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The Role of Supplements in Integrative Preventive Medicine 

The Role of Supplements in Integrative Preventive Medicine
The Role of Supplements in Integrative Preventive Medicine
Integrative Preventive Medicine

Joseph Pizzorno



Considering the human species has survived solely on the nutrients available in food, a strong case could be made that additional nutritional support is unnecessary. This might be true in an ideal world, composed of healthy humans with uniform biochemistry, living in a clean environment. However, such a world does not exist. Our diet has been mutated to include foods that contain an inherently lower ratio of nutrients in proportion to calories.1,2 Foods are now produced through modern agricultural methods resulting in decreased nutrient content.3 Food processing damages and even removes nutrients,4,5,6 and the standards used to determine nutrient adequacy are seriously flawed. More importantly, genetic research has revealed huge variations in individual nutrient needs within the general population. Aggravating the situation is the growing body load of environmental toxins that poison enzyme systems. This requires higher than normal levels of nutrients to compete for enzyme activation sites and help prevent oxidative and metabolic damage caused by these toxins. The World Health Organization (WHO) already includes recommendations for several micronutrients including iron + folic acid supplements for pregnancy,7 high-dose vitamin A supplementation for children <5 years,8 food fortification, and universal salt iodization.9,10 However, gaps still exist in micronutrient recommendations for several population groups.11 Many studies have shown that nutrients in supraphysiological dosages can be very effective therapeutic agents. In this context, maintaining and optimizing health depends on skilled nutritional supplementation.

The Incidence of Nutrient Deficiencies

The measures used to determine deficiency constitute a huge and controversial challenge in determining nutrient status. The NHANES (National Health and Nutrition Examination Survey) regularly assess the health and nutritional status of adults and children in the United States. Comprehensive nutritional reports are provided periodically, the latest of which was published in 2012. Table 12.1 shows the portion of the population deficient in selected nutrients according to the standards used in NHANES (which, as shown later, may be problematic). Note especially that these numbers include the use of dietary supplements. In other words, despite the fact that 50% of the population regularly takes nutritional supplements, many deficiencies still exist.12

Table 12.1 Percent of US Adults Deficient in Select Nutrients



Vitamin B6


Iron (women)


Vitamin D


Vitamin C


Vitamin B12


Vitamin A


Vitamin E




Source: Reference 13.

Although the data may suggest nutrient deficiencies are uncommon, the standards for nutrient status have substantial problems. For example, nutrient deficiencies are much more common in patients with chronic disease. A recent review of patients with heart failure found that 75% were deficient in vitamin D and 37% deficient in iron.14 Researchers also found studies showing supplementation with coenzyme Q10, vitamin D, iron, and L-carnitine improved clinical outcomes. Although unpublished, in a corporate wellness program I helped design and implement laboratory tests (serum levels) assessing several nutritional measures in 4,500 adult Canadian oil field workers showed that 90% were deficient in one or more nutrients.

A disease-by-disease review of nutrient deficiencies is beyond the scope of this chapter. Those interested in more deeply delving into this clinically important topic will find thousands of references in the Textbook of Natural Medicine, which evaluates nutrient status and the efficacy of nutrient supplementation in over 70 of the most common diseases. Table 12.2 provides a brief list of the typical nutrient deficiencies observed in representative diseases.

Table 12.2 Nutrient Deficiencies in Representative Diseases


Deficient Vitamins

Deficient Minerals

Deficient Nutrient Factors


Vitamin C, omega-3 fatty acids


Omega-3 fatty acids

Iron, magnesium, zinc

Cervical dysplasia

Folate, vitamin A, vitamin B6, vitamin C

Copper, zinc


Diabetes Type I

Vitamin D, omega-3 fatty acids

Heart failure

Vitamin B1



Vitamin D, vitamin K2

Calcium, magnesium

Source: Reference 15.

Foods of Commerce Now Contain Lower Levels of Nutrients

Agriculture precipitated the formation of cities resulting in civilization, and modern agricultural technology allowed growth of the human population. However, the effects on food quality have not all been beneficial. The nutrient content of conventionally grown foods has decreased precipitously. Modern agricultural methods produce food that is bigger and grows faster but is lower in nutrients. One study measured the mineral content of 56 commonly eaten foods—27 vegetables, 17 fruits, 10 meats, and 2 dairy products—from 1940 to 1991. As can be seen in Figure 12.1, every mineral, except phosphorus in fruits and vegetables (from high-phosphate fertilizers) and sodium in dairy (added salt), decreased significantly.16 Trace minerals showed the worst effects, with copper down a serious 77% in vegetables. The longest study evaluated the trace mineral content of 14 varieties of US wheat over a period of 122 years. Every mineral decreased 20%–33%.17 Unfortunately, the foods that the average American consumes are truly depleted of nutrients.

