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Metabolic Correction: a Functional Explanation of Orthomolecular Medicine

Metabolic Correction: a Functional Explanation of Orthomolecular Medicine

JOM Volume 27, Number 1, 2012 Viewpoint Article 13

Metabolic Correction: A Functional Explanation of

Michael J. Gonzalez, DSc, PhD, FACN;1 Jorge R. Miranda Massari, PharmD2

1 Corresponding author, University of Puerto Rico, Medical Sciences Campus, RECNAC 2 Project, School of Public , Dept. Human Development, Nutrition Program, GPO Box 365067, San Juan, PR 00936, Email: [email protected]; 2 University of Puerto Rico, Medical Sciences Campus, School of Pharmacy, Dept Pharmacy Practice

Abstract , minerals and other take critical roles in a wide variety of highly complex and integrated cellular processes in human biochemistry. !e rate and extent of the enzy- matic activity that determines these processes depend on the bioavailability of these micronutrients. !e healthy state where optimal (maximum) functioning, health and wellbeing is achieved; may be attained by metabolic optimization. !is state is achieved when we facilitate the to reach full velocity and completion of reactions which can be considered the optimal metabolic equilibrium. A combination of genetic makeup, , trauma, diseases, toxins and environmental stressors among others are conditions that will often elevate the demand of nutrients in order to achieve the optimal metabolic equilibrium. Metabolic Correction is a functional biochemical/physiological concept that explains how improvements in cellular biochemistry help the body achieve metabolic or physiological optimization. Brilliant minds such as Roger J. Williams, Linus C. Pauling, Je"rey Bland and Bruce N. Ames have contributed in a fundamental way to our understanding of the importance of micro- nutrients to attain the healthy state. !e Metabolic Correction concept becomes important since our food is decreasing in nutritional value; diseases increase the demand for nutrients and can deplete nutrients. !ese nutrient insu#ciencies are causing enormous cost due to increased mor- bidity and mortality. In summary, Metabolic Correction increases enzymatic function that enhances biological functions contributing to better health and wellbeing.

Origin of the Problem is commonly ignored and not fully appreci- Maximum or optimal health requires ated is the essential role that various min- metabolic harmony. !e multiplicity of criti- erals play in human biochemistry. Critical cal functions of vitamins, minerals and other enzymes require such metals as copper, zinc, nutrients at the cellular level, and especially manganese, selenium, etc. as an integral part their role as cofactors in enzyme reactions of their molecular structure or mechanism that protect genes from mutations and re- of action. Enzymes play a critical role in pair gene damage is probably unrecognized regulating and orchestrating the rates of the or unappreciated by most health profession- multitude of biochemical reactions that take als. It can be argued that the true impor- place in living organisms. tance of vitamins in human biochemistry is Metabolic nutrition is generally recog- far from fully elucidated, simply due to the nized as the study of how diet and nutri- high complexity of cellular processes. What tion a"ect the body’s metabolism. Nutrition 14 Journal of Orthomolecular Medicine Vol 27, No 1, 2012

