that prevailed during the evolution of
human physiology. Correspondingly, the burden of proof should fall on those maintaining that
there is no preventable disease or dysfunction at lower levels. The [Institute of Medicine] has
not met that standard.
Dr. Heaney later co-authored a paper with Dr. Michael Holick, “Why the IOM
Recommendations Are Deficient,” wherein they reiterated the naked ape hypothesis, this time
53
ramping the upper end of the range from 60 up to 80 ng/mL, and insisting with a more
elaborate argument that the burden of proof lies on anyone who disagrees (4):
Beyond [the other errors and inconsistencies Heaney and Holick argued exist in the Institute
of Medicine report], though, serious as they are, lies a much deeper flaw in the approach taken
by the panel, exemplified by a quote from one of the panel members to the New York Times at
the time of release of the report [reference]. The statement was simply that the “onus” (ie,
burden of proof) fell on anyone who claimed benefits for intakes higher than the panel’s
current recommendations. This is an approach that is correct for drugs, which are foreign
chemicals and which do carry an appropriately heavy requirement for proof. For drugs, the
position of privilege is given to the placebo. And in the current IOM report, the privilege is
given to a serum 25(OH)D level that is effectively the status quo. We judge that this is exactly
backward for nutrients. The privilege instead must be given to the intake that prevailed during
the evolution of human physiology, the intake to which, presumably, that physiology is finetuned. So far as can be judged from numerous studies documenting the magnitude of the
effect of sun exposure [references] the primitive intake would have been at least 4000 IU/day
and probably two to three times that level, with corresponding serum 25(OH)D levels ranging
from 40 to 80 ng/mL. The fact that primitive levels would have been higher than current IOM
recommendations does not, of course, prove their necessity today. But such intakes should be
given the presumption of correctness, and the burden of proof must be placed on those who
propose that lower intakes (and lower serum levels) are without risk of preventable
dysfunction or disease. The IOM, in its report, has utterly failed to recognize or meet that
standard.
While these arguments seem compelling on the surface, they rely on deeply problematic
assumptions: first, that humans evolved as “naked apes” whose skin would be exposed to
maximal sunshine; second, that we can estimate the 25(OH)D levels they would have
achieved by examining modern populations exposed to maximal amounts of sun, such as
lifeguards in Israel and Missouri; and third, that our requirement for a certain concentration of
25(OH)D circulating in our serum was somehow indelibly fixed into our genome “back when
we evolved” in the era of the naked ape.
To elaborate on these assumptions graphically, the naked ape hypothesis assumes that there
was some critical window between the loss of fur and the gain of clothing or other aspects of
modern, sun-aversive lifestyles, and that this window constitutes the era of the naked ape
(click to enlarge):
During this critical window, moreover, our
requirement for a precise concentration of 25(OH)D circulating in our serum was indelibly
fixed into our genome, never to be altered again (after all, we had already evolved), and this
very concentration can be determined quite easily by testing its value in modern lifeguards
(click to enlarge):
54
Let’s take a closer look at some of these
assumptions.
Were We Ever “Naked Apes”?
First, were we ever truly “naked apes”? In a recent paper (5), a group of scientists published
their estimation of when humans started wearing clothing based on when head lice diverged
from clothing lice. They made the reasonable assumption that clothing must have been in
widespread use prior to this divergence. While I’m skeptical of these types of “molecular
clock” estimates, and while I think certainty about these matters will always remain elusive,
we need to use what evidence we have if we’re going to base a scientific hypothesis on our
speculations about this era of prehistory, especially when those speculations are used as the
basis for clinical recommendations about vitamin supplementation. The authors of the lice
paper provided this useful timeline of evidence for the human use of clothing (click to
enlarge):
I modified the timeline by adding current estimates for the gain of dark skin pigmentation (as
reviewed in reference 6).
Archeological evidence for complex, tailored clothing dates back 40,000 years, whereas such
evidence for hide scrapers dates back 780,000 years. While the hide scrapers were not
necessarily used for clothing, they were likely used to make some type of shelter that would
have expanded the opportunities for shade-seeking behavior even beyond the abundance of
such opportunities that are naturally available in the absence of human ingenuity. Molecular
estimates for the divergence of head and clothing lice suggest clothing was in widespread use
by at least 170,000 years ago. Altogether, these data suggest clothing was in use at least for
most of the history of anatomically modern humans, and perhaps for most of human history.
55
When we consider that scientists estimate both the loss of fur and the gain of dark skin
pigmentation to date back to about 1.2 million years ago, moreover, but estimate that light
skin didn’t even begin evolving in Northern Europeans and East Asians until some 30,000
years ago (7), long after evidence for widespread use of clothing, it becomes clear that we
were never truly “naked apes” at all. Taken at face value, the available evidence instead
suggests that approximately as long ago as we lost the protection from the sun afforded by fur
we gained the protection afforded by dark skin, and that we began clothing ourselves in more
innovative ways long before we began losing the protection of dark skin.
Additionally, a 2002 review by Lawrence Barham pointed out that archaeological evidence
for the use of colored pigments in Africa dates back 270,000 years and that the use of these
pigments has remained from that time through the present a persistent presence in the
archeological, historical, and ethnographic record (8). While we don’t know what humans
were doing with these pigments a quarter million years ago, we know that nowadays they
cover their skin for ritual purposes, offering at least intermittently an additional source of
protection from the sun. This certainly could have been a feature of prehistoric human society.
Beyond this, isn’t it likely that our ancestors used botanical sunscreens? Weston Price, for
example, reported that it was universal traditional practice in the Pacific Islands to use
coconut oil as a sunscreen (9):
In several [Pacific] islands regulatory measures had been adopted requiring the covering of
the body. This regulation had greatly reduced the primitive practice of coating the surface of
the body with coconut oil, which had the effect of absorbing the ultra-violet rays thus
preventing injury from the tropical sun. This coating of oil enabled them to shed the rain
which was frequently torrential though of short duration.
