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Toward a new definition of essential nutrients: is it now time for a third ‘vitamin’ paradigm?
Medical Hypotheses (1999) 52(5), 417–422 © 1999 Harcourt Brace & Co. Ltd Article No. mehy.1997.0685
Toward a new definition of essential nutrients: is it now time for a third ‘vitamin’ paradigm? J. J. Challem Aloha, Oregon, USA
Summary The concepts of vitamin ‘deficiency’ diseases and the recommended dietary allowances (RDAs) have not kept pace with the growing understanding of the cellular and molecular functions of vitamins and other micronutrients. As a consequence, many researchers and clinicians rely on outdated signs and symptoms in assessing nutritional deficiencies. A new paradigm, presented here, proposes that: (1) deficiencies can be identified on biochemical and molecular levels long before they become clinically visible; (2) the definition of essential micronutrients be broadened to include some carotenoids and flavonoids, as well as various human metabolites, such as coenzyme Q10, carnitine, and alpha-lipoic acid, which are also dietary constituents; (4) individual nutritional requirements are partly fixed by genetics but also dynamically influenced by variations in the body’s biochemical milieu and external stresses; and (5) the distinction between nutritional and pharmacological doses of vitamins is meaningless, since high doses of micronutrients may be required to achieve normal metabolic processes in some people.
INTRODUCTION A number of researchers, from the 1930s through the present, have questioned the validity of the original concept of vitamins and minerals as micronutrients that prevent only ‘deficiency’ diseases, such as scurvy or beri-beri (1,2). The most widespread expression of this first vitamin paradigm can be found in the recommended dietary allowances (RDAs), described as being ‘adequate to meet the known nutrient needs of practically all healthy persons’ (3). However, the RDAs may have limited relevance because 45% of non-institutionalized Americans (~100 million) suffer from at least one chronic diseases (4), and large numbers of people apparently consume nutritionally inadequate diets (5). In contrast to the RDA-based perception of vitamin requirements, many studies have demonstrated that supra-RDA levels of micronutrients, such as vitamins C and E, can prevent and treat of a wide variety of diseases (6,7). To create a broader context for the different views of vitamins, some researchers have defined historical
Received 3 September 1997 Accepted 15 October 1997 Correspondence to: PO Box 5505, Aloha, OR 97006, USA E-mail: [email protected]
periods or paradigms with distinctive views of micronutrients. As knowledge about the roles of micronutrients increases, we must adapt our views accordingly. This paper briefly reviews previous paradigms and proposes a new way of thinking about vitamins and other micronutrients, i.e. a third paradigm (Table 1). THE FIRST AND SECOND VITAMIN PARADIGMS Since the early part of the 20th century, many vitamins have been recognized as essential nutrients. In the first paradigm, which came about immediately after the discovery of vitamins, researchers and clinicians concluded that these micronutrients were required in relatively small amounts from the diet to prevent classical deficiency diseases, such as scurvy, beri-beri, pellagra, and pernicious anemia. At that time, circa 80 years ago, the diagnosis of vitamin-deficiency diseases was based on easily observed signs and symptoms, such as hemorrhaging in scurvy and paralysis in beri-beri (8). Today, this archaic method of diagnosis remains the only one (other than simple blood tests) generally accepted by physicians and dietitians for recognizing vitamin deficiencies. It fails to recognize that classical deficiency diseases are advanced (not early) signs of malnutrition (9). Hence, vitamin deficiences are believed rare. 417
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Table 1 Three micronutrient paradigms
First paradigm Á Vitamins prevent classical deficiency diseases. Á Vitamins are obtained from foods, not produced in body. Second paradigm Á Strives for orthomolecular, or optimal, molecular/cellular levels of micronutrients. Á Recognizes biochemical individuality and variations in vitamin requirements. Á Micronutrients used to treat diseases not recognized as traditional vitamin-deficiency states. Third paradigm Á Builds on the second paradigm, embracing an understanding of the cellular and molecular roles of nutrients. Á Proposes that many ‘nonessential’ nutrients actually optimize molecular performance. Á Proposes that many metabolites may also be essential dietary constituents. Á Recognizes nutritional requirements both genetically defined and highly dynamic. Á Recognizes technologies can now measure molecular signs of deficiencies. Á Uses supplements toward achieving optimal molecular environment in cells and minimizing age-associated DNA damage.