in general is a very complex science but its production of immune system components importance is relatively easy to understand. and neurological chemicals. When there is a Aside from starvation there are three levels lack of synergistic components of the meta- of nutrition: poor, fair, and good. Poor nutri- bolic network, an array of negative metabolic tion brings severe underdevelopment to the repercussions arise, eventually leading to loss young as well as de#ciency diseases such as of healthy physiological equilibrium and the beriberi, scurvy, pellagra, rickets, kwashior- acceleration of degenerative diseases. kor and all the ill de#ned combinations and variations of these a$ictions.1 Fair nutrition Metabolic Correction is good enough to prevent the well-de#ned !e Metabolic Correction concept pro- de#ciencies, but not good enough to pro- vides the biochemical elucidation of the mote good health and proper development. utilization of nutrients for preventive and !is mediocre nutrition is unfortunately the therapeutic purposes against disease. Meta- kind which we have been taught to regard as bolic Correction is a functional biochemi- satisfactory.1 Good nutrition is the one that cal/physiological concept that explains how provides not only the needed but high improvements in cellular biochemistry help quality , carbohydrates and fats; in the body achieve metabolic or physiological addition to the necessary vitamins and min- optimization. Impaired or incomplete cellu- erals. !e concept of a balanced diet was de- lar biochemical reactions are amended with veloped to prevent de#ciency diseases based Metabolic Correction. on the knowledge that an appropriate mix- ture of food items will provide the minimum The History of Metabolic Correction requirements of the nutrients needed by the Brilliant and incredibly knowledgeable body. We should be aware that this suppos- pioneers provided the groundbreaking basis edly good nutrition may not be enough for of what we call Metabolic Correction. !eir physiological optimization leading to excel- innovative scienti#c contributions have sub- lent health. We should acknowledge that stantially advanced our understanding of food alone may not provide su%cient micro- molecular nutritional biochemistry, and es- nutrients for preventing de#ciency.2 pecially how it can in&uence the pathological Inadequate dietary intakes of vitamins or disease state. and minerals are widespread, most likely due In 1947, Dr. Roger J. Williams, contrib- to excessive consumption of calorie-rich, nu- uted to the evolution of the molecular origin trient poor, re#ned food. Sub-optimal intake of disease with the development of the con- of micronutrients often accompanies caloric cept of “Biochemical Individuality,” which excess. !ese inadequate intakes may result refers to the di"ering nutritional needs for in metabolic disruptions.3 Episodic short- optimal function among di"erent people.4 ages of micronutrients were common dur- He also described anatomical and physi- ing evolution. Natural selection favours short ological variations among people, and how term (emergency) survival at the expense of these impacted their disease susceptibility long term health.3 Short term survival was and nutritional requirements. achieved by allocating scarce micronutrients “” was a term used by triage.3 As micronutrients become scarce, by two-time Nobel laureate in chemistry and a triage mechanism for allocating scarce mi- peace, Dr. Linus C. Pauling, in his landmark cronutrients is activated. !is triage means, article on the mechanism of the cause of sickle prioritization of the use of relatively scarce nu- cell anaemia published in 1949.5 He de#ned a trients to the most fundamental life preserving new perspective on the origin of disease based functions. In metabolic reactions, enzymes in- upon the recognition that speci#c gene muta- volved in adenosine triphosphate (ATP) syn- tions can create an altered molecular environ- thesis would be favoured over deoxyribonucle- ment, which therefore modi#ed physiological ic acid (DNA) repair enzymes; as well as the function associated with speci#c diseases. Metabolic Correction: A Functional Explanation of Orthomolecular Medicine 15

