Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition
of this Disease as a Cause for Human Mortality
Matthias Rath M.D. and Linus Pauling Ph.D.
Journal of Orthomolecular Medicine 6: 139-143
We have recently presented ascorbate deficiency as the primary cause
of human CVD. We proposed that the most frequent pathomechanism leading
to the development of atherosclerotic plaques is the deposition of Lp(a)
and fibrinogen/fibrin in the ascorbate-deficient vascular wall (1, 2).
In the course of this work we discovered that virtually every pathomechanism
for human CVD known today can be induced by ascorbate deficiency. Beside
the deposition of Lp(a) this includes such seemingly unrelated processes
as foam cell formation and decreased reverse-cholesterol transfer, and
also peripheral angiopathies in diabetic or homocystinuric patients.
We did not accept this observation as a coincidence.
Consequently we proposed that ascorbate deficiency is the precondition
as well as a common denominator of human CVD. This far-reaching conclusion
deserves an explanation; it is presented in this paper. We suggest that
the direct connection of ascorbate deficiency with the development of
CVD is the result of extraordinary pressure during the evolution of man.
After the loss of the endogenous ascorbate production in our ancestors,
fatal blood-loss through the scorbutic vascular wall became a life-threatening
condition. The resulting evolutionary pressure favored genetic and metabolic
mechanisms predisposing to CVD.
The Loss of Endogenous Ascorbate Production in the Ancestor of Man
With few exceptions all animals synthesize their own ascorbate by conversion
from glucose. In this way they manufacture a daily amount of ascorbate
that varies between about 1 gram and 20 grams, when compared to the human
body weight. About 40 million years ago the ancestor of man lost the
ability for endogenous ascorbate production. This was the result of a
mutation of the gene encoding for the enzyme L-gulono-g -lactone oxidase
(GLO), a key enzyme in the conversion from glucose to ascorbate. As a
result of this mutation all descendants became dependent on dietary ascorbate
The precondition for the mutation of the GLO gene was a sufficient supply
of dietary ascorbate. Our ancestors at that time lived in tropical regions.
Their diet consisted primarily of fruits and other forms of plant nutrition
that provided a daily dietary ascorbate supply in the range of several
hundred milligrams to several grams per day. When our ancestors left
this habitat to settle in other regions of the world the availability
of dietary ascorbate dropped considerably and they became prone to scurvy.
Fatal Blood Loss Through the Scorbutic Vascular Wall -
An Extraordinary Challenge to the Evolutionary Survival of Man
Scurvy is a fatal disease. It is characterized by structural and metabolic
impairment of the human body, particularly by the destabilization of
the connective tissue. Ascorbate is essential for an optimum production
and hydroxylation of collagen and elastin, key constituents of the extracellular
matrix. Ascorbate depletion thus leads to a destabilization of the connective
tissue throughout the body. One of the first clinical signs of scurvy
is perivascular bleeding. The explanation is obvious: Nowhere in the
body does there exist a higher pressure difference than in the circulatory
system, particularly across the vascular wall. The vascular system is
the first site where the underlying destabilization of the connective
tissue induced by ascorbate deficiency is unmasked, leading to the penetration
of blood through the permeable vascular wall. The most vulnerable sites
are the proximal arteries, where the systolic blood pressure is particularly
high. The increasing permeability of the vascular wall in scurvy leads
to petechiae and ultimately hemorrhagic blood loss.
Scurvy and scorbutic blood loss decimated the ship crews in earlier
centuries within months. It is thus conceivable that during the evolution
of man periods of prolonged ascorbate deficiency led to a great death
toll. The mortality from scurvy must have been particularly high during
the thousands of years the ice ages lasted and in other extreme conditions,
when the dietary ascorbate supply approximated zero. We therefore propose
that after the loss of endogenous ascorbate production in our ancestors,
scurvy became one of the greatest threats to the evolutionary survival
of man. By hemorrhagic blood loss through the scorbutic vascular wall
our ancestors in many regions may have virtually been decimated and brought
close to extinction.
The morphologic changes in the vascular wall induced by ascorbate deficiency
are well characterized: the loosening of the connective tissue and the
loss of the endothelial barrier function. The extraordinary pressure
by fatal blood loss through the scorbutic vascular wall favored genetic
and metabolic countermeasures attenuating increased vascular permeability.
