Linus Carl Pauling (1901–1994) was an American chemist, peace activist, author and educator regarded as one of the most influential chemists in history. He was among the first scientists to work in the fields of quantum chemistry and molecular biology, and is the only individual to have won two unshared Nobel Prizes.
A paper submitted by Pauling to the Proceedings of the National Academy of Sciences and accepted for publication on June 11, 1991 was later revoked by the editor under questionable circumstances: “We are aware that this pullback was not the decision of an individual. It happened in the interest of those who are personally or economically dependent on the present dogma of human cardiovascular disease.”
In the mid-1930s, Pauling shifted his interest towards biological molecules and protein structures, although it was his work on vitamin C which generated much controversy. Pauling popularised vitamin C as an effective therapy for terminal cancer patients and the common cold. However, the failure of randomised trials by the Mayo Clinic to demonstrate any benefit and the public debate that ensued resulted in the medical establishment eventually rejecting his claims as quackery.
In his last years, Pauling continued to research vitamin C and became especially interested in its possible role in preventing atherosclerosis and heart disease. It is this forgotten work by Pauling and Matthias Rath at the Linus Pauling Institute which presents a compelling case for re-examining atherosclerosis research, prevention and treatment.
Our evolutionary loss of endogenous vitamin C production
Almost all animals are capable of synthesising their own ascorbate (vitamin C is the common name for ascorbate) by conversion from glucose, except humans who lost this ability about 40 million years ago. Our ancestors at that time lived in tropical regions and their diet provided an abundant ascorbate supply from several hundred milligrams to several grams per day (by comparison, modern government recommended intakes are set at 40-95 mg/day). When our ancestors eventually settled other regions of the world with less availability of dietary ascorbate, they became prone to scurvy.
After the loss of endogenous ascorbate production, lipoprotein(a)/Lp(a) and apolipoprotein(a)/apo(a) became greatly favoured by evolution. The frequency of occurence of elevated Lp(a) plasma levels in species that had lost the ability to synthesise ascorbate is so great that it is hypothesised that apo(a) functions as a surrogate for ascorbate.
The primary cause is ascorbate deficiency and lipoprotein(a) deposition
“Human CVD is multifactorial. Ascorbate deficiency, however, is the common denominator of this disease.”
In the course of their work, Pauling and Rath discovered that virtually every patho-mechanism for human cardiovascular disease (CVD) can be induced by ascorbate deficiency, as a consequence of the inability of humans to synthesise endogenous ascorbate combined with insufficient dietary intake.
To summarise their theory:
- Ascorbate deficiency leads to increased permeability of the vascular (blood vessel) wall because ascorbate is essential for the optimal production and hydroxylation of collagen and elastin.
- The physiological response to this blood loss results in vasoconstriction and haemostasis (blood vessel constriction and clotting), with the deposition of Lp(a) and fibrinogen being the most effective, specific and frequent of these countermeasures.
- In ascorbate deficiency, Lp(a) is selectively retained in the vascular wall. Apo(a) compensates for collagen by binding to fibrin. Lp(a) also has functions in the containment of diseases and the repair of tissues. Lp(a) can inhibit both free-radical induced and plasmin-induced tissue degradation.
- Chronic ascorbate deficiency leads to a sustained accumulation of Lp(a) in the vascular wall, which leads to the localised development of atherosclerotic plaques, premature CVD, heart attack and stroke.
The extracellular accumulation of Lp(a) in the vascular wall is an independent pathomechanism of human CVD which is at variance with concepts suggesting that the cellular uptake and degradation of lipoproteins by scavenger cells is a prerequisite for atherogenesis.
Cigarette smoking also damages the vascular endothelium directly or via oxidation of lipoproteins. Ascorbate, being the strongest antioxidant normally present in the body is a potent inhibitor of these pathomechanisms.
Other genetic and metabolic disorders associated with CVD
Inherited disorders of lipoprotein metabolism such as familial hypercholesterolaemia (elevated LDL), hypertriglyceridemia (elevated triglyceride) and hyperhomocysteinuria (elevated homocysteine) are frequently associated with CVD.