Figure 12.1 Content of Trace Minerals Decreased from 1940 to 1991

Figure 12.1 Content of Trace Minerals Decreased from 1940 to 1991

The cause of this mineral loss appears to be the result of three factors: (1) change in cultivars; (2) depletion of soil mineral content after decades of synthetic fertilizer use; and (3) high-phosphate fertilizers that cause foods to grow bigger but dilute their nutrient content. Figure 12.2 shows the impact of fertilization on the mineral content of raspberries. As can clearly be seen, the use of high-phosphate fertilizers proportionately decreases mineral content.18 Higher water content in conventionally grown foods leads to nutrient dilution. While the foods still provide calories, the nutrients critical for health are depleted. Several studies have shown the amounts of beneficial constituents are higher in organically grown foods compared to those grown with conventional agriculture practices.19,20,21 Speaking subjectively, the raspberries from my garden have dramatically more flavor than those bought at the grocery store. Considering the majority of people consume foods produced by conventional agricultural practices, an argument can easily be made showing the need for nutritional supplementation.

Figure 12.2 Increasing Use of High Phosphate Fertilizers Decreases Mineral Content

Figure 12.2 Increasing Use of High Phosphate Fertilizers Decreases Mineral Content

Nutrient Standards Do Not Adequately Address Biochemical Individuality

In 1941, the Food and Nutrition Board, a committee of the National Academy of Sciences, developed recommendations on the amount of essential nutrients that should be provided to the general public. This would come to be known as the recommended dietary allowances (RDAs). The guidelines were developed for the prevention of nutrient deficiency diseases (e.g., scurvy: deficiency of vitamin C, pellagra: deficiency of niacin, and beri-beri: deficiency of vitamin B1) and to serve as a guide for planning adequate nutrition. The RDAs were designed for the maintenance of good nutrition of normal healthy persons under present conditions in the United States.22 However, considering there is an almost universally sick population, normal may not actually be healthy. It is estimated that over 50% of the US population now suffers from one or more diagnosed chronic diseases, and 25% of the population has two or more chronic conditions. In addition, at least 16% of the population describe themselves as chronically unwell.23

Studies have now shown that it is inappropriate to use the RDA to assess the nutrient adequacy of groups.24 Box 12.1 lists several limitations of the RDAs.

In 1997, the dietary reference intake (DRI) was introduced to expand on the guidelines of the RDAs. The DRI includes several sets of values for nutrient intake: the RDA—(the daily dietary intake level of a nutrient considered sufficient by the Food and Nutrition Board to meet the requirements of 97.5% of healthy individuals); estimated average requirements (EAR—based on a review of scientific literature, these values are expected to satisfy the needs of 50% of the people in an age group); and adequate intake (AI—when an RDA cannot be determined, this is the recommended average daily intake level based on observed or experimentally determined approximations of nutrient intake by apparently healthy people that are assumed to be sufficient for everyone in the demographic group).25 In addition, the DRI includes a set of values known as tolerable upper intake levels (ULs). The UL is the maximum amount of a nutrient that appears safe for 97.5% of healthy individuals. Although more information is provided, the DRI has similar limitations to the RDA alone. Neither the DRI nor the RDA addresses biochemical individuality, and neither has the ability to provide specific recommendations for individuals seeking a long and disease-free lifespan. As knowledge of genetic variability in nutrient needs for health promotion and disease prevention arises, a greater case can be made for an individual’s need for supplementation of nutrients above the RDAs and RDIs.