In contrast, the second vitamin paradigm recognizes that vitamin supplements can be used to treat diseases not recognized as classical deficiency diseases (10,11). The beginning of this paradigm has been placed at 1955, when the US Food and Drug Administration permitted the use of niacin to lower serum cholesterol levels. However, its origins can be traced to scientific discussions of optimal nutrition in the 1930s (1). In the 1940s and 1950s, the benefits of optimal nutrient intake were demonstrated through therapeutic intervention in heart disease (12), infectious diseases (13), and schizophrenia (14). The concept of optimal nutrition was subsequently refined as a molecular theory of medicine and described as ‘orthomolecular’ psychiatry (and, by implication, orthomolecular medicine) in 1968 (15). Orthomolecular medicine, rooted in molecular biology and molecular medicine, recommended the use of molecules normally present in human biochemistry to correct metabolic defects and achieve optimal health. The evidence for the second nutritional paradigm (that of orthomolecular medicine), based on cell and molecular biology, is compelling and too extensive to cite here (16–17). Despite the current popularity of molecular biology and genetic research, the concept of optimizing nutrients on a molecular level has remained controversial and has not generally been put into practice by the medical profession. It is proposed here that the continued dominance of the first paradigm and the ongoing controversy surrounding the second paradigm stems, at least in part, from a fundamental clinical error: the failure to recognize the cellular Medical Hypotheses (1999) 52(5), 417–422
and molecular and, therefore, the earliest and most basic signs of vitamin deficiencies. Left untreated, severe deficiencies might become acute after months, whereas more subtle (subclinical) deficiencies would damage deoxyribonucleic acid (DNA), proteins, enzymes, lipids, and mitochondrial bioenergetics, and only after many decades become manifest as degenerative diseases. EXPANDING THE CONCEPT OF ESSENTIAL NUTRIENTS The idea that signs of nutrient deficiencies may not always be visible to the naked eye, or readily identifiable through blood tests, sets the stage for the proposed new paradigm. This is not strictly a vitamin paradigm; rather, it should enlarge the concept of what is an essential micronutrient. The best way of elucidating this paradigm is to contrast it with the previous ones. In the first paradigm, essential nutrients are generally defined as those that the body does not manufacture, must be obtained from the diet, and the absence of which results in deficiency symptoms (18). Held to the first paradigm, carotenoids and flavonoids are not produced by the body, and their dietary deficiencies result in no clinically acute or obvious symptoms; therefore, they cannot be essential. Held to the second paradigm, many carotenoids and flavonoids are increasingly considered beneficial but not essential for health. In this view, carotenoids and flavonoids are no more than discretionary nutrients. As in the case of vitamins, researchers and clinicians may be looking at incorrect signs and symptoms in assessing deficiencies of carotenoids and flavonoids. For example, a deficiency of the carotenoid lutein has no acute symptoms; however, it appears that long-term deficiency results in macular degeneration, the leading cause of blindness among the elderly in the USA and the UK (19). Cell and molecular biology studies of many carotenoids and flavonoids have identified some of the detailed mechanisms and have confirmed that they play key regulatory roles in cells and protect them from oxidative damage (20,21). Indeed, some carotenoids and flavonoids function as antioxidants and influence gene expression (21) and repair (22). Instead of immediate and visible symptoms of a deficiency, there is evidence that inadequate intake of these nutrients permits excessive DNA damage over many years, becoming visible as cancer or heart disease after many years. Epidemiological and experimental studies suggest that these nutrients reduce the risk of cancer and heart disease (23,24) and, as in the case of lutein and macular degeneration, these degenerative diseases might be considered deficiency diseases. A further argument in favor of the essentiality of many © 1999 Harcourt Brace & Co. Ltd
Toward a new definition of essential nutrients
carotenoids and flavonoids can be made in view of their likely roles in the evolution of Homo sapiens. The genetic and, therefore, nutritional requirements of H. sapiens have been shaped by millions of years of mammalian, primate, and hominid evolution. Although our genetic requirements are virtually the same as those of Paleolithic humans, the modern diet provides fewer micronutrients and is substantially different in composition from the diet of 15 000 years ago (25,26). It is likely, since our genetic ancestors ate large quantities of plant foods, that carotenoids and flavonoids (and other phytonutrients) were among the nutrients they depended on for survival (27). METABOLITES AS ESSENTIAL NUTRIENTS The proposed third paradigm should also recognize that many metabolites – including choline, inositol, coenzyme Q10, carnitine, and alpha-lipoic acid – may be essential nutrients. These substances are not currently recognized as essential nutrients because the body can manufacture them. However, there is evidence that the body may not