Ascorbate deficiency unmasks these underlying genetic defects and leads to an increased blood concentration of lipids (cholesterol, triglycerides) and lipoproteins (LDL, VLDL) and their deposition in the impaired vascular wall.
The deposition of these lipoproteins other than Lp(a) is a less specific defense mechanism and frequently follows Lp(a) deposition. With sustained ascorbate deficiency the continued deposition of lipids and lipoproteins leads to atherosclerotic plaque development and CVD.
Peripheral vascular disease
Lp(a) is predominantly deposited at predisposition sites and is therefore found to be significantly correlated with coronary, cervical and cerebral atherosclerosis but not with peripheral vascular disease (PVD). In about half of the CVD patients the mechanism of Lp(a) deposition contributes significantly to the development of atherosclerotic plaques.
The vascular defense mechanisms associated with most genetic disorders are non-specific. These mechanisms can aggravate the development of atherosclerotic plaques at predisposition sites. Other nonspecific mechanisms lead to peripheral forms of atherosclerosis by causing a thickening of the vascular wall throughout the arterial system. PVD is characteristic for angiopathies associated with type 3 hyperlipidemia, diabetes mellitus, hyperhomocysteinuria and many other inherited metabolic diseases.
In general, inherited metabolic disorders resulting in an elevated concentration of noxious plasma constituents, such as hyperhomocysteinuria, are frequently associated with peripheral vascular disease.
After the loss of endogenous ascorbate production, scurvy and fatal blood loss rendered our ancestors in danger of extinction. Under this evolutionary pressure, genetic and metabolic countermeasures that could counteract the increased permeability of the vascular wall were favoured. By favouring 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.
These genetic disorders were conserved during evolution largely because of their association with mechanisms that lead to the thickening of the vascular wall. Inherited disorders associated with CVD became the most frequent among all genetic predispositions, lipid and lipoprotein disorders occuring particularly often. The more effective and specific a certain generic feature conteracted the increasing vascular permeability in scurvy, the more advantageous it became during evolution and the more frequently this genetic feature occurs today.
Familial hypercholesterolaemia (FH) increases the risk for premature CVD primarily when combined with elevated plasma levels of Lp(a) or triglycerides. The incidence of CVD was shown to be significantly determined by the Lp(a) plasma concentration, with total cholesterol and LDL cholesterol in the plasma not related to the clinical manifestations of CVD.
Ascorbate supplementation prevents the exacerbation of hypercholesterolaemia and related CVD by increased catabolism of cholesterol, stimulating 7-a-hydroxylase, a key enzyme in the conversion of cholesterol to bile acids and increasing the expression of LDL receptors on the cell surface. Furthermore, ascorbate is known to inhibit endogenous cholesterol synthesis as well as oxidative modification of LDL.
Triglyceride rich lipoproteins are particularly subject to oxidative modification, cellular lipoprotein uptake and foam cell formation. Ascorbate supplementation prevents the exacerbation of CVD by stimulating lipoprotein lipases and thereby enabling a normal catabolism of triglyceride rich lipoproteins. Ascorbate prevents the oxidative modification of these lipoproteins, their uptake by scavenger cells and foam cell formation.
Hypoalphalipoproteinemia (low HDL)
Hypoalphalipoproteinemia (HA) is a frequent lipoprotein disorder (reflecting its evolutionary usefulness) characterised by a decreased synthesis of HDL particles. HDL is part of the reverse-cholesterol-transport pathway and is critical for the transport of cholesterol and other lipids from the body periphery to the liver. Ascorbate supplementation can increase HDL production, leading to an increased uptake of lipids deposited in the vascular wall and to a decrease of the atherosclerotic lesion.
This mechanism was important during evolution. 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, the ascorbate content in the diet increased significantly and mechanisms were favoured that decreased the vascular deposits.
In an earlier clinical study it was shown that 500 mg of daily dietary ascorbate can lead to a reduction of atherosclerotic deposits within 2 to 6 months. This concept also explains why heart attack and stroke occur today with a much higher frequency in winter than during spring and summer, seasons with increased ascorbate intake.