Serum levels for several vitamins and minerals may not always be sufficient in assessing vitamin and mineral deficiencies. The latest NHANES report is an improvement from the prior report as a number of biochemical markers of nutrient deficiency were added to the assessment rather than just blood levels of nutrients. As seen in Figure 12.3, an entirely different picture is presented when these markers are included. While only 4% of the older population show deficient levels of vitamin B12 according to serum levels alone, when including the metabolites that increase when vitamin B12 is deficient—such as methylmelonic acid and homocysteine—the number quadruples to 17%–19%.26

Figure 12.3 Incidence of Nutrient Level Deficiency Versus Nutrient Deficiency According to Function

Figure 12.3 Incidence of Nutrient Level Deficiency Versus Nutrient Deficiency According to Function

Now that so many of the human single nucleotide polymorphisms (SNPs) have been mapped, the way genetics affect nutritional needs is much better understood. Three examples out of many that are available—VDR, MTHFR, and COMT polymorphisms—clearly document the need for nutritional supplements.

VDR Polymorphisms

The vitamin D receptor site gene has six known polymorphisms with well-researched clinical effects: Apa1 (A/a), Bsml (B/b), Cdx-2, Fok1 (F/f), and Taq1 (T/t). These polymorphisms have multiple effects, most mediated by decreased absorption of vitamin D or impaired ability to bind to and activate cell receptor sites. The clinical impact is huge. In cancer, for example, compared to “wild types”:27

  • Cdx2: 12% increased risk of all cancers

  • Taq1: 43% increased risk of colon cancer

  • Apa1: increased cancer risk, but only when in combination with other polymorphisms

Many other disease associations with VDR polymorphisms include breast cancer, prostate cancer, pancreatic cancer, cancer metastases, multiple sclerosis, osteoporosis, Parkinson’s disease—the list continues to increase as research accumulates.28,29 For these patients, high-dose vitamin D supplementation is essentially the only solution.30,31,32

A patient example is illustrative. A 50-year-old perimenopausal woman (normal weight) presented with osteopenia. Physical examination was normal. Diet and lifestyle were exemplary. Of particular relevance was a family history of every woman in her family dying from complications of osteoporosis, typically broken hips. Standard treatment with bioidentical estrogen, vitamin D (1,500 IU/d) and calcium (1,200 mg/d) for 3.5 years was ineffective, with bone loss progressing unabated. An SNP panel revealed she had several of the undesirable VDR polymorphisms. The patient was then given progressively larger dosages of vitamin D, eventually reaching 12,000 IU per day—far beyond RDIs. Other than additional supplementation with vitamin K2, no changes were made in diet, lifestyle, prescriptions, or nutrients. As can be seen in Figure 12.4, her DEXXA results were remarkable. The vitamin D dosage was determined by progressively increasing supplementation until her 25-OH3 was 50 ng/mL.

Figure 12.4 DEXA Response to High Dose Vitamin D in Patient with Dysfunctional VDR Receptor Site Polymorphisms

Figure 12.4 DEXA Response to High Dose Vitamin D in Patient with Dysfunctional VDR Receptor Site Polymorphisms

MTHFR Polymorphisms

Polymorphisms in methylenetetrahydrofolate reductase (MTHFR), the enzyme that converts dietary folate to its active physiological form, have been extensively studied. Several polymorphisms have been shown to increase rates of cancers such as leukemia and squamous cell carcinoma with stronger associations found in cardiovascular disease.33,34 These polymorphisms are extremely common, affecting 29%–42% of the population, depending on ethnicity.35 Effective intervention for such polymorphisms requires activated forms of folate that are not possible through food.36,37,38 Low folate levels have been found in many patients with depression. In a trial of nearly 3,000 participants, low RBC and/or serum folate was found in patients who met the criteria for major depression.39 Polymorphisms in the MTHFR gene, in particular the C677T polymorphism, have been reported to influence depression risk.40,41,42 Treatment with high-dose L-methylfolate has shown benefit in individuals with depression when used alone and/or in conjunction with SSRI treatment.43,44

COMT Polymorphisms

Phase II catechol-O-methyltransferase (COMT) is a key enzyme for detoxifying genotoxic estrogen metabolites and catecholamines. Polymorphisms that decrease activity of this enzyme have been shown to increase risk of breast cancer and post-traumatic stress syndrome.45,46 The impact of impaired ability to detoxify catecholamines impairs resiliency to stress. Figure 12.5 shows the impact of the COMT SNP polymorphisms for risk of PTSD in soldiers returning from Iraq.