Ascorbate Deficiency and Genetic Countermeasures
The genetic countermeasures are characterized by an evolutionary advantage
of genetic features and include inherited disorders that are associated
with atherosclerosis and CVD. With sufficient ascorbate supply these
disorders stay latent. In ascorbate deficiency, however, they become
unmasked, leading to an increased deposition of plasma constituents in
the vascular wall and other mechanisms that thicken the vascular wall.
This thickening of the vascular wall is a defense measure compensating
for the impaired vascular wall that had become destabilized by ascorbate
deficiency. With prolonged insufficient ascorbate intake in the diet
these defense mechanisms overshoot and CVD develops.
The most frequent mechanism to counteract the increased permeability
of the ascorbate-deficient vascular wall became the deposition of lipoproteins
and lipids in the vessel wall. Another group of proteins that generally
accumulate at sites of tissue transformation and repair are adhesive
proteins such as fibronectin, fibrinogen, and particularly apo(a). It
is therefore no surprise that Lp(a), a combination of the adhesive protein
apo(a) with a low density lipoprotein (LDL) particle, became the most
frequent genetic feature counteracting ascorbate deficiency (1). Beside
lipoproteins, certain metabolic disorders, such as diabetes and homocysteinuria,
are also associated with the development of CVD. Despite differences
in the underlying pathomechanism, all these mechanisms share a common
feature: they lead to a thickening of the vascular wall and thereby can
counteract the increased permeability in ascorbate deficiency.
In addition to these genetic disorders, the evolutionary pressure from
scurvy also favored certain metabolic countermeasures.
Ascorbate Deficiency and Metabolic Countermeasures
The metabolic countermeasures are characterized by the regulatory role
of ascorbate for metabolic systems determining the clinical risk profile
for CVD. The common aim of these metabolic regulations is to decrease
the vascular permeability in ascorbate deficiency. Low ascorbate concentrations
therefore induce vasoconstriction, hemostasis and affect vascular wall
metabolism in favor of atherogenesis. Towards this end ascorbate interacts
with lipoproteins, coagulation factors, prostaglandins, nitric oxides,
and second messenger systems such as cyclic monophosphates (1, 3-5).
It should be noted that ascorbate can affect these regulatory levels
in a multiple way. In lipoprotein metabolism low density lipoproteins
(LDL), Lp(a), and very low density lipoproteins (VLDL) are inversely
correlated with ascorbate concentrations, whereas ascorbate HDL levels
are positively correlated. Similarly, in prostaglandin metabolism ascorbate
increases prostacyclin and prostaglandin E concentrations and decreases
thromboxane levels. In general, ascorbate deficiency induces vascular
constriction and hemostatis, as well as cellular and extracellular defense
measures in the vascular wall.
In the following sections we will exemplify the role of ascorbate for
frequent and well established pathomechanisms of human CVD. In general,
the inherited disorders described below are polygenic. Their separate
description, however, will allow the characterization of the role of
ascorbate on the different genetic and metabolic levels.
Apo(a) and Lp(a), the Most Effective and Most Frequent Countermeasures
After the loss of endogenous ascorbate production, apo(a) and Lp(a)
were greatly favored by evolution. The frequency of occurrence of elevated
Lp(a) plasma levels in species that had lost the ability to synthesize
ascorbate is so great that we formulated the theory that apo(a) functions
as a surrogate for ascorbate (6). There are several genetically determined
isoforms of apo(a). They differ in the number of kringle repeats and
in their molecular size (7). An inverse relation between the molecular
size of apo(a) and the number of synthesized Lp(a) molecules has been
established. Patients with the high molecular weight apo(a) isoform carry
fewer LDL particles in their Lp(a) fraction. Vice versa, patients with
the genetic pattern of low apo(a) isoform have more LDL particles in
their Lp(a) plasma fraction and thus have increased Lp(a) plasma levels.