always manufacture them efficiently or in sufficient quantities. For example, coenzyme Q10 levels decrease with age and are abnormally low among people with cancer and heart disease (28,29). It is possible that endogenous production does not by itself satisfy an animal’s requirements for such substances (30). Just as supplemental vitamin C can increase the lifespan of mice (for which ascorbate is a metabolite) (31), dietary or supplemental sources of human metabolites may be very important to health, particularly when endogenous manufacture is inefficient (29). Given the demonstrated therapeutic effects of these nutrient/metabolites, such as coenzyme Q10 and alpha-lipoic acid, it appears that supplements can compensate for dietary deficiencies or metabolic defects and correct disease processes (28,32). A NEW VIEW OF ADEQUACY The predecessor to today’s recommended dietary allowances (RDAs) was conceived in 1941, during World War II – a time when classical vitamin-deficiency diseases were still relatively common in the USA. Its original objective was to provide a ‘guide for advising “on nutrition problems in connection with national defense’’ ’ (3). Since then, the minimum daily requirements (MDRs), RDAs, reference dietary intakes (RDIs), and daily values (DVs) have formed the basis of much of the USA’s peacetime public nutrition policy. The RDAs, RDIs, and DVs are generally believed to provide a margin of nutritional adequacy above the minimal doses required to prevent the overt and acute symptoms of classical deficiency diseases. In light of the growing genetic, molecular, and bio© 1999 Harcourt Brace & Co. Ltd
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chemical evidence on the molecular roles of vitamins and other micronutrients, the RDAs may be seriously inadequate guidelines for health. By accounting for the differences among people only in terms of weight, age, and sex, the RDAs remain an anachronistic and simplistic standard. The concept of biochemical individuality, described at length in 1956, challenged the validity of the RDAs and other broad population-based standards for nutrient intake. It was based on a large body of anatomical, physiological, biochemical, and genetic data showing substantial differences in the quantitative requirements of nutrients, even among species with strong genetic similarities (33). Subsequent research has confirmed widespread genetic individuality in terms of human nutritional requirements. As but one illustration, one in seven Irish women possesses a genetic defect interfering with folic acid utilitization. Based on this finding with one nutrient and one gene, the researchers identifying this trait argued that there is no ‘normal’ population on which to base nutritional recommendations (34). Indeed, with dozens of essential nutrients and thousands of conceivable genetic defects (inborn or acquired), it is likely that many people have elevated genetic requirements for many micronutrients. THE DYNAMIC NATURE OF NUTRITIONAL REQUIREMENTS Although many nutrient requirements are defined by genetics, they also fluctuate in response to environmental changes. For example, excessive free radicals lead to oxidative stress and disrupt the steady state, i.e. the relative metabolic balance between free radicals and antioxidants, and accelerate cell damage (35). Many factors create oxidative stresses, including exposure to tobacco smoke, air pollution, ultraviolet light, ionic radiation, and malnutrition (including a relative lack of antioxidant nutrients). The impact of these stresses, even mild oxidative stresses, is profound and can cause aberrations in bioenergetics, such as decreases in nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP) and damage to DNA (36,37). Oxidative stresses are rarely if ever constant, suggesting that a person’s need for antioxidants and other nutrients fluctuates daily and perhaps even more frequently (34). For example, the acute phase response (which occurs when a person responds to trauma, inflammation, infection, or chronic disease) results in a decrease in plasma levels of carotenoids, including lycopene, alpha-carotene, and beta-carotene (38). Changes in a person’s immediate environment, such as heat, cold, and high-altitude exposure, also increase oxidative stress and antioxidant requirements (39). Medical Hypotheses (1999) 52(5), 417–422
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Unless remedied, oxidative stresses can have a cumulative effect and aggravate many diseases, including atherosclerosis, cancer, rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative diseases (40). Very severe stresses, such as sepsis, also increase systemic oxidation, resulting in decreased body levels of antioxidants (41). Indeed, there is extensive evidence that oxidative stress is a major cause of aging (42). However, antioxidant supplements reduce oxidative stress, ameliorate disease, and increase life-expectancy (43).
Similarly, low levels of coenzyme Q10, essential for mitochondrial electron transfer and production of adenosine triphosphate (ATP, energy) are a cause of cardiomyopathy. Substantial evidence indicates that supplemental coenzyme Q10 restores normal levels of coenzyme Q10, increases the electron gradient in bioenergetics, and normalizes heart function. Although the use of coenzyme Q10 in these circumstances might be viewed as therapeutic, it actually compensates for an inborn or acquired defect in bioenergetics (29).