Figure 12.5 COMT SNPs Impact Susceptibility to PTSD

Figure 12.5 COMT SNPs Impact Susceptibility to PTSD

Supplementation with S-adenosyl-methionine (SAM-e) has been shown to increase activity of COMT in patients with genetically lower activity.47 Administration of SAM-e has also shown benefit in the reduction of aggressive behavior and improvement in overall quality of life in patients with schizophrenia and the low activity COMT polymorphism.48

These are just a few examples of the emerging SNP research showing the huge variations in need for nutritional supplementation in dosages and forms unavailable in food. With SNP testing now relatively inexpensive, this tool will over time become key for optimizing and personalizing nutritional therapy. (Note, while complete genetic profiling provides even more clinically relevant measures like deletions and duplications, such testing is 1–2 orders of magnitude more expensive and much less available.)

Environmental Toxin Load Greatly Changes Nutrient Need

It is estimated that over 60,000 different chemicals are now in use, with 6.5 billion pounds of chemicals released into the air per year in the United States alone. Considering only 20% of disease is genetically influenced and 80% of disease results from diet, lifestyle, and environmental factors, there is mounting evidence that this high level of toxin exposure is responsible for the rising incidence of chronic disease.

Exposure to environmental toxins has a significant impact on nutrient needs. Humans are now exposed to a number of toxins at rates higher than the trace minerals and vitamins they compete with for binding sites. Toxins induce oxidative stress, increasing the need for antioxidant nutrients; displace nutrients from enzyme cofactor binding sites, requiring higher levels for activation; damage DNA, resulting in apoenzymes that are less responsive to nutrient cofactors; replace structure minerals; damage cell membranes, causing fatty acid imbalances; and block insulin receptor sites, requiring increased insulin production and increased amounts of the nutrients needed to produce insulin.49,50 The combination of nutrient depletion, cofactor displacement, and high toxin-contamination in the food supply may be the main reason the incidence of all chronic disease is increasing.

A few examples:

  • Lead aggravates folate, B6, and B12 deficiencies, thus increasing homocysteine. Studies have shown that increasing intake of folate and vitamin B6 may reduce lead-associated increases in homocysteine.51

  • Cadmium increases production of reactive oxygen species, resulting in increased need for antioxidant nutrients. Antioxidants, such as curcumin, have been shown to protect against cardiovascular dysfunction resulting from oxidative stress associated with cadmium exposure through free radical scavenging, metal chelation, regulation of inflammatory enzymes, and increasing nitric oxide (NO + ).52,53

  • Poison enzyme systems (compete with nutritional cofactors for binding sites).

  • Lead poisons delta aminolevulinic acid dehydratase, resulting in impaired utilization of vitamin B12.

  • Lead displaces calcium in bones, making them weaker.54,55

  • Arsenic blocks vitamin A receptor sites. Studies have shown that supplementation with vitamin A may have a protective role toward cells from arsenic-induced injury.56

Persistent organic pollutants (POPs) are compounds designed for specific chemical/physical/biological effects as well as resistance to environmental degradation through chemical, biological, and photolytic processes.57 Examples of these organic pollutants include pesticides, plasticizers, herbicides, and industrial chemicals. The POPs bioaccumulate in human and animal tissue and biomagnify in food chains, thus increasing their concentration and toxicity in the environment. People are exposed to POPs mostly through the diet, with most of exposure coming from the ingestion of animal products.57 Nine times as many pesticide residues were found in children eating conventionally grown foods compared to those consuming organic foods.58 This further emphasizes the need for additional supplementation, perhaps beginning as early as childhood.

Several studies show an association between serum concentrations of POPs and prevalence of disease. Individuals with higher concentrations of POPs had a greater occurrence of cardiovascular disease (specifically hypertension), cancer, obesity, and diabetes.59,60,61,62,63 Neurodegenerative diseases such as Parkinson’s, developmental defects, atherosclerosis, and arthritis have also been associated with exposure to persistent organic pollutants.64,65 Organic, mostly plant-based foods should be consumed when possible. Eating organic foods has been shown to measurably decrease POP levels within 3 days.66

Therapeutic Nutrition Works

A key challenge in determining the efficacy of nutritional therapy is that almost all research follows the standard drug trial methodology. Randomized clinical trials (RCTs) are designed to determine statistical efficacy in a generic population with a specific disease. This works for pharmaceuticals, especially those designed to alleviate symptoms by poisoning enzyme systems. The problem with using this model for nutrients is that the supplemented nutrients typically only work where there is a substantial deficiency or an SNP polymorphism requiring above normal dosages. In other words, the supplemented nutrients only work for those who need them and are ineffective for everyone else, while drugs will poison enzymes for virtually everyone. Table 12.3 provides a brief summary of nutritional supplements effective in representative diseases.