The glucose and ascorbate molecule share structural similarities and compete for the same transport system for cellular uptake. Elevated blood glucose levels prevent many cellular systems in the human body, including endothelial cells, from optimum ascorbate uptake, leading to the chronic depletion of ascorbate. Ascorbate supplementation prevents diabetic angiopathy by optimising the ascorbate concentration in the vascular wall and also by lowering the need for insulin.
Hyperhomocysteinuria is characterised by the accumulation of homocysteine and its metabolic derivatives in the blood plasma, tissues and urine as a result of decreased homocysteine catabolism. Elevated concentrations of homocysteine damage the endothelial cells throughout the arterial and venous system, leading to peripheral vascular disease and thromboembolism. These clinical manifestions have been estimated to occur in 30 percent of patients before age 20 and in 60 percent of patients before age 40. Ascorbate supplementation prevents homocysteinuric angiopathy and other clinical complications by increasing the rate of homocysteine catabolism.
Ascorbate supplementation may be a universal treatment
The overall rate of ascorbic depletion in an individual is largely determined by the polygenic pattern of disorders. The earlier the ascorbate reserves in the body are depleted without resupplementation, the earlier CVD develops.
Optimum ascorbate supplementation prevents the development of CVD independently 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.
What is to become of a lost legacy?
“Fifty years ago ascorbate deficiency was established as a prominent risk factor in CVD, 37 years ago ascorbate was shown in preliminary angiographic studies to reduce atherosclerotic plaques in man. There is no rational explanation why these early observations of the therapeutic value of ascorbate were ignored and did not become common knowledge in the medical profession long ago.”
Pauling and Rath also believed that the significance of their discovery was not limited to CVD; Lp(a) and ascorbate are involved in cancer, inflammatory diseases, and other diseases including the process of aging. Abolition of ascorbate deficiency may profoundly improve human health and increase the life expectancy of human beings.
Lessons learned from randomised controlled trials
In the last two decades, several randomised controlled trials have shown no effect of antioxidant supplements on hard endpoints such as morbidity and mortality. Lykkesfeldt and Poulsen (2010) reviewed the literature on vitamin C and were disappointed that at present we do not have the necessary scientific evidence to judge the effect on health – be that beneficial or deleterious – from vitamin C supplementation as a single substance.
They found that no study has used vitamin C deficiency as an inclusion criterion. No dose-response relationships for pharmacodynamic evaluation are available. For most of the available studies, the population status at entry with regard to vitamin C is unclear and may have been severely or marginally deficient, suboptimal or optimal. Major confounders are, for example, dietary vitamin C and smoking status, and these factors need to taken into account in the study design.
The authors regard that there is a dire need for high-quality trials to examine the effect of vitamin C as a single supplement in populations which have been carefully defined with inclusion criteria of different levels of vitamin C status and with variable demand for vitamin C, for example, smokers v. non-smokers.
Ed: given the significance of the claims, we sincerely hope our readers will further investigate and scrutinise this theory. How does vitamin C supplementation compare with statin treatment? More clinical trials are needed to support this profound hypothesis, which may yet prove to be Pauling’s last legacy.
- Rath M, Pauling L. Solution to the puzzle of human cardiovascular disease: it’s primary cause is ascorbate deficiency leading to the deposition of lipoprotein(a) and fibrinogen/fibrin in the vascular wall. J Orthomol Med. 1991;6(3&4):125-134. [Fulltext]
- Rath M, Pauling L. A unified theory of human cardiovascular disease leading the way to abolition of this disease as a cause for human mortality. J Orthomol Med. 1992;7(1):5-12. [PDF]
- Lykkesfeldt J, Poulsen HE. Is vitamin C supplementation beneficial? Lessons learned from randomised controlled trials. Br J Nutr. 2010 May;103(9):1251-9. Epub 2009 Dec 15. Review. [PDF]
- Li Y, Schellhorn HE. New developments and novel therapeutic perspectives for vitamin C. J Nutr. 2007;137: 2171–2184. [Fulltext]