DIETARY VERSUS PHARMACOLOGICAL LEVELS OF NUTRIENTS
MEASUREMENTS OF SUBTLE NUTRIENT DEFICIENCES
Discussions of supra-RDA nutrient requirements often lead to controversy about whether high, or so-called optimal, supplemental doses are nutritional or pharmacological (drug-like) in effect. This controversy should also be resolved in the proposed third vitamin paradigm. It is proposed here that the distinction between nutritional and pharmacological levels of nutrients is artificial and has little meaning in the context of biochemical individuality or molecular biology. So-called pharmacological doses may simply compensate for genetic defects, or environmental stresses. For example, the current adult RDA for vitamin C is 60 mg daily. For tobacco users, it is 100 mg daily (44). The higher amount is not pharmacologic; rather, it is a compensatory dose meant to offset some of the oxidative stress suffered by smokers. Similarly, consuming 1000–6000 mg of vitamin C daily to reduce symptoms of the common cold is often considered a pharmacologic dose, but it is similarly a compensatory dose intended to restore the steady state, which was disrupted by the infection (7). Rather than use the confusing terminology of nutritional or therapeutic doses, it is suggested that the optimal dose (whatever it is) be considered the effective metabolic dose, i.e. the one that helps a person maintain a steady state. Two examples will further clarify the meaning of compensatory or effective metabolic doses. Vitamin E requirements increase with a higher consumption of polyunsaturated fatty acids (PUFAs). The vitamin reduces oxidation of the PUFAs (45), and the high modern consumption of PUFAs through fried foods (e.g. French fries) and refined oils (e.g. salad dressings) has likely increased vitamin E requirements. However, food refining has reduced the amount of vitamin E in the diet. Researchers recently reported that 400–800 IU of vitamin E reduced the incidence of nonfatal myocardial infarct by 77%. These doses are believed to minimize the atherogenic oxidation of low-density lipoproteins (6). Rather than being pharmacological, these high doses of vitamin E might actually be compensating for modern high-PUFA diets.
The routine measurement of optimal nutrient levels is within the grasp of current and emerging technologies, although these technologies are not frequently applied in medicine. In contrast to earlier periods of vitamin research, the effects of inadequate micronutrient levels can now be identified and measured on molecular levels and biochemically by how they interfere with cell function (rather than by simple nutrient levels) (34). Oxidative stress can be measured through a variety of techniques, including thiobarbituric acid-reactive substances (TBARSs), lipid peroxidation, and malondialdehyde in the serum (35). Serum homocysteine levels are far a more accurate indicator of folic acid utilization than are serum folate levels pe se (34). Glycosylated proteins can also be measured as a marker of cell damage and the aging process (46). Recently, a new method has been developed to identify precancerous damage to DNA at a time when antioxidant supplementation could retard or reverse the damage (47).
Medical Hypotheses (1999) 52(5), 417–422
CONCLUSION When vitamins were first discovered, the molecular basis of disease was largely unimaginable because DNA had not yet been discovered. Today, cell and molecular biologists are rapidly discovering the details of how vitamins and many other nutrients maintain the integrity of DNA, proteins, and lipids. Diseases emanate from cell damage and dysfunction to physiological symptoms, not vice versa. Furthermore, cell and molecular biology provides us with a window to the important roles carotenoids, flavonoids, and nutrient/metabolites play in reducing the risk of disease and in slowing the aging process. The current RDAs and similar standards do not reflect these significant findings and, in fact, represent the state of knowledge 50–80 years ago. Indeed, the latest US Food and Drug Administration dietary standard, the daily value (DV), is based on the 1968 RDAs – as if no research has been conducted since that date (48). Although the second vitamin paradigm remains medi© 1999 Harcourt Brace & Co. Ltd
Toward a new definition of essential nutrients
cally controversial, molecular and cell biologists have already established a sound scientific basis for it. As a result, it is becoming clear that all we are physically, and much of what are mentally and emotionally, has roots in the interplay of genetics and our nutritional environment: for diet is the ultimate source of the molecules genes use to construct the body’s biochemicals. Furthermore, there is evidence that nutritional requirements vary greatly among individuals, appear to be higher than often believed, and may fluctuate greatly within an individual. This paper is intended to encourage thinking toward a new, broader, and more rational view of essential nutrients. The new paradigm described would extend the definition of essential nutrients by recognizing the important molecular roles of many carotenoids, flavonoids, as well as human metabolites when found in food. It would also recognize the highly variable and dynamic nutritional requirements of individuals. ACKNOWLEDGMENT The author wishes to thank Rodney L. Ausich, James P. Clark, Richard P. Huemer, Richard Kunin, Cynthia Schweitzer, and John Thoreson for their roles in helping me refine the ideas in this paper.