Table 12.3 Nutrients Shown Effective in Representative Diseases




Nutrient Factors


A, E

Chromium, zinc




Arginine, carnitine, coenzyme Q10

Diabetes Type II

B6, biotin, C, E, niacin, omega-3 fatty acids

Chromium, magnesium, manganese, zinc



B2, omega-3 fatty acids


5-HTP, coenzyme Q10


C, D, pantothenic acid

Glucosamine, niacinamide sulfate, SAMe

Premenstrual Syndrome

B6, E, omega-3 fatty acids

Calcium, magnesium, zinc

Source: Reference 15.


Multivitamin/mineral supplements are the most commonly used nutritional supplements in the United States, with many containing nutrients two to six times the RDAs.67 A broad spectrum multivitamin/mineral containing vitamins A, B6, B12, C, D, E, folate, zinc, iron, copper, and selenium is likely to have benefit for innate and adaptive immunity as well as for maintaining the integrity of physical barriers (Table 12.4).68 Studies have shown that multivitamin/mineral supplements may prevent advanced age-related macular degeneration in high-risk individuals and may prevent cancer in individuals with poor or suboptimal nutritional status.69,70

Table 12.4 Sites of Action of Micronutrients on the Immune System

Epithelial Barriers

Cellular Immunity

Antibody Production

Vitamin A

Vitamin A

Vitamin A

Vitamin C

Vitamin B6

Vitamin B6

Vitamin E

Vitamin B12

Vitamin B12


Vitamin C

Vitamin D

Vitamin D

Vitamin E

Vitamin E

Folic acid

Folic acid








Source: Reference 68.

Vitamin D

It is estimated that only 4% of individuals age 51 or older meet the adequate intake level of vitamin D.71 Vitamin D has been shown to improve bone density,72 prevent the progression of osteoarthritis,73 reduce the risk of hypertension,74 and prevent osteoporosis.75

Considering the relationship between stress symptoms, depression, and low serum levels of 25(OH)-vitamin D, ensuring optimal vitamin D levels is important.76,77 Studies have shown that supplementation with vitamin D reduces symptoms of depression compared to placebo, and daily supplementation increased positive affect when given to healthy subjects during the winter.78,79 In individuals diagnosed with major depressive disorder (MDD), vitamin D supplementation has been shown to have beneficial effects on the Beck Depression Inventory (BDI) and improvements in biomarkers of oxidative stress.80

In a trial of over 400 overweight men and women, serum levels of 25(OH)-D were compared with scores on the Beck Depression Inventory. Supplementation of either 20,000 or 40,000 IU per week was associated with improved scores compared to placebo.81 Additionally, in a small study of patients with fibromyalgia, a deficiency in vitamin D was not only common but also more commonly associated with depression and anxiety.82

Vitamin D has been shown to increase innate immunity while modulating adaptive immunity. Researchers have found that in patients with vitamin D deficiency, the normal production of cathelicidin antimicrobial protein (hCAP), which kills invading bacteria, was inhibited without supplemental vitamin D. A direct correlation was found between serum concentration of 25-hydroxyvitamin D3 and monocyte expression of hCAP following treatment with ligands to pathogen-responsive TLRs. Vitamin D supplementation in patients with vitamin D insufficiency significantly enhanced innate immune responses by rescuing TLR-mediated suppression of hCAP expression suggesting that a key function of vitamin D is to prevent pathogen-induced evasion of innate immunity.83

Vitamin D insufficiency is associated with an increased prevalence of many autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), and inflammatory bowel disease.84 A 30-year cohort study showed that those who regularly took supplemental vitamin D at a dose of 2,000 IU daily had a nearly 80% lower risk of developing type 1 diabetes compared with those who received less than 2,000 IU per day.85 Inflammation may also play a role in the development of type I diabetes, as studies have shown an increase in specific TLRs associated with inflammatory markers on monocytes.86 Supplemental vitamin D modulated some of the monocyte abnormalities in patients with type 1 diabetes and seems to protect against the development of type I diabetes by reducing the activation of TLRs.87,88