In most population studies the genetic pattern of high apo(a) isoform/low
Lp(a) plasma level proved to be the most advantageous and therefore most
In ascorbate deficiency Lp(a) is selectively retained in the vascular
wall. Apo(a) counteracts increased permeability by compensating for collagens,
by its binding to fibrin, as a proteinthiol and antioxidant, and as an
inhibitor of plasmin-induced proteolysis (1). Moreover, as an adhesive
protein apo(a) is effective in tissue-repair processes (8). Chronic ascorbate
deficiency leads to a sustained accumulation of Lp(a) in the vascular
wall. This leads to the development of atherosclerotic plaques and premature
CVD particularly in individuals with genetically determined high plasma
Lp(a) levels. Because of its association with apo(a), Lp(a) is the most
specific repair particle among all lipoproteins. Lp(a) is predominantly
deposited at predisposition sites and it is therefore found to be significantly
correlated with coronary, cervical, and cerebral atherosclerosis but
not with peripheral vascular disease.
The mechanism by which ascorbate resupplementation prevents CVD in any
condition is by maintaining the integrity and stability of the vascular
wall. In addition, ascorbate exerts in the individual a multitude of
metabolic effects that prevent the exacerbation of a possible genetic
predisposition and the development of CVD. If the predisposition is a
genetic elevation of Lp(a) plasma levels the specific regulatory role
of ascorbate is the decrease of apo(a) synthesis in the liver and thereby
the decrease of Lp(a) plasma levels. Moreover, ascorbate decreases the
retention of Lp(a) in the vascular wall by lowering fibrinogen synthesis
and by increasing the hydroxylation of lysine residues in vascular wall
constituents, thereby reducing the affinity for Lp(a) binding (1).
In about half of the CVD patients the mechanism of Lp(a) deposition
contributes significantly to the development of atherosclerotic plaques.
Other lipoprotein disorders are also frequently part of the polygenic
pattern predisposing the individual patient to CVD in the individual.
Other Lipoprotein Disorders Associated with CVD
In a large population study Goldstein identified three frequent lipid
disorders, familial hypercholesterolemia, familial hypertriglyceridemia,
and familial combined hyperlipidemia (9). Ascorbate deficiency unmasks
these underlying genetic defects and leads to an increased plasma concentration
of lipids (e.g. cholesterol, triglycerides) and lipoproteins (e.g. LDL,
VLDL) as well as to their deposition in the impaired vascular wall. As
with Lp(a), this deposition is a defense measure counteracting the increased
permeability. It should, however, be noted that the deposition of lipoproteins
other than Lp(a) is a less specific defense mechanism and frequently
follows Lp(a) deposition. Again, these mechanisms function as a defense
only for a limited time. With sustained ascorbate deficiency the continued
deposition of lipids and lipoproteins leads to atherosclerotic plaque
development and CVD. Some mechanisms will be described in more detail:
Hypercholesterolemia, LDL-receptor defect.
A multitude of genetic defects lead to an increased synthesis and/or
a decreased catabolism of cholesterol or LDL. A well characterized although
rare defect is the LDL-receptor defect. Ascorbate deficiency unmasks
these inherited metabolic defects and leads to an increased plasma concentration
of cholesterol-rich lipoproteins, e.g. LDL, and their deposition in the
vascular wall. Hypercholesterolemia increases the risk for premature
CVD primarily when combined with elevated plasma levels of Lp(a) or triglycerides.
The mechanisms by which ascorbate resupplementation prevents the exacerbation
of hypercholesterolemia and related CVD include an increased catabolism
of cholesterol. In particular, ascorbate is known to stimulate 7a-hydroxylase,
a key enzyme in the conversion of cholesterol to bile acids and to increase
the expression of LDL receptors on the cell surface. Moreover, ascorbate
is known to inhibit endogenous cholesterol synthesis as well as oxidative
modification of LDL (1).
Hypertriglyceridemia, Type III hyperlipidemia.
A variety of genetic disorders lead to the accumulation of triglycerides
in the form of chylomicron remnants, VLDL and intermediate density lipoproteins
(IDL) in plasma. Ascorbate deficiency unmasks these underlying genetic
defects and the continued deposition of triglyceride-rich lipoproteins
in the vascular wall leads to CVD development. These triglyceride-rich
lipoproteins are particularly subject to oxidative modification, cellular
lipoprotein uptake, and foam cell formation. In hypertriglyceridemia
non specific foam cell formation has been observed in a variety of organs
(10). In the vascular wall foam cell formation, although a less specific
repair mechanism than the extracellular deposition of Lp(a), may have
also conferred stability on the ascorbate-deficient vascular wall.