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© 1999 Harcourt Brace & Co. Ltd
Toward a new definition of essential nutrients: is it now time for a third ‘vitamin’ paradigm? J. J. Challem Aloha, Oregon, USA
Summary The concepts of vitamin ‘deficiency’ diseases and the recommended dietary allowances (RDAs) have not kept pace with the growing understanding of the cellular and molecular functions of vitamins and other micronutrients. As a consequence, many researchers and clinicians rely on outdated signs and symptoms in assessing nutritional deficiencies. A new paradigm, presented here, proposes that: (1) deficiencies can be identified on biochemical and molecular levels long before they become clinically visible; (2) the definition of essential micronutrients be broadened to include some carotenoids and flavonoids, as well as various human metabolites, such as coenzyme Q10, carnitine, and alpha-lipoic acid, which are also dietary constituents; (4) individual nutritional requirements are partly fixed by genetics but also dynamically influenced by variations in the body’s biochemical milieu and external stresses; and (5) the distinction between nutritional and pharmacological doses of vitamins is meaningless, since high doses of micronutrients may be required to achieve normal metabolic processes in some people.
INTRODUCTION A number of researchers, from the 1930s through the present, have questioned the validity of the original concept of vitamins and minerals as micronutrients that prevent only ‘deficiency’ diseases, such as scurvy or beri-beri (1,2). The most widespread expression of this first vitamin paradigm can be found in the recommended dietary allowances (RDAs), described as being ‘adequate to meet the known nutrient needs of practically all healthy persons’ (3). However, the RDAs may have limited relevance because 45% of non-institutionalized Americans (~100 million) suffer from at least one chronic diseases (4), and large numbers of people apparently consume nutritionally inadequate diets (5). In contrast to the RDA-based perception of vitamin requirements, many studies have demonstrated that supra-RDA levels of micronutrients, such as vitamins C and E, can prevent and treat of a wide variety of diseases (6,7). To create a broader context for the different views of vitamins, some researchers have defined historical
Received 3 September 1997 Accepted 15 October 1997 Correspondence to: PO Box 5505, Aloha, OR 97006, USA E-mail: [email protected]
periods or paradigms with distinctive views of micronutrients. As knowledge about the roles of micronutrients increases, we must adapt our views accordingly. This paper briefly reviews previous paradigms and proposes a new way of thinking about vitamins and other micronutrients, i.e. a third paradigm (Table 1). THE FIRST AND SECOND VITAMIN PARADIGMS Since the early part of the 20th century, many vitamins have been recognized as essential nutrients. In the first paradigm, which came about immediately after the discovery of vitamins, researchers and clinicians concluded that these micronutrients were required in relatively small amounts from the diet to prevent classical deficiency diseases, such as scurvy, beri-beri, pellagra, and pernicious anemia. At that time, circa 80 years ago, the diagnosis of vitamin-deficiency diseases was based on easily observed signs and symptoms, such as hemorrhaging in scurvy and paralysis in beri-beri (8). Today, this archaic method of diagnosis remains the only one (other than simple blood tests) generally accepted by physicians and dietitians for recognizing vitamin deficiencies. It fails to recognize that classical deficiency diseases are advanced (not early) signs of malnutrition (9). Hence, vitamin deficiences are believed rare. 417
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Table 1 Three micronutrient paradigms
First paradigm Á Vitamins prevent classical deficiency diseases. Á Vitamins are obtained from foods, not produced in body. Second paradigm Á Strives for orthomolecular, or optimal, molecular/cellular levels of micronutrients. Á Recognizes biochemical individuality and variations in vitamin requirements. Á Micronutrients used to treat diseases not recognized as traditional vitamin-deficiency states. Third paradigm Á Builds on the second paradigm, embracing an understanding of the cellular and molecular roles of nutrients. Á Proposes that many ‘nonessential’ nutrients actually optimize molecular performance. Á Proposes that many metabolites may also be essential dietary constituents. Á Recognizes nutritional requirements both genetically defined and highly dynamic. Á Recognizes technologies can now measure molecular signs of deficiencies. Á Uses supplements toward achieving optimal molecular environment in cells and minimizing age-associated DNA damage.