We know that the polyphenols from coconut oil absorb ultraviolet light in the UV-B
spectrum, the set of wavelengths responsible for producing vitamin D (10), so we can
reasonably expect this practice to have decreased the synthesis of vitamin D in the skin. Plants
in general, moreover, produce compounds that protect against UV-B exposure. In fact, the
more plants are exposed to UV-B, the more of these compounds they produce (11). This
would suggest that humans have always had a rich array of UV-B-protective botanical
sunscreens at their fingertips, and that as climate change produced varying levels of UV-B
exposure, botanical sunscreens would become proportionally more or less effective at
affording such protection, perhaps helping humans reach an equilibrium with their
environment by regulating their UV-B exposure as needed.
Thus, our prehistoric ancestors were unlikely to ever have been “naked apes” because they
seem to always have been clothed by at least dark skin, and to have used animal hides,
clothing, colored pigments, and perhaps botanical sunscreens throughout huge portions of
their history, some of these things being used, according to current estimates, long before light
skin ever developed.
Do Modern Lifeguards Provide Proxies for
Prehistoric 25(OH)D?
Naked apes or not, humans certainly lived in prehistoric times. To what extent can modern
lifeguards or any other group provide a proxy for the 25(OH)D levels of prehistoric humans?
56
If there is any such proxy, modern lifeguards certainly don’t fit the bill.
To begin with, lifeguards are paid to work throughout the day. Traditionally living humans,
like other animals, seek shade from the hot sun in a way that lifeguards can’t, even if they
have some sunscreen and an umbrella. One paper noted the universality of shade-seeking
behavior among non-human primates such as gorillas, chimpanzees, and baboons, and
suggested that humans dwelling in the African savannah would similarly have engaged in
these behaviors throughout their evolution (12):
Reduced activity during the hottest period of the day is typical of the African hominoids Pan
troglodytes and Gorilla gorilla and savannah-dwelling baboons of the genus Papio. In these
living primates foraging behavior peaks in the early to mid-morning, and again in the late
afternoon. Similar daily activity patterns would probably have been adopted by early
hominids.
I think their suggestion about what “would probably have been adopted by early hominids” is
awfully speculative, but we know that traditionally living humans in equatorial Africa engage
in similar shade-seeking behavior. For example, scientists from Fritz Muskiet’s lab recently
measured vitamin D status in Hadza hunter-gatherers and Maasai cattle-herders from this
region, and described their behavior at mid-day as follows (13):
Maasai spend most of their days in the sun, wearing clothes that cover mainly their upper
body and upper legs. It is important to note that, whenever possible, they avoid direct
exposure to the sun and prefer a shady place, especially during midday. . . .
Hadzabe spend most of their days in the sun. Similar to the Maasai tribe, they avoid direct
exposure to the fierce sun whenever possible, and most of their activities are planned in the
early morning and late afternoon, while spending the middle part of the day sleeping, eating
or talking in a cooler place under a tree or rock.
By contrast, how did the authors who wrote the paper showing that Israeli lifeguards have
high 25(OH)D describe their behavior? Quite differently (14):
On the job lifeguards are exposed to heat and intense sunlight over almost their entire body
surface, for at least eight hours per day, six months per year.
The authors made no qualification that these lifeguards spent mid-day in cool places under
trees or rocks. Of course the authors didn’t describe their behavior in great detail, and one
could suppose that lifeguards wear sunscreen and use umbrellas to protect themselves from
the sun. The lifeguards nevertheless seem to be getting altogether too much sunshine. The
most damning evidence that these lifeguards are terrible proxies for judging optimal and safe
25(OH)D, in fact, is their 20-fold increase in the incidence of kidney stones (click to enlarge):
57
The 25(OH)D reported for Israeli lifeguards in
this book chapter (53.4 ng/mL) is similar but somewhat lower than Vieth reported for the
same reference in his 1999 paper (148 nmol/L or 59.2 ng/mL). It’s about twice as high as that
found in controls matched for age, sex, and season. The lifeguards had 20-fold the risk of
kidney stones compared to the general population in northern Israel. In southern Israel, the
risk was only elevated 12-fold, but this is because the general population in southern Israel
had twice the risk of kidney stones as the general population of northern Israel, consistent
with observational studies cited in the paper showing that the closer you get to the equator, the
more the risk of kidney stones increases, likely because calcification of the kidneys is the
most sensitive sign of vitamin D toxicity (15).
These lifeguards did not have elevated levels of calcium in their blood, but they did have
elevated levels of calcium in their urine, which the authors attributed to excess 25(OH)D;
insufficient urinary output, which the authors attributed to dehydration; and elevated levels of
uric acid in their blood, which the authors suggested resulted from “solar damage to the skin.”
All three of these could be attributed to too much sun exposure, and the authors suggested that
they “probably all contribute to the susceptibility of lifeguards to form kidney stones.”
These data seem to flatly contradict both the idea that vitamin D is only toxic at doses that
cause hypercalcemia (contradicted also by animal experiments, including 15) and the idea that
you can’t get too much vitamin D from the sun.
It seems unlikely that Dr. Vieth missed this point when he cited the high 25(OH)D of these
lifeguards as safe and optimal when one considers that the title of the chapter is “Increased
Incidence of Nephrolithiasis in Lifeguards in Israel,” and that “nephrolithiasis” is just a fancy
name for kidney stones.
There’s another problem with the lifeguards, however. Like all the other groups cited in
Vieth’s 1999 paper, including Puerto Rican farmers and hospital workers, lifeguards from
Israel and Missouri have substantial European ancestry.
As I pointed out back in December of 2010 in my post, “Vitamin D — Problems With the
Latitude Hypothesis,” a 2009 meta-analysis (16) that pooled together the results of 394
studies examining 25(OH)D levels in over 30,000 people across the globe found that while
25(OH)D declined in Caucasians with increasing distance from the equator, non-Caucasians
had similar 25(OH)D levels regardless of their distance from the equator. As a result,
Caucasians living quite far away from the equator had higher 25(OH)D than non-Caucasians
living in equatorial environments. This hints that vitamin D metabolism could differ between
Caucasians and non-Caucasians, and it strongly suggests that if we used people without
substantial European ancestry as our model for 25(OH)D status in sun-rich environments, we
would generate much lower estimates.
58
Indeed, a paper entitled “Low Vitamin D Status Despite Abundant Sun Exposure” (17) found
that, among students and skateboarders with abundant exposure to the Hawaiian sun, whites
had a mean 25(OH)D of 37 ng/mL while Asians had a mean value of only 25 ng/mL.