In 1950, Williams also coined the term ni#cant genetic variability and diseases such “Genetotrophic Disease” to describe dis- as atherosclerosis, , or eases which resulted from genetically deter- depression are associated with speci#c bio- mined nutritional metabolic needs not being chemical abnormalities which are causal or met by the individual, and which result in contributing factors of the illness. 6 poor gene expression. Patients with gene- Dr. Je"rey S. Bland created the concept totrophic conditions have increased needs of “” in 1991, which is of one or more nutrients in order to achieve a form of personalized medicine that deals normal physiologic functioning. !ese con- with primary prevention and underlying ditions respond favourably when enough of causes, rather than only the symptoms, of the required nutrients are provided. Many serious chronic diseases. Functional medi- chronic diseases can be conceived as subtle cine is anchored by an examination of core genetotrophic diseases, as long as nutri- clinical imbalances that underlie various dis- ent supplementation #lls a metabolic need ease conditions. !ose imbalances arise from to improve a patient’s condition. With this environmental inputs, such as diet, nutrients concept, Williams opened the eyes of the (including air and water), toxins, exercise, and research and medical communities that ex- trauma together with a unique set of genetic pression of genes and therefore phenotypic predispositions, attitudes, psychological stress function was modi#able through altered diet and beliefs. !e core clinical imbalances that and nutritional status. He pointed out that arise from malfunctions include: hormonal human biochemical variation in function and neurotransmitter; oxidation-reduction was much greater than nutrition and medi- and mitochondropathy; detoxi#cation and cine recognized prior to his publications. biotransformation; immune; in&ammatory; !e need for essential nutrients, which he digestive, absorptive, and microbiological; referred to as “nutrilites” (i.e., vitamins, es- and structural imbalances from cellular mem- sential amino acids, and essential fatty acids), brane function to the musculoskeletal system. di"ers from the (average) daily amounts rec- Improving balance is the precursor to restor- ommended for the general population. ing health and it involves much more than !e word “Orthomolecular” was intro- treating the symptoms. Functional medicine duced by Pauling in his seminal paper, Or- is dedicated to improving the management 7 thomolecular , published in 1968. of chronic disease by integrating the inter- Pauling de#ned Orthomolecular Psychiatry ventions at multiple levels to address these as the treatment of mental disease by the pro- core clinical imbalances and to restore each vision of the optimum molecular environment patient’s functionality and health. Functional for the mind, especially the optimum concen- medicine is not a unique and separate body trations of substances normally present in the of knowledge. It is grounded in scienti#c body. He later broadened this de#nition to principles and information widely available include other diseases and amended it to “Or- in medicine today, combining research from thomolecular Medicine,” which he de#ned as various disciplines into highly detailed yet the preservation of good health and the treat- clinically relevant models of disease patho- ment of disease by varying the concentrations genesis and e"ective clinical management. in the human body of substances that are Bland published a landmark book in 1999, normally present in the body, and are required Genetic Nutritioneering, in which he explains for health. !e term, “orthomolecular” is used how proper nutrition and supplementation to express the idea of the right molecules in can modify genetic expression to create bet- the right concentration. !e key idea in or- ter health outcomes.8 thomolecular medicine is that genetic factors In 2006, Dr. Bruce N. Ames presented a"ect not only the physical characteristics of his “Triage !eory” of optimal nutrition that individuals, but also their biochemical milieu. states that the human body prioritizes the use Biochemical pathways of the body have sig- of vitamins and minerals when it is getting an 16 Journal of Orthomolecular Medicine Vol 27, No 1, 2012

insu%cient amount of them to be able to keep lem we face is that the nutritional values functioning.3 Triage means deciding which of foods that people eat seem to be greatly patients to treat when faced with limited re- inferior to the listed values given in food ta- sources. When faced with limited nutritional bles. A study that assessed this issue showed resources, the human physiology must decide declines in: protein (-6%), calcium (-16%), which biological functions to prioritize in or- phosphorus (-9%), iron (-15%), ribo&avin der to give the total organism and the species, (-38%), and C (-20%).14 !ere is the best chance to survive and reproduce. a dilution e"ect, in which yield-enhancing While short-term de#ciencies or insu%cien- methods like fertilization and irrigation cies are common, they are often not taken may decrease nutrient concentrations, an seriously by mainstream physicians. Under environmental dilution e"ect. Recently, ev- such limited scenario, the body will always idence has emerged that genetically based direct nutrients toward short-term health and increases in yield may have the same result, survival capability and away from regulation a genetic dilution e"ect. Modern crops that and repair of cellular DNA and that grow larger and faster are not necessarily optimizes health and increases longevity. Dr. able to acquire nutrients at the same, faster Ames’s research shows how bodily insults ac- rate, whether by synthesis or from the soil. cumulated over time as a result of vitamin and Today’s foods are not as nutritious as those insu%ciencies and can lead directly eaten in the past. A report pointed out that to age-related diseases. !e triage hypothesis US and UK Government statistics show a states that the risk of degenerative diseases decline in trace minerals of up to 76% in (associated with aging, including cancer, cog- fruit and vegetables over the period 1940 nitive decline, and immune dysfunction), can to 1991.15 !e nutritional decline #ndings be decreased by ensuring adequate intake of alone give reason to eat organic fruits and micronutrients.3,9-12 vegetables. In fact, for nearly all nutrients, “Metabolic Correction” is a functional organic fruits and vegetables remain the term introduced by Drs. Michael J. Gonza- most nutrient-dense foods. !is informa- lez and Jorge R. Miranda-Massari in 2011 tion makes the updated food pyramid not to explain the mechanism of how nutrients so much current as re&ective of the need for are capable of correcting biochemical dis- an increase in fruits and vegetables in order ruptions that promote the disease state.13 to get the same nutritional bene#ts. Ameri- Metabolic correction embraces all these cans on average do not even come close to previously described biochemical/physi- the recommendations to limit added sugars, ological concepts to explain how improve- re#ned carbohydrates, added fats and oils. ments in cellular biochemistry may help the body achieve metabolic or physiological Adverse side e!ects of and optimization. Metabolic correction inter- iatrogenic deaths venes with impaired biochemical reactions !ere are more than 100,000 deaths that are associated with a lack of well be- annually due to medication properly pre- ing. In other words, metabolic correction scribed and taken as directed.16,17 !e in- is a #ne tuning of the cellular physiology cidence of serious and fatal adverse side to improve function; therefore, preserving e"ects in US hospitals is extremely high, health, preventing tissue damage and re- as they are frequent and more so than gen- verting disease. erally recognized. Fatal adverse side e"ects appear to be the fourth leading cause of Why Metabolic Correction? death in the US. If medication is necessary, Inferior nutritional value of food and providing metabolic correction principles availability of nutrient dense foods may reduce medication requirement, re- We need to eat a wide variety of food to duce adverse side e"ects and improve out- obtain the substances we need. A big prob- come.13 Metabolic Correction: A Functional Explanation of Orthomolecular Medicine 17