In contrast, the second vitamin paradigm recognizes that vitamin supplements can be used to treat diseases not recognized as classical deficiency diseases (10,11). The beginning of this paradigm has been placed at 1955, when the US Food and Drug Administration permitted the use of niacin to lower serum cholesterol levels. However, its origins can be traced to scientific discussions of optimal nutrition in the 1930s (1). In the 1940s and 1950s, the benefits of optimal nutrient intake were demonstrated through therapeutic intervention in heart disease (12), infectious diseases (13), and schizophrenia (14). The concept of optimal nutrition was subsequently refined as a molecular theory of medicine and described as ‘orthomolecular’ psychiatry (and, by implication, orthomolecular medicine) in 1968 (15). Orthomolecular medicine, rooted in molecular biology and molecular medicine, recommended the use of molecules normally present in human biochemistry to correct metabolic defects and achieve optimal health. The evidence for the second nutritional paradigm (that of orthomolecular medicine), based on cell and molecular biology, is compelling and too extensive to cite here (16–17). Despite the current popularity of molecular biology and genetic research, the concept of optimizing nutrients on a molecular level has remained controversial and has not generally been put into practice by the medical profession. It is proposed here that the continued dominance of the first paradigm and the ongoing controversy surrounding the second paradigm stems, at least in part, from a fundamental clinical error: the failure to recognize the cellular Medical Hypotheses (1999) 52(5), 417–422
and molecular and, therefore, the earliest and most basic signs of vitamin deficiencies. Left untreated, severe deficiencies might become acute after months, whereas more subtle (subclinical) deficiencies would damage deoxyribonucleic acid (DNA), proteins, enzymes, lipids, and mitochondrial bioenergetics, and only after many decades become manifest as degenerative diseases. EXPANDING THE CONCEPT OF ESSENTIAL NUTRIENTS The idea that signs of nutrient deficiencies may not always be visible to the naked eye, or readily identifiable through blood tests, sets the stage for the proposed new paradigm. This is not strictly a vitamin paradigm; rather, it should enlarge the concept of what is an essential micronutrient. The best way of elucidating this paradigm is to contrast it with the previous ones. In the first paradigm, essential nutrients are generally defined as those that the body does not manufacture, must be obtained from the diet, and the absence of which results in deficiency symptoms (18). Held to the first paradigm, carotenoids and flavonoids are not produced by the body, and their dietary deficiencies result in no clinically acute or obvious symptoms; therefore, they cannot be essential. Held to the second paradigm, many carotenoids and flavonoids are increasingly considered beneficial but not essential for health. In this view, carotenoids and flavonoids are no more than discretionary nutrients. As in the case of vitamins, researchers and clinicians may be looking at incorrect signs and symptoms in assessing deficiencies of carotenoids and flavonoids. For example, a deficiency of the carotenoid lutein has no acute symptoms; however, it appears that long-term deficiency results in macular degeneration, the leading cause of blindness among the elderly in the USA and the UK (19). Cell and molecular biology studies of many carotenoids and flavonoids have identified some of the detailed mechanisms and have confirmed that they play key regulatory roles in cells and protect them from oxidative damage (20,21). Indeed, some carotenoids and flavonoids function as antioxidants and influence gene expression (21) and repair (22). Instead of immediate and visible symptoms of a deficiency, there is evidence that inadequate intake of these nutrients permits excessive DNA damage over many years, becoming visible as cancer or heart disease after many years. Epidemiological and experimental studies suggest that these nutrients reduce the risk of cancer and heart disease (23,24) and, as in the case of lutein and macular degeneration, these degenerative diseases might be considered deficiency diseases. A further argument in favor of the essentiality of many © 1999 Harcourt Brace & Co. Ltd
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carotenoids and flavonoids can be made in view of their likely roles in the evolution of Homo sapiens. The genetic and, therefore, nutritional requirements of H. sapiens have been shaped by millions of years of mammalian, primate, and hominid evolution. Although our genetic requirements are virtually the same as those of Paleolithic humans, the modern diet provides fewer micronutrients and is substantially different in composition from the diet of 15 000 years ago (25,26). It is likely, since our genetic ancestors ate large quantities of plant foods, that carotenoids and flavonoids (and other phytonutrients) were among the nutrients they depended on for survival (27). METABOLITES AS ESSENTIAL NUTRIENTS The proposed third paradigm should also recognize that many metabolites – including choline, inositol, coenzyme Q10, carnitine, and alpha-lipoic acid – may be essential nutrients. These substances are not currently recognized as essential nutrients because the body can manufacture them. However, there is evidence that the body may not always