Ascorbate resupplementation prevents the exacerbation of CVD associated
with hypertriglyceridemia, Type III hyperlipidemia, and related disorders
by stimulating lipoprotein lipases and thereby enabling a normal catabolism
of triglyceride-rich lipoproteins (11). Ascorbate prevents the oxidative
modification of these lipoproteins, their uptake by scavenger cells and
foam cell formation. Moreover, we propose here that, analogous to the
LDL receptor, ascorbate also increases the expression of the receptors
involved in the metabolic clearance of triglyceride-rich lipoproteins,
such as the chylomicron remnant receptor.
The degree of build-up of atherosclerotic plaques in patients with lipoprotein
disorders is determined by the rate of deposition of lipoproteins and
by the rate of the removal of deposited lipids from the vascular wall.
It is therefore not surprising that ascorbate is also closely connected
with this reverse pathway.
A frequent lipoprotein disorder is the genetically determined decreased
synthesis of HDL particles. HDL is part of the 'reverse-cholesterol-transport'
pathway and is critical for the transport of cholesterol and also other
lipids from the body periphery to the liver. In ascorbate deficiency
this genetic defect is unmasked resulting in decreased HDL levels and
a decreased reverse transport of lipids from the vascular wall to the
liver. This mechanism is highly effective and the genetic disorder hypoalphalipoproteinemia
was greatly favored during evolution.
With ascorbate resupplementation HDL production increases (12), leading
to an increased uptake of lipids deposited in the vascular wall and to
a decrease of the atherosclerotic lesion. A look back in evolution underlines
the importance of this mechanism. During the winter seasons, with low
ascorbate intake, our ancestors became dependent on protecting their
vascular wall by the deposition of lipoproteins and other constituents.
During spring and summer seasons the ascorbate content in the diet increased
significantly and mechanisms were favored that decreased the vascular
deposits under the protection of increased ascorbate concentration in
the vascular tissue. It is not unreasonable for us to propose that ascorbate
can reduce fatty deposits in the vascular wall within a relatively short
time. In an earlier clinical study it was shown that 500 mg of dietary
ascorbate per day can lead to a reduction of atherosclerotic deposits
within 2 to 6 months (13).
This concept, of course, also explains why heart attack and stroke occur
today with a much higher frequency in winter than during spring and summer,
the seasons with increased ascorbate intake.
Other Inherited Metabolic Disorders Associated with CVD
Beside lipoprotein disorders many other inherited metabolic diseases
are associated with CVD. Generally these disorders lead to an increased
concentration of plasma constituents that directly or indirectly damage
the integrity of the vascular wall. Consequently these diseases lead
to peripheral angiopathies as observed in diabetes, homocysteinuria,
sickle-cell anemia (the first molecular disease described (14)), and
many other genetic disorders. Similar to lipoproteins the deposition
of various plasma constituents as well as proliferative thickening provided
a certain stability for the ascorbate-deficient vascular wall. We illustrate
this principle for diabetic and homocystinuric angiopathy.
The pathomechanism in this case involves the structural similarity between
glucose and ascorbate and the competition of these two molecules for
specific cell surface receptors (15,16). Elevated glucose levels prevent
many cellular systems in the human body, including endothelial cells,
from optimum ascorbate uptake. Ascorbate deficiency unmasks the underlying
genetic disease, aggravates the imbalance between glucose and ascorbate,
decreases vascular ascorbate concentration, and thereby triggers diabetic
Ascorbate resupplementation prevents diabetic angiopathy by optimizing
the ascorbate concentration in the vascular wall and also by lowering
insulin requirement (17).
Homocystinuria is characterized by the accumulation of homocyst(e)ine
and a variety of its metabolic derivatives in the plasma, the tissue
and the urine as the result of decreased homocysteine catabolism (18).
Elevated plasma concentrations of homocyst(e)ine and its derivatives
damage the endothelial cells throughout the arterial and venous system.
Thus homocystinuria is characterized by peripheral vascular disease and
thromboembolism. These clinical manifestations have been estimated to
occur in 30 per cent of the patients before the age of 20 and in 60 per
cent of the patients before the age of 40 (19).
Ascorbate resupplementation prevents homocystinuric angiopathy and other
clinical complications of this disease by increasing the rate of homocysteine
Thus, ascorbate deficiency unmasks a variety of individual genetic predispositions
that lead to CVD in different ways. These genetic disorders were conserved
during evolution largely because of their association with mechanisms
that lead to the thickening of the vascular wall. Moreover, since ascorbate
deficiency is the underlying cause of these diseases, ascorbate resupplementation
is the universal therapy.