Unfortunately the authors did not report sun exposure separately by race, but the average
among all the subjects was over 22 hours per week exposing half the body to the sun without
any sunscreen.
Consistent with the possibility that Asians have lower 25(OH)D than whites even when
exposed to abundant tropical sun exposure, rural Indians who expose their face, chest, back,
legs, arms, and forearms to the Indian sun for nine hours per day have even lower levels. One
study reported a mean of 24 ng/mL in males and 19 ng/mL in females (18).
Of course if we really wanted to understand likely 25(OH)D values in our prehistoric African
ancestors, we would do well to look at Africans rather than Asians. At first glance, the studies
of the Maasai and Hadza from Fritz Muskiet’s lab (13) may seem to contradict the point I am
making. After all, the means for these populations were between 40 and 50 ng/mL.
We can resolve these discrepancies, however, simply by adjusting the values to account for
discrepancies in different methods of measuring 25(OH)D. I’ll explore this problem in more
detail in a later post in the series, but for now I’ll just present the adjusted values (click to
enlarge):
I adjusted the values to correspond to those of
the DiaSorin radioimmunoassay using the discrepancies found in references 17 and 19. While
this does not necessarily make the values more accurate, it makes them easier to compare to
one another, and since the DiaSorin assay is the one most commonly used in the literature, it
makes it easier to situate these values in the context of the general body of scientific literature.
What we see is that the variation in values among the different groups is significantly reduced
after adjustment, and with the exception of rural Indians, the values lie between 30 and 40
ng/mL. This is considerably lower than the values presented in Dr. Vieth’s 1999 paper, which
ranged from 42 to 65 ng/mL.
I suspect that the rural Indians have lower values because they have low intakes of
bioavailable calcium. I will explore the effect of calcium intake on 25(OH)D status in a future
post in this series.
Having found some commonalities among non-white populations inhabiting tropical regions,
have we finally arrived at our best proxies for prehistoric values?
No, for a rather simple reason: there are no true proxies.
Scientists estimate that the climate was much colder through most of our existence (20). We
are currently living in an interglacial period of an ice age, and scientists estimate that for most
of our history we lived in glacial periods. While reflective snow and ice cover could increase
UV-B exposure during glacial periods in some parts of the world, and thus increase vitamin D
synthesis in those regions, this would not have been the case in equatorial Africa. It would
59
have been colder, encouraging a more extensive use of clothing, but not covered in ice.
Aerosolized dust and salt were much higher in the colder periods, moreover, which would
presumably have decreased UV-B exposure even further.
While no one has yet estimated prehistoric UV-B exposure in fine enough detail for us to
reliably estimate the relative opportunities humans had for vitamin D synthesis in the
prehistoric past, Barry Lomax, a paleoclimatologist from the University of Nottingham, told
me in August that he has received funding to produce such estimates for the past half million
years and that we should see such publications emerge in the next year or so. He agreed with
me, pending hard data he expects to generate over the course of his research, that it is likely
that prehistoric exposure was, on the whole, lower than it is now, with occasional localized
pockets of higher exposure.
Overall, then, modern lifeguards with evidence of excessive sun exposure and an
incomprehensibly elevated risk of kidney stones are not good proxies for estimating
prehistoric serum 25(OH)D in equatorial Africa. Traditionally living non-whites in tropical
regions have lower 25(OH)D, in the range of 30-40 ng/mL when adjusted to correspond to the
most common assay used in the literature. These populations, however, are not good proxies
for prehistoric 25(OH)D because the climate was different in the prehistoric past and vitamin
D synthesis probably tended to be lower back then.
Was the Serum 25(OH)D Fixed Into Our
Genome Long Ago?
Should we conclude, then, that a serum 25(OH)D requirement somewhat lower than 30-40
ng/mL was indelibly fixed into our genome long, long ago, when we existed as moderately
clothed, painted, and sunscreened sophisticated ape-like creatures seeking shade at mid-day
under trees, rocks, and shelters constructed out of leather in equatorial Africa?
No, because the evidence suggests that the requirement for 25(OH)D was never indelibly
fixed into our genome.
As I pointed out in a previous post entitled “The Scientific Approach of Weston Price, Part 2:
Problems With Comparing Different ‘Racial Stocks’ With Inuit Adaptations in Vitamin D
Metabolism as an Example,” evidence suggests that the Inuit are adapted to a lower 25(OH)D
status than whites with European ancestry (21). On their traditional diet, at least as roughly
estimated by a high intake of seal oil, their 25(OH)D is only about 20 ng/mL, yet they have a
higher than normal level of the more active form, calcitriol, and a lower than normal amount
of parathyroid hormone, a hormone that increases during a deficiency of vitamin D or
calcium. The evidence suggests they have heritable adaptations that allow them to boost the
total biological activity of vitamin D despite a low supply of 25(OH)D without any sign of a
true deficiency.
African Americans may have a similar adaptation (22). We know that at least part of the
reason African Americans have lower 25(OH)D than whites is because of genetic differences
in vitamin D metabolism (23), and when we consider that despite lower 25(OH)D than whites
they have higher levels of the more active calcitriol and greater bone mass, it seems they are
likely adapted to a lower level of 25(OH)D.
60
I will explore the effects of genetics on 25(OH)D status in more detail in future posts. The
purpose of briefly presenting this evidence here is simply to point out that there seem to be
variations in the normal or optimal 25(OH)D status between different populations. This
suggests that the 25(OH)D requirement was not indelibly fixed into our genome at some time
in the distant prehistoric past before humans ever emerged out of Africa. It suggests that, on
the contrary, the requirement has continued to evolve over time.
The Naked Ape Hypothesis Bites the Dust
The evidence suggests we were never truly naked apes, that modern lifeguards and other
populations dominated by European ancestry are not good proxies for the 25(OH)D levels of
our prehistoric ancestors inhabiting equatorial Africa, and that the 25(OH)D requirement was
never indelibly fixed into our genome but has continued to evolve over time.