manufacture them efficiently or in sufficient quantities. For example, coenzyme Q10 levels decrease with age and are abnormally low among people with cancer and heart disease (28,29). It is possible that endogenous production does not by itself satisfy an animal’s requirements for such substances (30). Just as supplemental vitamin C can increase the lifespan of mice (for which ascorbate is a metabolite) (31), dietary or supplemental sources of human metabolites may be very important to health, particularly when endogenous manufacture is inefficient (29). Given the demonstrated therapeutic effects of these nutrient/metabolites, such as coenzyme Q10 and alpha-lipoic acid, it appears that supplements can compensate for dietary deficiencies or metabolic defects and correct disease processes (28,32). A NEW VIEW OF ADEQUACY The predecessor to today’s recommended dietary allowances (RDAs) was conceived in 1941, during World War II – a time when classical vitamin-deficiency diseases were still relatively common in the USA. Its original objective was to provide a ‘guide for advising “on nutrition problems in connection with national defense’’ ’ (3). Since then, the minimum daily requirements (MDRs), RDAs, reference dietary intakes (RDIs), and daily values (DVs) have formed the basis of much of the USA’s peacetime public nutrition policy. The RDAs, RDIs, and DVs are generally believed to provide a margin of nutritional adequacy above the minimal doses required to prevent the overt and acute symptoms of classical deficiency diseases. In light of the growing genetic, molecular, and bio© 1999 Harcourt Brace & Co. Ltd
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chemical evidence on the molecular roles of vitamins and other micronutrients, the RDAs may be seriously inadequate guidelines for health. By accounting for the differences among people only in terms of weight, age, and sex, the RDAs remain an anachronistic and simplistic standard. The concept of biochemical individuality, described at length in 1956, challenged the validity of the RDAs and other broad population-based standards for nutrient intake. It was based on a large body of anatomical, physiological, biochemical, and genetic data showing substantial differences in the quantitative requirements of nutrients, even among species with strong genetic similarities (33). Subsequent research has confirmed widespread genetic individuality in terms of human nutritional requirements. As but one illustration, one in seven Irish women possesses a genetic defect interfering with folic acid utilitization. Based on this finding with one nutrient and one gene, the researchers identifying this trait argued that there is no ‘normal’ population on which to base nutritional recommendations (34). Indeed, with dozens of essential nutrients and thousands of conceivable genetic defects (inborn or acquired), it is likely that many people have elevated genetic requirements for many micronutrients. THE DYNAMIC NATURE OF NUTRITIONAL REQUIREMENTS Although many nutrient requirements are defined by genetics, they also fluctuate in response to environmental changes. For example, excessive free radicals lead to oxidative stress and disrupt the steady state, i.e. the relative metabolic balance between free radicals and antioxidants, and accelerate cell damage (35). Many factors create oxidative stresses, including exposure to tobacco smoke, air pollution, ultraviolet light, ionic radiation, and malnutrition (including a relative lack of antioxidant nutrients). The impact of these stresses, even mild oxidative stresses, is profound and can cause aberrations in bioenergetics, such as decreases in nicotinamide adenine dinucleotide (NAD) and adenosine triphosphate (ATP) and damage to DNA (36,37). Oxidative stresses are rarely if ever constant, suggesting that a person’s need for antioxidants and other nutrients fluctuates daily and perhaps even more frequently (34). For example, the acute phase response (which occurs when a person responds to trauma, inflammation, infection, or chronic disease) results in a decrease in plasma levels of carotenoids, including lycopene, alpha-carotene, and beta-carotene (38). Changes in a person’s immediate environment, such as heat, cold, and high-altitude exposure, also increase oxidative stress and antioxidant requirements (39). Medical Hypotheses (1999) 52(5), 417–422
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Unless remedied, oxidative stresses can have a cumulative effect and aggravate many diseases, including atherosclerosis, cancer, rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative diseases (40). Very severe stresses, such as sepsis, also increase systemic oxidation, resulting in decreased body levels of antioxidants (41). Indeed, there is extensive evidence that oxidative stress is a major cause of aging (42). However, antioxidant supplements reduce oxidative stress, ameliorate disease, and increase life-expectancy (43).
Similarly, low levels of coenzyme Q10, essential for mitochondrial electron transfer and production of adenosine triphosphate (ATP, energy) are a cause of cardiomyopathy. Substantial evidence indicates that supplemental coenzyme Q10 restores normal levels of coenzyme Q10, increases the electron gradient in bioenergetics, and normalizes heart function. Although the use of coenzyme Q10 in these circumstances might be viewed as therapeutic, it actually compensates for an inborn or acquired defect in bioenergetics (29).