The Determining Principles of This Theory
The determining principles of this comprehensive theory are schematically
summarized in Figures 1 to 3.
1. Cardiovascular disease is the direct consequence of the inability
for endogenous ascorbate production in man in combination with low
dietary ascorbate intake
2. Ascorbate deficiency leads to increased permeability of the vascular
wall by the loss of the endothelial barrier function and the loosening
of the vascular connective tissue.
3. After the loss of endogenous ascorbate production scurvy and fatal
blood loss through the scorbutic vascular wall rendered our ancestors
in danger of extinction. Under this evolutionary pressure over millions
of years genetic and metabolic countermeasures were favored that counteract
the increased permeability of the vascular wall.
4. The level is characterized by the fact that inherited disorders associated
with CVD became the most frequent among all genetic predispositions.
Among those predispositions lipid and lipoprotein disorders occur particularly
5. The metabolic level is characterized by the direct relation between
ascorbate and virtually all risk factors of clinical cardiology today.
Ascorbate deficiency leads to vasoconstriction and hemostasis and affects
the vascular wall metabolism in favor of atherogenesis. The genetic level
can be further characterized. The more effective and specific a certain
genetic feature counteracted the increasing vascular permeability in
scurvy, the more advantageous it became during evolution and, generally,
the more frequently this genetic feature occurs today.
7. The deposition of Lp(a) is the most effective, most specific, and
therefore most frequent of these mechanisms. Lp(a) is preferentially
deposited at predisposition sites. In chronic ascorbate deficiency the
accumulation of Lp(a) leads to the localized development of atherosclerotic
plaques and to myocardial infarction and stroke.
8. Another frequent inherited lipoprotein disorder is hypoalphalipoproteinemia.
The frequency of this disorder again reflects its usefulness during evolution.
The metabolic upregulation of HDL synthesis by ascorbate became an important
mechanism to reverse and decrease existing lipid deposits in the vascular
9. The vascular defense mechanisms associated with most genetic disorders
is unspecific. These mechanisms can aggravate the development of atherosclerotic
plaques at predisposition sites. Other unspecific mechanisms
lead to peripheral forms of atherosclerosis by causing a thickening of
the vascular wall throughout the cardiovascular system. This peripheral
form of vascular disease is characteristic for angiopathies associated
with Type III hyperlipidemia, diabetes, and many other inherited metabolic
10. Of particular advantage during evolution and therefore particularly
frequent today are those genetic features that protect the ascorbate-deficient
vascular wall until the end of the reproduction age. By favoring these
disorders nature decided for the lesser of two evils: the death from
CVD after the reproduction age rather than death from scurvy at a much
earlier age. This also explains the rapid increase of the CVD mortality
today from the 4th decade onwards.
11. After the loss of endogenous ascorbate production the genetic mutation
rate in our ancestors increased significantly (21). This was an additional
precondition favouring not only the advantage of apo(a) and Lp(a) but
also of many other genetic countermeasures associated with CVD.
Genetic predispositions are characterized by the rate of ascorbate depletion
in a multitude of metabolic reactionsspecific for the genetic disorder
(22). The overall rate of ascorbate depletion in an individual is largely
determined by polygenic pattern of disorders. The earlier the ascorbate
reserves in the body are depleted without being resupplemented, the earlier
13. The genetic predispositions with the highest probability for early
clinical manifestation require the highest amount of ascorbate resupplementation
in the diet to prevent CVD development. The amount of ascorbate for patients
at high risk should be comparable to the amount of ascorbate our ancestors
synthesized in their body before they lost this ability: between 10,000
and 20,000 milligrams per day.
14. Optimum ascorbate resupplementation prevents the development of
CVD independent of the individual predisposition or pathomechanism. Ascorbate
reduces existing atherosclerotic deposits and thereby decreases the risk
for myocardial infarction and stroke. Moreover, ascorbate can prevent
blindness and organ failure in diabetic patients, thromboembolism in
homocystinuric patients and many other manifestations of CVD.
In this paper we present a unified theory of human CVD. This disease
is the direct consequence of the inability of man to synthesize ascorbate
in combination with insufficient intake of ascorbate in the modern diet.