We can summarize the problems with the naked ape hypothesis graphically as follows (click
to enlarge):
What the evidence from modern lifeguards tells us is that it seems to be possible to get too
much vitamin D even from the sun, and their 20-fold elevated risk of kidney stones could
perhaps be a harbinger of worse things to come, like an increased risk of heart disease from
arterial calcification.
As always, of course, context is critical. Perhaps the levels of 25(OH)D found in Israeli
lifeguards are harmless or even beneficial in the context of a nutrient-dense and balanced diet
rich in all of vitamin D’s synergistic partners. But where does the burden of evidence lie? Drs.
Heaney and Holick maintain that “the burden of proof must be placed on those who propose
that lower intakes (and lower serum levels) are without risk of preventable dysfunction or
disease.” Why shouldn’t the burden of “proof” lie on those who advocate high levels of
25(OH)D as safe and optimal when they are considerably higher than those found in
numerous populations with abundant sun exposure and when they are known to be associated
with large increases in the risk of soft tissue calcification?
Do we really need to prove a negative — that no problems exist at lower levels — when we
have positive evidence of harm at higher levels?
Towards a Better Approach
61
If we are to construct a more balanced, objective, and useful approach to assessing vitamin D
status and determining strategies to remedy insufficiency, we first need to understand vitamin
D metabolism in a more nuanced and sophisticated way. I will eventually conclude this series
with a practical how-to guide, but we have a bit of ground to cover. The next couple of posts
will explain why 25(OH)D is not a specific marker of vitamin D status, despite being
consistently used in this way.
I hope you stay tuned and share your thoughts in the comments along the way!
References
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Pathophysiology and Clinical Management, edited by Robert A. Adler, 2010. [Google Books]
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12. Wheeler PE. The thermoregulatory advantages of heat storage and shade-seeking behavior
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et al., eds. Phosphate and Minerals in Health and Disease. Plenum Press, New York, 1980.
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toxicity and metabolic effects of cholecalciferol and 25-hydroxycholecalciferol in chicks. J
Nutr. 1977;107(6):1027-34.
16. Hagenau T, Vest R, Gissel TN, Poulsen CS, Erlandsen M, Mosekilde L, Vestergaard P.
Global vitamin D levels in relation to age, gender skin pigmentation and latitude: an ecologic
meta-regression analysis. Osteoporosis Int. 2009;20(1):133-40. [PubMed]
17. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, Hollish BW,
Drezner MK. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab.
2007;92(6):2130-5. [PubMed]
18. Harinarayan CV, Ramalakshmi T, Prasad UV, Sudhakar D. Vitamin D status in Andhra
Pradesh: a population based study. Indian J Med Res. 2008;127(3):211-8. [PubMed]
19. de Koning L, Al-Turkmani MR, Berg AH, Shkreta A, Law T, Kellogg MD. Variation in
clinical vitamin D status by DiaSorin Liaison and LC-MS/MS in the presence of elevated 25OH vitamin D2. Clin Chim Acta. 2013;415:54-8. [PubMed]
20. Petit JR, Jouzel J, Raynaud D, Barkov NI, Barnola J-M, Basile I, Bender M, Chappellaz J,
Davis M, Delaygue G, Delmotte M, Kotlyakov VM, Legrand M, Lipenkov VY, Lorius C,
Pepin L, Ritz C, Saltzman E, Stievenard M. Climate and atmospheric history of the past
420,000 years from the Vostok ice core, Antarctica. Nature. 1999;399:429-36. [Nature]
21. Rejnmark L, Jorgensen ME, Pedersen MB, Hansen JC, Heickendorff L, Lauridsen AL,
Mulvad G, Siggaard C, Skjoldborg H, Sorensen TB, Pedersen EB, Mosekilde L. Vitamin D
insufficiency in Greenlanders on a westernized fare: ethnic differences in calcitropic
hormones between Greenlanders and Danes. Calcif Tissue Int. 2004;74(3):255-63. [PubMed]
22. Weaver CM, McCabe LD, McCabe GP, Braun M, Martin BR, Dimeglio LA, Peacock M.
Vitamin D status and calcium metabolism in adolescent black and white girls on a range of
controlled calcium intakes. J Clin Endocrinol Metab. 2008;93(10):3907-14. [PubMed]
23. Signorello LB, Shi J, Cai Q, Zheng W, Williams SM, Long J, Cohen SS, Li G, Hollis BW,
Smith JR, Blot WJ. Common variation in vitamin D pathway genes predicts circulating 25hydroxyvitamin D Levels among African Americans. PLoS One. 2011;6(12):e28623.
[PubMed]
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An Ancestral Perspective on Vitamin D Status, Part 2: Why Low 25(OH)D Could Indicate a Deficiency of Calcium
Instead of Vitamin D →
http://www.westonaprice.org/blogs/cmasterjohn/2013/12/19/an-ancestral-perspective-on-vitamin-d-status-part-2-whylow-25ohd-could-indicate-a-deficiency-of-calcium-instead-of-vitamin-d/
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25(OH)D
An Ancestral Perspective on Vitamin D
Status, Part 2: Why Low 25(OH)D Could
Indicate a Deficiency of Calcium Instead of
Vitamin D
Posted on December 19, 2013 by Chris Masterjohn
In the first post in this series, I critiqued the “naked ape hypothesis of optimal serum
25(OH)D,” which I believe influences many researchers to interpret uncertainties in the
scientific literature in a way that is biased towards recommendations for high intakes of
vitamin D that could be harmful to some people, especially without appropriate attention to
the nutrient density and balance of the diet, and to the overall context of a healthy diet and
lifestyle.
Now I would like to begin critiquing the use of low 25(OH)D on its own to determine vitamin
D status. As the series progresses, I will discuss numerous explanations for low 25(OH)D
besides vitamin D deficiency. In this post, I will discuss why a deficient intake of calcium can
probably cause low 25(OH)D.
I’ve explained the gist of this post and its bottom line over at the Daily Lipid Video Blog. The
details follow.
25(OH)D Is Not a Specific Marker of
Vitamin D Status
Although commonly used as one, 25(OH)D is not a specific marker of vitamin D status.
25(OH)D is a compound that we make from vitamin D in our liver. Vitamin D will indeed
dose-dependently increase 25(OH)D, but many other factors affect the rate at which 25(OH)D
is synthesized, used, or degraded. These include variations in the genetics of vitamin D
metabolism, intakes of other nutrients, crisis states such as inflammation, and disease states
such as cancer.