Compensate for the increased demand an increase in the substrate concentration. of nutrients due to the disease state !is mechanism of action of gene mutation lead to loss of protein and essential is only one of several that lead to disadvanta- nutrients.18 Surgery increases the need for geous manifestations that could be overcome zinc, and other nutrients involved by an increase in the concentration of en- in cellular-tissue repair.19 Broken bones need zymatic cofactors. !ese binding problems calcium, magnesium and vitamin c for heal- may result in metabolic ine%ciency with the ing.20 Infections challenge the immune sys- accumulation of metabolic by-products. In tem and place high demands on nutritional general, this is the Law of Mass Action as resources such as zinc, B-complex vitamins the vitamin and mineral concentration in- and vitamin C.21 !e same nutritional de- creases, enzyme e%ciency increases. !ese mand is present when exposed to chemi- considerations obviously suggest a rationale cal, physical and emotional stress. Chronic for Metabolic Correction where you provide disease su"erers are at higher risk of inter- the needed cofactors in the amount needed actions between drugs and nutrients. !ere to improve function. !is increased enzyme are thousands of conceivable genetic defects e%ciency may allow a genetic defect to be (inborn or acquired), so it is likely that many overcome. !is biochemical activity follows people have higher genetic requirements for the chemical principle of Le Chatlier, which many micronutrients. We need a better un- states that when stress is applied in an equi- derstanding of the interrelationship between librium situation; it will move to the direc- nutritional biochemistry and the disease- tion to minimize stress. In this case there is pathological state. an unfavourable equilibrium of active en- zyme that with the addition of the neces- Biochemical Mechanism of Metabolic sary nutrients will be moved toward a more Correction: Molecular Concentrations physiologically favourable metabolic state.22 and Rate of Reaction Many human genetic diseases due to de- !e majority of the chemical reactions fective enzymes can be remedied or amelio- that take place in living organisms are cata- rated by the administration of high doses of lyzed by enzymes. !e mechanisms of en- the vitamin component of the correspond- zyme-catalyzed reactions in general involve: ing coenzyme, which can partially restore 9 (1) the formation of a complex between the the enzymatic activity. Several single nucle- enzyme and a substrate, and (2) the break- otide polymorphisms in which the variant down of this complex to form the products reduces coenzyme binding and of the reaction. !e rate determining step thus enzymatic activity can be remedied by is usually the breakdown of the complex to raising cellular concentrations of the cofac- form the products. Under conditions such tor through high dose nutrient therapy. that the concentration of the complex corre- Inadequate intakes of vitamins and min- sponds to equilibrium with the enzyme and erals from food can lead to DNA damage, 3 the substrate, the rate of the reaction is given mitochondrial decay, and other pathologies. by the Michaelis-Menten equation.7 Ames suggests that evolutionary allocation !e rate of an enzyme-catalyzed reac- of scarce micronutrients by enzyme triage is tion is approximately proportional to the an explanation of why DNA damage is com- 3 concentration of the reactant, until concen- monly found on de#ciency. trations that largely saturate the enzyme Also, Motulsky has argued that many of the are reached. !e saturating concentration is common degenerative diseases are the result larger for a defective enzyme with decreased of the imbalance nutritional intake with ge- 23,24 combining power for the substrate than for netically determined needs. the normal enzyme. For such a defective en- As an example, folic acid and vitamin B12 zyme the catalyzed reaction could be made have an important function in the mainte- to take place at or near its normal rate by nance of nuclear and mitochondrial genome 18 Journal of Orthomolecular Medicine Vol 27, No 1, 2012