Vitamin C

Vitamin C is a water soluble vitamin that is involved in many biological functions including bone metabolism, immune function, and detoxification,89 and acts as a potent antioxidant.90 Vitamin C is involved in collagen synthesis and therefore may help in the prevention or treatment of osteoarthritis.73 Vitamin C was found to reduce the duration of the common cold, and in populations engaging in significant physical exercise or living in cold environments, vitamin C showed a 50% reduction in incidence of the common cold.91 Taken at the onset of cold and flu symptoms, vitamin C (1,000 mg per hour for 6 hours, followed by 1,000 mg three times per day) demonstrated an 85% decrease in symptoms compared with the control group.92 Increased intake of vitamin C has been associated with a decreased risk of cervical, stomach, colon, and lung cancers.93,94,95 Vitamin C is also beneficial for cardiovascular health and has been shown to inhibit platelet aggregation,96 increase HDL cholesterol,97 and lower blood pressure.98

Vitamin E

Vitamin E is a combination of eight different fat-soluble compounds—tocopherols (alpha, beta, gamma, and delta) and tocotrienols. Tocopherols tend to be more biologically active, with alpha-tocopherol being the most active of the group, depending on the measure used. The primary function of vitamin E is to scavenge free radicals, thereby protecting the body from oxidative damage.99 The typical US diet often provides less than the RDA of alpha-tocopherol. Healthy individuals who consumed a balanced diet that supplied adequate (RDA) vitamin E amounts had decreased oxidative damage when supplemented with vitamin E at 10 times the RDA.100 Vitamin E supplementation has been shown to enhance immunity,101 help protect LDL from oxidative damage,102 repair membranes,103 and decrease platelet aggregation and blood clot formation.104 Studies have also shown that supplementation with vitamin E reduced prostate cancer incidence by 32%, reduced prostate cancer mortality by 41%,105 and reduced colorectal cancer in heavy smokers by 22%.106


Minerals are inorganic compounds that are naturally occurring solids found in nature. Minerals have important and wide-ranging actions in the body for both structure and function. Among the most important minerals in the body are magnesium, calcium, selenium, and zinc.


Magnesium deficiency is not uncommon in the West, as magnesium intake has decreased significantly with the increased consumption of processed foods. Magnesium has many critical functions including but not limited to relaxation effects on smooth muscle, regulating heart muscle contractility, regulating calcium absorption, modulating neurotransmitter systems, and reducing HPA axis activity. Magnesium deficiency is associated with increased anxiety-related behavior as well as elevated ACTH levels indicating an up-regulated stress system.107 Several studies show treatment with magnesium may be beneficial for insomnia, anxiety, depression, seizures, muscle cramping, and fatigue.108,109,110


Calcium is primarily stored in bones and is associated with multiple functions in the body including energy production, bone formation, nerve transmission, protein and fat digestion, and neuromuscular activity. The average calcium intake in American adults is approximately 761 mg/day which is significantly below the RDA for adults (1,000–1,200 mg/day).111 Calcium is important in regulating blood pressure and is often recommended for osteoporosis prevention.112,113,114 in addition, calcium has shown some benefit in cancer prevention.115,116


Geographical location is significant in determining if there is adequate selenium, as dietary intake depends on the selenium content of the soil. In regions of China where soils are selenium depleted, a cardiomyopathy known as Keshan disease has been attributed to an endemic coxsackievirus. Supplemental selenium not only elevates antiviral immunity but also prevents genetic adaptations in the viral genomic RNA that lead to increased virulence and cardiac pathology. Selenium supplementation also appears to reduce cancer rates,117,118 induce better host response to viral infections, improve the effects of aging on immunity, and enhance lymphocyte counts and mitogenic responses (Th1).119 An association exists in areas with increased levels of selenium and lower rates of several cancer types including lung, bladder, colorectal, ovarian, breast, esophageal, pancreatic, and cervical cancers.120


Zinc has been shown to induce thymic regrowth and activation.121 Supplementation of zinc significantly improves immune function in those with even a marginal zinc deficiency. The activities of virtually all immune cells of both the adaptive and innate systems are modulated by zinc.122,123 Additionally, the decline in zinc status with aging is likely a significant contributor to immunosenescence.124 Zinc (at dosages 10x the RDA) has been shown to be beneficial in treating individuals with intermediate age-related macular degeneration.70


Antioxidants protect the liver from damage and support detoxification processes. Antioxidants counteract oxidative stress by reducing the formation of free radicals. Dark colored fruits and vegetables are rich sources of antioxidants. Several vitamins, minerals, and nutraceuticals also function as antioxidants.