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Some of the factors that cause low 25(OH)D are bad and some of them are good. While there
is likely some critical threshold below which low 25(OH)D almost certainly indicates a major
problem, this is not necessarily the case with moderately low 25(OH)D. In order to determine
whether moderately low 25(OH)D is a good thing or a bad thing, and in order to understand
what, if anything, to do about it, we need to understand why it’s low.
Let’s begin by considering one of the “bad” things that can cause low 25(OH)D besides a
deficiency of vitamin D itself: a deficiency of calcium.
Vitamin D Regulates Serum Calcium
In order to understand why a deficiency of calcium can cause low 25(OH)D, we need only
consider the most well established and best understood role of vitamin D: to regulate the level
of calcium in our blood.
If our blood level of calcium drops for any reason — for example, if we aren’t consuming or
absorbing enough calcium from our food — our endocrine system quickly launches a
systematic program to bring that level back to normal (1). Our parathyroid glands ramp up
their production of parathyroid hormone, which sends a signal to our kidneys to ramp up their
conversion of 25(OH)D to calcitriol, the most active form of vitamin D. Calcitriol then
increases serum calcium in two ways: preventing loss of calcium in the urine and feces, and
extracting calcium from bone.
Or one could splice it three ways: we absorb more calcium from our food, and we lose more
from our bones into our blood, but we lose less from our blood into our urine.
Even a slight increase in calcitriol can lead to a big drop in 25(OH)D. This may seem counterintuitive at first, but it makes more sense if we realize that when we look at the concentration
of a compound in the blood, we are taking a static snapshot of a dynamic process. Molecules
are always coming and going. As a result, maintaining a constant blood level of a given
compound requires a continuous supply of that compound itself. Since calcitriol is made from
25(OH)D, maintaining a given concentration of calcitriol also requires a continuous supply of
25(OH)D.
Calcitriol disappears far more rapidly than 25(OH)D (2). The amount of 25(OH)D that would
sustain a certain concentration of itself in the blood for a day would only maintain the same
concentration of calcitriol for an hour. So if the body decides to maintain a slightly higher
concentration of calcitriol, it would have to levy a much heavier tax on the supply of
25(OH)D.
We should expect, then, that a deficient intake of calcium will lead to increased production of
calcitriol, and thereby to depletion of 25(OH)D.
Would an excess of calcium, conversely, cause higher than normal 25(OH)D? Maybe, but not
necessarily. While excess calcium would be expected to suppress the production of
parathyroid hormone and calcitriol, thereby sparing 25(OH)D, it also elicits additional
responses to suppress serum calcium: in response to high levels of calcium, our thyroid glands
produce calcitonin, which not only blocks the loss of calcium from bone (1), but appears to
stimulate the production of an enzyme that degrades both 25(OH)D and calcitriol to other
products generally thought to be inactive (3). Excess calcium could, therefore, have
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conflicting effects on 25(OH)D, preventing its conversion to calcitriol but increasing its
degradation through an alternative pathway, perhaps leading to no net change in 25(OH)D at
all.
Overall, then, we would expect that a deficiency in calcium would cause low 25(OH)D, and
that correcting the deficiency would normalize the 25(OH)D, but that beyond a certain
threshold, increasing calcium intake might not increase 25(OH)D any further.
Let’s take a look at some of the evidence suggesting this is indeed the case.
Calcium Deficiency Depletes 25(OH)D in
Rats
In rats, experimental calcium deficiency in the presence of adequate vitamin D caused a more
than four-fold elevation of calcitriol and a more than 60 percent drop in 25(OH)D from just
under 40 ng/mL to about 15 ng/mL (4) (click to enlarge):
Consistent with the physiology I described
above, calcium deficiency also caused a large increase in parathyroid hormone. These
findings indicate that, as expected, dietary calcium deficiency causes our parathyroid glands
to make more parathyroid hormone, thus increasing the conversion of 25(OH)D to the more
active calcitriol. As a result, 25(OH)D tanks.
A similar study came to similar conclusions, but also looked at a number of additional
enzymes involved in vitamin D metabolism (5). This study found that calcium deficiency
stimulates the production of calcitriol regardless of vitamin D intake, while vitamin D
deficiency has no effect on calcitriol levels. When both calcium and vitamin D were adequate,
the rats produced more of an enzyme that degrades 25(OH)D. Despite the increase in this
enzyme, 25(OH)D was nevertheless highest in that group. This suggests that at least up
through the recommended intakes, the predominant effect of calcium is to spare 25(OH)D.
Perhaps with excessive calcium intake, the sparing and degrading effects would balance out
differently. If that is the case, it could explain why some human studies described below have
had trouble demonstrating an effect of calcium intake on 25(OH)D.
Ambiguous But Supportive Evidence in
Humans
66
To my knowledge, no studies have definitively demonstrated an effect of calcium intake on
25(OH)D in humans. This is most likely because it has hardly been studied rather than
because the effect does not exist. Indeed, the basic physiology works the same in humans and
rats, and the likelihood that calcium deficiency doesn’t deplete 25(OH)D in humans strikes
me as extremely small.
Several randomized controlled trials have failed to show any effect of calcium
supplementation on 25(OH)D (6, 7, 8).
Should we have expected them to? Not really. There are some important obstacles to showing
this effect in humans, particularly in Americans, who tend to have high calcium intakes,
especially the older Americans targeted for calcium supplementation studies who are usually
already keeping an eye on their calcium intake.
First, none of these studies were dealing with true calcium deficiency. Before
supplementation, mean calcium intakes were roughly 700 mg/day (8), 800 mg/day (7), and
1000 mg/day (6). It may be that calcium intakes lower than these cause drops in 25(OH)D,
but that calcium intakes higher than these have little effect on 25(OH)D.
Second, as I am in the process of explaining through this series, many different factors affect
25(OH)D. 25(OH)D levels in these studies were roughly 26 ng/mL (8), 30 ng/mL (7), or
unreported (6). Since the individuals in these studies by definition fall both above and below
the mean, these studies likely had some individuals who had pretty low 25(OH)D and others
who did not. Similarly, while the mean calcium intakes were reasonably adequate there may
have been individuals with calcium intakes much lower than the mean. Of those with low
25(OH)D, then, there may have been some individuals whose low 25(OH)D was a result of
calcium deficiency, but these individuals could have been few and far between.