integrity. Both in vivo and in vitro studies factors and genetics, should tune-up me- with human cells show that de#ciency of tabolism and markedly increase health at a these vitamins causes an array of problems in modest cost, particularly for the poor, obese, the nuclear and mitochondrial DNA which and elderly.10 can be minimized with increased folate and cobalamin concentrations. In order to ac- Ten Principles that Identify the quire the protective e"ect of these vitamins, Concept of Metabolic Correction in they are needed in concentrations that are Disease Therapy obtained at intake levels above the current 1. Metabolic correctors, along with prop- recommended dietary intakes of folate (>400 er nutrition come #rst in medical treatment. 25 µg/day) and vitamin B12 (>2µg/day). Knowledge of the safe and e"ective use of Chromosome breaks lead to mutations the combination of nutrients, enzymes, hor- that precede tissue damage and disease. Many mones, and other naturally occurring mol- types of physiological impairments due to in- ecules in their active forms, is essential to adequacy of vitamins and minerals can lead assure an e"ective outcome. However, some to suboptimal organ-system function in- patients may need more acute treatment for cluding poor drug metabolism, insu%cient their particular condition, for which phar- neurotransmitter production and impaired macological therapy is recommended. immune defences. Chronic vitamin-mineral 2. Metabolic correctors have a low risk undernutrition reduces immune competency of toxicity. Pharmacological drugs always and central nervous system e%ciency; while carry a higher risk and should be the second increases morbidity which may lead to in- choice if there is a metabolic correction al- creases in degenerative diseases. !is approach ternative available. to optimize health by improving enzyme ef- 3. Some laboratory tests might be use- #ciency and thereby metabolism and physiol- ful in identifying the nutritional needs of ogy, is the basis of metabolic correction. some patients these tests may not be read- An example of metabolic correction is ily accessible to all patients or may present that high dose B vitamins can counteract a certain limitations. In addition, some labora- poor Km. As many as one-third of muta- tory tests do not necessarily re&ect nutrient tions in a gene result in the corresponding and enzyme levels within speci#c organs or enzyme having an increased Km (decreased tissues, particularly in the nervous system. binding a%nity) for a coenzyme, causing a For many patients therapeutic trial and dose lower rate of reaction.9,10 About 50 di"er- titration is often the most practical therapy ent human genetic diseases due to a poorer approach, especially when utilizing synergis- binding a%nity of the mutant enzyme for tic metabolic correction formulations. its coenzyme can be remedied by feeding 4. Biochemical individuality is a cen- high dose B vitamins, which raise levels of tral precept of metabolic correction. Hence, the corresponding coenzyme; many poly- the search for optimal nutrient combination morphisms also result in a lowered a%nity doses is a practical issue. Doses of nutrients of enzyme for coenzyme9 and thus may be in and their combinations above the recom- part remediable. mended daily allowances are often e"ective. To summarize, metabolic correction has Many patients tolerate optimal doses and two important biological actions: (1) opti- respond well; however, dose titration is indi- mization of cellular function by improving cated in otherwise unresponsive cases. enzymatic e%ciency, and (2) producing a 5. Recommended daily allowances of pharmacological e"ect to correct abnormal nutrients are intended for normal, healthy cell function due to biochemical disarray people. By de#nition, diseased patients are occasioned by the disease process. An opti- not normal or healthy and not likely to be mum intake of micronutrients and metabo- adequately served by obtaining recommend- lites, which varies with age, environmental ed daily allowances. Practically every person Metabolic Correction: A Functional Explanation of Orthomolecular Medicine 19