DIETARY VERSUS PHARMACOLOGICAL LEVELS OF NUTRIENTS
MEASUREMENTS OF SUBTLE NUTRIENT DEFICIENCES
Discussions of supra-RDA nutrient requirements often lead to controversy about whether high, or so-called optimal, supplemental doses are nutritional or pharmacological (drug-like) in effect. This controversy should also be resolved in the proposed third vitamin paradigm. It is proposed here that the distinction between nutritional and pharmacological levels of nutrients is artificial and has little meaning in the context of biochemical individuality or molecular biology. So-called pharmacological doses may simply compensate for genetic defects, or environmental stresses. For example, the current adult RDA for vitamin C is 60 mg daily. For tobacco users, it is 100 mg daily (44). The higher amount is not pharmacologic; rather, it is a compensatory dose meant to offset some of the oxidative stress suffered by smokers. Similarly, consuming 1000–6000 mg of vitamin C daily to reduce symptoms of the common cold is often considered a pharmacologic dose, but it is similarly a compensatory dose intended to restore the steady state, which was disrupted by the infection (7). Rather than use the confusing terminology of nutritional or therapeutic doses, it is suggested that the optimal dose (whatever it is) be considered the effective metabolic dose, i.e. the one that helps a person maintain a steady state. Two examples will further clarify the meaning of compensatory or effective metabolic doses. Vitamin E requirements increase with a higher consumption of polyunsaturated fatty acids (PUFAs). The vitamin reduces oxidation of the PUFAs (45), and the high modern consumption of PUFAs through fried foods (e.g. French fries) and refined oils (e.g. salad dressings) has likely increased vitamin E requirements. However, food refining has reduced the amount of vitamin E in the diet. Researchers recently reported that 400–800 IU of vitamin E reduced the incidence of nonfatal myocardial infarct by 77%. These doses are believed to minimize the atherogenic oxidation of low-density lipoproteins (6). Rather than being pharmacological, these high doses of vitamin E might actually be compensating for modern high-PUFA diets.
The routine measurement of optimal nutrient levels is within the grasp of current and emerging technologies, although these technologies are not frequently applied in medicine. In contrast to earlier periods of vitamin research, the effects of inadequate micronutrient levels can now be identified and measured on molecular levels and biochemically by how they interfere with cell function (rather than by simple nutrient levels) (34). Oxidative stress can be measured through a variety of techniques, including thiobarbituric acid-reactive substances (TBARSs), lipid peroxidation, and malondialdehyde in the serum (35). Serum homocysteine levels are far a more accurate indicator of folic acid utilization than are serum folate levels pe se (34). Glycosylated proteins can also be measured as a marker of cell damage and the aging process (46). Recently, a new method has been developed to identify precancerous damage to DNA at a time when antioxidant supplementation could retard or reverse the damage (47).
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CONCLUSION When vitamins were first discovered, the molecular basis of disease was largely unimaginable because DNA had not yet been discovered. Today, cell and molecular biologists are rapidly discovering the details of how vitamins and many other nutrients maintain the integrity of DNA, proteins, and lipids. Diseases emanate from cell damage and dysfunction to physiological symptoms, not vice versa. Furthermore, cell and molecular biology provides us with a window to the important roles carotenoids, flavonoids, and nutrient/metabolites play in reducing the risk of disease and in slowing the aging process. The current RDAs and similar standards do not reflect these significant findings and, in fact, represent the state of knowledge 50–80 years ago. Indeed, the latest US Food and Drug Administration dietary standard, the daily value (DV), is based on the 1968 RDAs – as if no research has been conducted since that date (48). Although the second vitamin paradigm remains medi© 1999 Harcourt Brace & Co. Ltd
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cally controversial, molecular and cell biologists have already established a sound scientific basis for it. As a result, it is becoming clear that all we are physically, and much of what are mentally and emotionally, has roots in the interplay of genetics and our nutritional environment: for diet is the ultimate source of the molecules genes use to construct the body’s biochemicals. Furthermore, there is evidence that nutritional requirements vary greatly among individuals, appear to be higher than often believed, and may fluctuate greatly within an individual. This paper is intended to encourage thinking toward a new, broader, and more rational view of essential nutrients. The new paradigm described would extend the definition of essential nutrients by recognizing the important molecular roles of many carotenoids, flavonoids, as well as human metabolites when found in food. It would also recognize the highly variable and dynamic nutritional requirements of individuals. ACKNOWLEDGMENT The author wishes to thank Rodney L. Ausich, James P. Clark, Richard P. Huemer, Richard Kunin, Cynthia Schweitzer, and John Thoreson for their roles in helping me refine the ideas in this paper.
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