The ideal way to test this principle in humans would be to specifically target individuals with
low calcium intakes and low 25(OH)D and randomize them to supplementation with calcium
or a placebo, but I am not aware of such studies.
Reference 8 nevertheless seems to provide some slightly supportive evidence, statistically
underpowered thought it may be (click to enlarge):
As can be seen when comparing the data in the
red square to that in the green square, the placebo group had zero people with “sufficient”
25(OH)D, while the calcium supplementation group had five fewer people in the “deficient”
and “insufficient” ranges, with those five missing folks being found — score! — in the
“sufficient” range.
The evidence is not all that convincing because the difference is not statistically significant
and calcium supplementation didn’t seem to help the people who were also getting vitamin D
67
at all, but it is possible that if this study had been much larger or had specifically targeted
people with low calcium intake and low 25(OH)D, it would have demonstrated the effect
more convincingly.
There is some observational evidence suggesting that one of the reasons rural Indians with
abundant sun exposure have such low 25(OH)D is because of low intakes of bioavailable
calcium (9). These particular Indians consume diets dominated by cereal grains, with
relatively few animal products and vegetables providing only five percent of calories. Cereal
grains provide very little calcium but large amounts of phytate, which inhibits the absorption
of calcium. As calcium intake increases among these subjects and phytate intake declines,
25(OH)D status improves:
Perhaps one of the reasons that the Maasai and
Hadza have considerably higher 25(OH)D status than rural Indians (as discussed in the
previous post in this series) despite all three groups being exposed to abundant sunshine is
because calcium deficiency is prevalent among neither the Maasai nor the Hadza. The Maasai
herd cattle and consume large amounts of dairy products. In addition to animal products, the
Hadza consume some 14 percent of their diet as baobab, which some investigators have said
is one of the Hadza’s five food groups (10), and which is very rich in calcium (11).
Low 25(OH)D? Check Your Calcium
Intake!
Although randomized controlled trials have thus far not provided the definitive evidence that
low calcium intake is a cause of low 25(OH)D in humans, this is far more likely to be because
no trials have adequately addressed the question than because the interaction does not exist.
Experimental evidence in rats has demonstrated the interaction beyond doubt, and the
physiology — which very clearly implies the interaction — appears to be, for all relevant
intents and purposes, identical between humans and rats. It is thus extremely unlikely in my
opinion that low calcium intake is not a cause of low 25(OH)D in humans.
The practical implications are two-fold. First, we are in desperate need of clinical trials to
address this question adequately. In the mean time, if someone has low 25(OH)D, they should
assess their calcium intake.
Obtaining a bird’s-eye view of one’s calcium intake is relatively easy to do without the help
of a professional, any fancy software, or even an internet database. Most Americans and
others in modern, industrial society have easy access to just three sets of foods that are rich in
highly absorbable and utilizable calcium: dairy products, edible bones, and cruciferous
vegetables.
Most people are well aware that dairy products are rich in calcium.
68
Bone broth is delicious and provides important bone-building trace minerals and amino acids,
but it contains relatively little calcium relative to our overall requirement. The soft edible
bones in canned fish, however, or, for adventurous eaters, the soft edible knobs on the ends of
small chicken bones, are all very rich in calcium.
Calcium is widely distributed in plant foods, but the amounts are often small and in some
calcium-rich leafy greens like spinach, the availability is terrible. Calcium absorption from
kale, however, is better than that from conventional, commercial milk (12). Numerous
cruciferous vegetables provide anywhere from half as much to twice as much absorbable
calcium, cup for cup, as commercial milk (13).
As a rule of thumb, then, I would say that if someone has low 25(OH)D and she is eating two
to three servings of dairy products or soft, edible bones, or two to three cups of cruciferous
vegetables per day (which have their downsides), then calcium deficiency is unlikely to be the
explanation. If one is not eating these foods, however, it could very easily be the explanation.
In such a case, the person has little to lose and much to gain by including more calcium-rich
foods.
Because the calcium content and availability is quite variable even between different
cruciferous vegetables, and because many other plant foods contain smaller amounts of
calcium that could contribute to the overall intake or, on the other hand, anti-nutrients that
could detract from the overall intake, greater attention should be paid to this possibility if
someone is attempting to meet their calcium requirement with plant foods alone. If such a
person has low 25(OH)D and thinks she is getting enough calcium, she would do well to
record her dietary habits, research the relative amounts of calcium and anti-nutrients in the
foods she is eating, and consider consulting a registered dietician or another type of
professional nutritional consultant.
If poor calcium intake is depleting vitamin D stores and thereby causing low 25(OH)D,
throwing extra vitamin D at the problem is not the optimal solution. It will not be the most
effective way of normalizing the hormonal milieu or preventing bone loss. Only calcium can
correct a calcium deficiency. Throwing a calcium supplement at the problem is not the ideal
solution either. Both vitamin D and calcium supplements leave the diet lacking in a broad
spectrum of other important nutrients found in dairy products, bones, and leafy greens.
In future posts in this series, I will discuss other potential causes of low 25(OH)D besides
poor vitamin D exposure. By the end of the series, I’ll provide a systematic approach for
interpreting the likely cause of low 25(OH)D. In the mean time, I’d love to hear your thoughts
in the comments!
References
1. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D
and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for
Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. p. 40.
[NCBI Bookshelf]
2. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008;88(2):582S-6S.
[Pubmed]
69
3. Gao XH, Dwivedi PP, Omdahl JL, Morris HA, May BK. Calcitonin stimulates expression
of the rat 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter in HEK-293 cells
expressing calcitonin receptor: identification of signaling pathways. J Mol Endocrinol.
2004;32(1):87-98. [PubMed]
4. D’Amour P, Rousseau L, Hornyak S, Yang Z, Cantor T. Influence of Secondary
Hyperparathyroidism Induced by Low Dietary Calcium, Vitamin D Deficiency, and Renal
Failure on Circulating Rat PTH Molecular Forms. Int J Endocrinol. 2011;2011:469783.