is de#cient or insu%cient at some level due Certain individuals have a greater need than to an insu%cient diet. that supplied by the diet (even if on a good 6. Environmental pollution of air, water dietary regime). !is could be caused by di- and food is common. Diagnostic search for gestive problems, malabsorption, food sen- toxic pollutants is justi#ed. sitivities, metabolic dysfunction, low levels 7. Optimal health is a lifetime challenge. in neurotransmitter precursors, etc. !is lack Biochemical needs change and our Metabol- of needed micronutrient cofactors manifests ic Correction prescriptions need to change insidiously and is di% to identify. Some based upon follow-up, repeated testing and vague symptoms, such as lethargy, irritabil- therapeutic trials to permit #ne-tuning of ity, insomnia and di%culty in concentrating, each prescription and to provide a degree of may be present. Also, this a"ects the body’s the best possible health outcome. ability to resist disease and infection, its abil- 8. Nutrient-related disorders are always ity to recover from exercise, surgery, disease, treatable and de#ciencies and insu%ciencies and the ability of the brain to function at an are curable. To ignore their existence is mal- optimal level. Detecting and treating disease practice. at its earliest stages of cellular biochemical 9. Genetic and hereditary disorders are abnormality, rather than waiting for clear often responsive to metabolic correction. clinical symptoms is cost e"ective and of 10. Inspire patients to realize that health bene#t to the patient. Nutrient de#ciency is not merely the absence of disease, but the diseases are the end product of a long and positive attainment of optimal function and complex series of nutrient depletion reac- well-being. !is requires an active role of tions. We need to abandon outdated para- the individual in his lifestyle, and a commit- digms of nutrient intake merely to prevent ment to continuous education along with a de#ciencies and expand them to prevent responsible attitude about health. chronic diseases and achieve optimal health with metabolic correction. Conclusion To encourage the most e%cient metabo- Competing Interests lism, we need the basic macronutrients re- !e authors declare that they have no quired for fuel, fat, protein and carbohydrate. competing interests. But we also need 15 or so vitamins that are co-enzymes and 15 or so minerals that are References required in enzymes, and then we need two 1. Williams RJ: Supernutrition as a strategy for the essential fatty acids, omega-3 and omega-6, control of disease. J Orthomolec Psych, 1972; 1: 98- 103. and also there are seven or eight essential 2. Misner B: Food alone may not provide su%cient amino acids. In addition, other important micronutrients for preventing de#ciency. J Int Soc nutrients, such as coenzyme Q10, acetyl-L- Sports Nutr, 2006; 3: 51-55. carnitine, and lipoic acid, must be considered 3. Ames BN: Low micronutrient intake may accel- in our quest for physiological optimization. erate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc Virtually every metabolic pathway requires Natl Acad Sci USA, 2006; 103: 17589-17594. micronutrients. 4. Williams RJ: Biochemical individuality and its What determines the optimal con- implications. Chem Eng News, 1947; 25: 1112- centration of a nutrient is its physiological 1113. functionality. While most people function 5. Pauling L, Itano H, Singer SJ, et al: Sickle cell anemia, a molecular disease. Science, 1949; 110: below 100% e%ciency, they nevertheless do 543-548. not present with any detectable disease or 6. Williams R: Concept of genetotrophic disease. obvious (i.e., signi#cant symptoms), yet we Nutr Rev, 1950, 8: 257-260. can improve their functionality if we sup- 7. Pauling L: Orthomolecular psychiatry. Varying ply them with the needed micronutrient the concentrations of substances normally present in the human body may control mental disease. substances in the optimum concentrations. 20 Journal of Orthomolecular Medicine Vol 27, No 1, 2012

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