Since ascorbate deficiency is the common cause of human CVD, ascorbate
resupplementation is the universal treatment for this disease. The available
epidemiological and clinical evidence is reasonably convincing. Further
clinical confirmation of this theory should lead to the abolition of CVD
as a cause of human mortality for the present generation and future generations
1. Rath, M, Pauling L. Solution of the puzzle of human cardiovascular
disease: Its primary cause is ascorbate deficiency, leading to the deposition
of lipoprotein(a) and fibrinogen/fibrin in the vascular wall. Journal
of Orthomolecular Med 1991;6:125-134.
2. Pauling L, Rath M. Vitamin C and lipoprotein(a) in relation to cardiovascular
disease and other diseases. Journal of Applied Nutrition 1992; this issue.
3. Ginter E. Marginal vitamin C deficiency, lipid metabolism, and atherosclerosis.
Lipid Research 1973;16:162-220.
4. Third Conference on Vitamin C, Annals of the New York Academy of
Sciences 498 (BurnsJJ, Rivers JM, Machlin LJ, eds) 1987.
5. Pauling L. How to Live Longer and Feel Better 1986; Freeman, New
6. Rath M, Pauling L. Hypothesis: Lipoprotein(a) is a surrogate for
ascorbate. Proceedings of the National Academy of Sciences USA 1990;87:6204-6207.
7. Koschinsky ML, Beisiegel U, Henne-Bruns D, Eaton DL, Lawn RM. Apolipoprotein(a)
size heterogeneity is related to variable number of repeat sequences
in its mRNA. Biochemistry 1990;29:640-644.<
8. Rath M, Pauling L. Apoprotein(a) is an adhesive protein. Journal
of Orthomolecular Medicine 1991;6:139-143.
9. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia
in coronary heart disease. Journal of Clinical Investigation 1973; 52:1544-1568.
10. Roberts WC, Levy RI, Fredrickson DS. Hyperlipoproteinemia-A review
of the five types, with first report of necropsy findings in type 3.
Archives of Pathology 1970;59:46-56.
11. Sokoloff B, Hori M, Saelhof CC, Wrzolek T, Imai T. Aging, atherosclerosis
and ascorbic acid metabolism. Journal of the American Geriatric Society
12. Jacques PF, Hartz SC, McGandy RB, JacobRA, Russell RM. Vitamin C
and blood lipoproteins in an elderly population. Third Conference on
Vitamin C, Annals of the New York Academy of Sciences 498 (Burns JJ,
Rivers JM, Machlin LJ, eds) 1987.
13. Willis GC, Light AW, Gow WS. Serial arteriography in atherosclerosis.
Canadian Medical Association Journal 1954;71:562-568.
14. Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a
molecular disease. Science 1949;110:543-548.
15. Mann GV, Newton P. The membrane transport of ascorbic acid. Second
Conference on Vitamin C. Annals of the New York Academy of Sciences 1975;243-252.
16. Kapeghian JC, Verlangieri J. The effects of glucose on ascorbic
acid uptake in heart endothelial cells: possible pathogenesis of diabetic
angiopathies. Life Sciences 1984;34:577-584.
17. Dice JF, Daniel CW. The hypoglycemic effect of ascorbic acid in
a juvenile-onset diabetic. International Research Communications System
18. Mudd SH, Levey HL, Skovby F. Disorders of Transsulfuration. In Scriver
CR, Beaudet AL, Sly WS, Valle D (eds), The Metabolic Basis of Inherited
Disease 1989 McGraw-Hill:693-734.
19. Boers GHJ, Smals AGH, Trijbels FJM, Fowler B, Bakkeren JAJM, Schoonderwaldt
HC, Kleijer WJ, Kloppenborg PWC. Heterozygosity for homocystinuria in
premature peripheral and cerebral occlusive arterial disease. New England
Journal of Medicine 1985; 313:709-715.
20. McCully KS. Homocysteine metabolism in scurvy, growth and arteriosclerosis.
21. Fraga CG, Motchnik PA, Shigenaga MK, Helbock HJ. Jacob RA, Ames
BN. Ascorbic acid protects against endogenous oxidative DNA damage in
human sperm. Proceedings of the National Academy of Sciences USA 1991;88:11003-11006.
22. Pauling L. Orthomolecular psychiatry. Science 1968;160:265-271.