[PubMed]
5. Anderson PH, Lee AM, Anderson SM, Sawyer RK, O’Loughlin PD, Morris HA. The effect
of dietary calcium on 1,25(OH)2D3 synthesis and sparing of serum 25(OH)D3 levels. J
Steroid Biochem Mol Biol. 2010;121(1-2):288-92. [PubMed]
6. Elders PJ, Lips P, Netelenbos JC, van Ginkel FC, Khoe E, van der Vijgh WJ, van der Stelt
PF. Long-term effect of calcium supplementation on bone loss in perimenopausal women. J
Bone Miner Res. 1994;9(7):963-70. [PubMed]
7. McKane WR, Khosla S, Egan KS, Robins SP, Burritt MF, Riggs BL. Role of calcium
intake in modulating age-related increases in parathyroid function and bone resorption. J Clin
Endocrinol. Metab. 1996;81(5):1699-703. [PubMed]
8. McCullough ML, Bostick RM, Daniel CR, Flanders WD, Shaukat A, Davison J,
Rangaswamy U, Hollis BW. Vitamin D status and impact of vitamin D3 and/or calcium
supplementation in a randomized pilot study in the Southeastern United States. J Am Coll
Nutr. 2009;28(6):678-86. [PubMed]
9. Harinarayan CV, Ramalakshmi, Prasad UV, Sudhakar D, Srinivasarao PV, Sarma KV,
Kumar EG. High prevalence of low dietary calcium, high phytate consumption, and vitamin
D deficiency in healthy south Indians. Am J Clin Nutr. 2007;85(4):1062-7. [PubMed]
10. Berbesque JC, Marlowe FW, Crittenden AN. Sex differences in Hadza eating frequency
by food type. Am J Hum Biol. 2011;23(3):339-45. [PubMed]
11. Prentice A, Laskey MA, Shaw J, Hudson GJ, Day KC, Jarjou LM, Dibba B, Paul AA. The
calcium and phosphorus intakes of rural Gambian women during pregnancy and lactation. Br
J Nutr. 1993;69(3):885-96. [PubMed]
12. Heaney RP, Weaver CM. Calcium absorption from kale. Am J Clin Nutr. 1990;51(4):6567. [PubMed]
13. Weaver CM, Heaney RP. 2006. Food sources, supplements, and bioavailability. In:
WeaverCM, HeaneyRP, editors. Calcium & human health. Totowa , N.J. : Humana Press. 137
p. [Springer]
This entry was posted in WAPF Blog and tagged Vitamins A D and K. Bookmark the permalink.
← An Ancestral Perspective on Vitamin D Status, Part 1: Problems With the “Naked Ape” Hypothesis of Optimal Serum
25(OH)D
70
Here:
http://www.westonaprice.org/blogs/cmasterjohn/2013/06/08/the-scientific-approach-of-weston-price-part-7-placingprices-work-in-context/
The Scientific Approach of Weston Price,
Part 7: Placing Price’s Work in Context
Posted on June 8, 2013 by Chris Masterjohn
This is the seventh and final installment in a series of posts in which I am laying out the most
salient points from my 2012 Real Food Summit talk, “Weston Price on Primitive Wisdom.”
See these links for part 1, part 2, part 3, part 4, part 5, and part 6.
How are we to place Price’s work in its appropriate context? How are we to respect and
embrace the wisdom of our ancestors, while using modern science and our personal
experience to refine and enrich the pool of accumulated wisdom? I will explore these
questions in this final post.
There are many legitimate uses of evidence, some of which are as simple as collecting
observations about the world for the sake of curiosity and appreciation. When it comes to
evidence that should inform our decisions about how to eat and live to be healthy, I broadly
categorize this evidence into three levels that should inform our decisions in a concerted
manner, although each level should do so in its own particular way:



Evidence supporting a framework for interpreting how to act in the face of uncertainty
Experimental evidence demonstrating general cause-and-effect relationships
Personal experience and self-experimentation
A Framework for Interpreting Uncertainty
Scientific uncertainty is all around us, and likely will be forever. The randomized experiment
provides the closest approximation to a definitive demonstration of a cause-and-effect
principle that we can obtain, but one experiment is never definitive and, no matter how many
similar experiments scientists perform, questions are always left unanswered. This leaves us
with scientific uncertainty, and the need for some kind of paradigm to help us decide what to
do in the face of it.
This framework should form our “common sense,” a set of things we tentatively take for
granted, pending more definitive evidence.
We all constantly act in the face of uncertainty. When we do so without an evidence-based
framework, we still have a framework. What we have, however, is a “common sense” that
takes the status quo for granted. This approach may seem sensible to those who have no
71
reason to question it, but it leaves us captive to the status quo, one where degenerative
diseases rein supreme.
In part 6, I shared the following quote from Nutrition and Physical Degeneration:
There are two programs now available for meeting the dental caries problem. One is to know
first in detail all the physical and chemical factors involved and then proceed. The other is to
know how to prevent the disease as the primitives have shown and then proceed. The former
is largely the practice of the moderns. The latter is the program suggested by these
investigations.
The first approach, the one Price opposed and the one based on knowledge without wisdom,
superficially appeared to be based on scientific certainty. In reality, however, it took the status
quo as its framework for interpreting uncertainty. Refined flour and sugar were the norm, and
society’s managers added nutrients back to the diet one by one as science demonstrated their
importance. Price argued for a “common sense” that took for granted diets associated with
health rather than those associated with disease. In other words, a “common sense” rooted in
evidence rather than in the status quo.
I argued in part 1 that Price’s basic study design was to examine “nature’s closest thing to a
randomized controlled trial (RCT)” repeated in series for many peoples with different
genetics and living in wildly different parts of the world. Price provided strong evidence that
the replacement of traditional diets with the “displacing foods of modern commerce” caused
the physical degeneration that ensued, especially the massive increase in cavities and dental
deformities.
Much of what we can glean from Price’s work, however, is more observational in nature.
Once we begin breaking down the dietary patterns into their individual components or begin
looking at dietary changes specific to one of the “racial stocks” Price studied rather than those
that were replicable across most or all of the groups, we leave “Nature’s RCT” and enter the
realm of simple observations where inferences of cause and effect are much less clear.