Glutathione (GSH) is the major endogenous antioxidant produced by cells. It is involved in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Glutathione, therefore, affects every system in the body, especially the nervous system, gastrointestinal system, immune system, and the respiratory system.

Glutathione is made available in three ways: (1) synthesis via a two-step process catalyzed by the enzymes glutamate cysteine ligase (GCL) and glutathione synthetase; (2) regeneration of oxidized glutathione (GSSG) to reduced glutathione (GSH) by glutathione reductase; and (3) recycling of cysteine from conjugated glutathione.125

Glutathione can be depleted by oxidative stress, exposure to toxic metals, and alcohol. Glutathione levels decline as conjugation reactions exceed the cells’ ability to regenerate GSH. Chemicals such as polychlorinated biphenyls (PCBs) and organochlorine pesticides increase oxidative damage and deplete glutathione levels.126 If GSH is depleted, de novo synthesis of GSH is up-regulated, as is cysteine synthesis.127 Depleted glutathione has been implicated in several degenerative conditions including neurodegenerative disorders (Alzheimer’s, Parkinson’s, and Huntington’s diseases; amyotrophic lateral sclerosis; Friedreich’s ataxia); pulmonary disease (COPD, asthma, and acute respiratory distress syndrome); immune diseases (HIV, autoimmune disease); cardiovascular diseases (hypertension, myocardial infarction, cholesterol oxidation); liver disease; cystic fibrosis; chronic age-related diseases (cataracts, macular degeneration, hearing impairment, and glaucoma); and the aging process itself.128 There is also an increased risk of cancer and smoking-related heart disease as a result of glutathione conjugation polymorphisms in glutathione transferase.129

Considering the significant consequences associated with depleted glutathione, it is essential to maintain adequate glutathione levels. This can be done by decreasing need for glutathione and oxidative stress; increasing production through supplementation with N-acetylcysteine (NAC),130 whey protein powder,131 S-adenosyl L-methionine (SAMe rather than methionine to avoid increasing homocysteine),132 alpha-lipoic-acid,133 meditation,134 and exercise;135 and/or direct administration of GSH via intravenous, nebulized, or intranasal route.136,137,138,139,140

Omega-3 Fatty Acids

Omega-3 fatty acid intake has been directly correlated to decreased symptoms of depression and to reduced anger and anxiety levels in substance users.141 Omega-3 supplementation has been shown to improve white matter integrity, which may explain the positive effects of fish oil in neuropsychiatric conditions.142 Fish oil has been shown to blunt the increase in cortisol and epinephrine following a stressful exposure.143 Considering the anti-inflammatory function of fish oil, it is also likely to reduce the inflammatory component of insomnia.144

A number of mechanisms may explain the relationship between omega-3 fatty acids and depression risk. The content of omega-3s is known to affect membrane fluidity and the functioning of enzymes, ion channels, and receptor binding affinity and expression. Omega-3 levels have been found to be low in RBC membranes of depressed patients.145 Omega-3s also affect neuroplasticity and cell survival through their impact on neurotrophins such as BDNF, which has been shown to be associated with depression risk. Omega-3 fatty acids affect gene expression and decrease the production of proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha, which have been shown to be elevated in depressed patients and inhibited by some antidepressant medications.146

Omega-3 fatty acids have well-established anti-inflammatory effects and also improve cellular membrane function, a specific age-related deficit found in neutrophils.147 A blunting of immunosenescence in aging mice given omega-3 fatty acids has been established, likely the result of an increase in Th1-stimulating cytokines and a lowering of Th2-associated cytokines. In humans, fish oil supplementation also increased interferon gamma production and lymphocyte proliferation.148


Nutritional deficiencies in the general population are much more common than generally recognized, and SNP polymorphisms can dramatically impact nutritional requirements. Patients with chronic disease almost certainly benefit from nutritional supplementation. Expert use of nutritional supplements is a critical skill for integrative medicine doctors. The effective integrative medicine clinician is knowledgeable about the signs and symptoms of nutrient deficiencies, recognizes the nutrients most useful for each chronic disease, and is able to prescribe the correct dosages and dosage forms needed by their patients.


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