It would be foolish, however, to dismiss all these more specific observations as having no
value. Inferring cause and effect is not the only reason we observe things. Careful
observations are almost always good for at least one thing: establishing the way things are.
Price’s observations of groups that were nearly or completely free of certain diseases
establishes two critical facts:
1.
2.
This level of freedom from disease is possible, which is why Price called these groups standards of
excellence.
All of the characteristics of the diets and lifestyles of these groups are at least consistent with freedom from
disease.
These observations are remarkable because they show that such characteristics are consistent
with freedom of disease on a population level, which means that they protected even the
members of those populations who were most vulnerable to disease.
An evidence-based “common sense” should take diets and lifestyles consistent with
population-wide freedom from disease for granted. This should not be the end of the story.
The other levels of evidence discussed below should also be included, but this should be the
common sense background.
72
The alternative would be to take for granted diets and lifestyles inconsistent with populationwide freedom from disease, such as the refined and industrialized diets that prevail in our own
society, simply because they represent the status quo.
In order to build this framework, we should expand our data to include that of other
investigators taking Price’s approach. This could include, for example, studies of the freedom
from heart disease enjoyed by the Maasai and Kitavans. Many of these findings lack a clear
demonstration that these groups suffer from heart disease when modernized, but at least they
provide us with examples of diets and lifestyles consistent with freedom from heart disease.
Further investigations of the genetics and mortality structures of these groups would be
valuable to more clearly elucidate the causes of their freedom from heart disease.
Ethnographic studies that shed further light on the details of diets and lifestyles traditional to
such groups are also of great value.
While archeological investigations are of some value, their utility is much more limited than
investigations of living people: sample size is generally poor; samples may be incomplete,
such as isolated teeth or bones rather than complete skeletons with all parts intact; only a
handful of health metrics are recorded in a skeleton; characterizing pre-historic diets is
extremely difficult, and doing so with accuracy comparable to that achieved with living
populations is probably impossible.
Finally, some have argued that there is an “osteological paradox” where improvements in
health with increased longevity can allow diseases to more prominently record in the skeleton,
giving a false appearance of decreased health. Nevertheless, as long as these limitations are
acknowledged, archeological evidence can make a supplemental contribution to the
framework.
Overall, I believe our “common sense” about diet and lifestyle should be to presume that the
range of characteristics consistent with population-wide freedom from disease range from
harmless to protective and vital until and unless clearly demonstrated otherwise, and to view
deviations from this range of characteristics as suspect until and unless clearly exonerated
from any role in disease.
Experimental Evidence Demonstrating
Cause-and-Effect Relationships
As I argued in part 1, Price provided strong evidence that the transition from diets based on
traditional, nutrient-dense foods to diets based on the “displacing foods of modern commerce”
caused the physical degeneration that ensued.
While this finding is incredibly powerful in itself, it leaves much to be answered. Were some
traditional diets superior to others? Were certain factors protective rather than others? Were
some neutral, or some harmful? How do they work together in the proper balance? What is
the full range of diseases attributable to diet?
For diseases that are less clearly attributable entirely to the nutritional transition, such as heart
disease, what are the roles of sleep, stress, social structure, infection and other variables? How
73
do all these factors interact with features unique to our own society? Do our modern lives
place special demands on us?
We can broaden, deepen, and strengthen our understanding of Price’s work with experimental
science, through which we can begin to provide answers to some of these questions. Valuable
experimental evidence ranges from experimental animal and cell models that deepen our
understanding of physiology to randomized, controlled, clinical trials in humans that provide
clear evidence for effects on human health.
Personal Experience and SelfExperimentation
Each individual is unique and dynamic. As a result, one person’s nutritional needs may differ
from another’s, and her needs at one time in her life may differ from her needs at another time
in her life. Even after all the foregoing evidence is taken into account, then, a person must
take into account her own experience.
Individual-level evidence can be broken down into two types: anecdotal and experimental.
This division is similar to the division between evidence for consistency with good health and
causation we saw between the first two levels.
If my body appears to respond well to a particular way of eating, for example, this doesn’t
prove that this way of eating caused the positive response, but it shows that this way of eating
is consistent with the positive response.
Alternatively, one can perform a randomized “n=1″ experiment on oneself, which I’ve
provided instructions for here. Such a randomized experiment provides clear evidence of a
cause-and-effect relationship for the individual performing it. This approach, in its medically
supervised manifestation, has its own body of scientific literature and is recognized by
prestigious statisticians including those at the Centre for Evidence-Based Medicine at Oxford
(see here).
Performing randomized self-experiments, of course, is resource-intensive, and whether it is a
wise approach to pursue depends on how critical it is that someone find the most effective
approach for himself.
Fitting It All Together
As an example of how all this might fit together, traditional diets of populations free of heart
disease were rich in fat-soluble vitamins, while not necessarily high in fat, contained animal
fats or tropical oils rather than vegetable oils.
As I’ve reviewed in Good Fats, Bad Fats, clinical trial evidence is inconclusive but more
supportive of traditional oils than of modern vegetable oils.
Our knowledge of biochemistry and physiology, taken from many levels of experimental
science, suggests that the micronutrient content of the oil and the overall diet is critical. As an
example, vitamin K2 is found in animal fats and activates proteins that protect against soft
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tissue calcification. An individual might use this knowledge to verify that his diet is consistent
with (or causing, if he chooses to randomize) freedom from coronary calcification, or, in due
time, adequate activation of vitamin K-dependent proteins.
The work of Price and others following his approach thus lays our foundation of common
sense, while experimental science broadens and deepens our understanding of how to achieve
health, and our personal experience and self-experimentation fine-tunes our approach to an
individual level best suited to each person. In this way, we seek knowledge not to replace the
wisdom accumulated by our ancestors, but to build upon, expand, refine, and enrich this pool
of accumulated wisdom.
Read more about the author, Chris Masterjohn, PhD, here.
This entry was posted in WAPF Blog and tagged Nutrition and Physical Degeneration, Scientific Method, Statistics.
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2 Responses to The Scientific Approach of Weston Price, Part 7: Placing Price’s
Work in Context
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Price's Work in Context
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