.

And what is “nutrition”? It is not merely “food” nor “that which-nourishes” as some lay dictionaries define it. It consists in the taking-in and assimilation through chemical changes – metabolism – of materials with which the tissues of the body are built up, their waste repaired, and their deterioration prevented; by which the processes of the body are regulated and co-ordinated, from which energy is liberated for the internal and external work of the body, and from which heat is generated for the maintenance of its temperature.

Sir Robert McCarrison MD (1936)

Introduction

It is difficult to imagine a more comprehensive definition of nutrition than that of Sir Robert McCarrison, speaking in 1936 at the inauguration of a new section of the British Medical Association devoted to nutritional science. McCarrison had been a British army doctor in India. His work there in nutrition, especially the nutritional origins of goitre, eventually led to his appointment in 1928 as Director of Nutritional Research. McCarrison carried out extensive research on the then newly discovered vitamins, and was one of the first to demonstrate links between nutrition and the epidemiology of disease (1936).

At that time only severe nutritional deficiency diseases like scurvy or rickets were public health concerns. But McCarrison’s work showed that “minor manifestations of ill health” – troublesome but not life-threatening symptoms like fatigue, susceptibility to infection, impaired fertility, slow growth, and poor wound healing – were also signs of deficiencies, and often harbingers of serious disease to come. Placing nutrition at the very heart of medicine,

McCarrison argued, would result in a more rational approach to health, since there was no branch of medicine to which nutrition was not central. As summed up by McCarrison, faulty nutrition led to faulty function, faulty structures, faulty health and ultimately, disease.

But although he himself was widely published and the recipient of many scientific awards, the clinical relevance of McCarrison’s work went unrecognized during his lifetime. However, in recent years the idea that inadequate intakes of essential nutrients are a preventable cause of chronic disease is rapidly gaining ground (Micha et al. 2012, Ames 2010). Faced with epidemiological evidence implicating shortfalls of many vitamins and minerals in the development of non-communicable diseases, the clinician is faced with two questions:

  • What is an optimal intake of any particular nutrient?
  • How do I determine nutritional adequacy in individual patients?

 

Osteoporosis as an Archetypical Nutritional Disease

Although often thought of as inert and static, bones are highly dynamic structures, constantly being resorbed and remodeled. The continual breakdown of bone plays an important physiological role, releasing minerals into the circulation as needed, and maintaining calcium and phosphate homeostasis. When diet provides sufficient minerals, as well as the vitamins needed as cofactors in bone rebuilding, healthy bones are maintained. Osteoporosis occurs when bone loss outpaces bone renewal, a phenomenon that increases with age.

Although their functions are different, all the essential components of nutrition unite to direct and control the maintenance of bone, and a range of micronutrients as well as macronutrients has been shown to influence bone health (Cashman, 2017). Suboptimal intakes of vitamin D and calcium (Binkley, 2012), magnesium (Castiglioni, Cazzaniga, Maier & Albisetti, 2013), zinc (Yamaguchi, 2010), vitamin K (Falcone, Kim & Cortazzo, 2011), B-vitamins (Dai, Koh, 2015), vitamin C (Aghajanian, Hall, Wongworawat & Mohan, 2015), and polyunsaturated fats (Longo, Ward, 2016) can all compromise bone health.

Contrary to the long held belief that high protein diets are detrimental to bone health, current research suggests that intakes of protein above those currently recommended are required for the development of strong bones and their conservation throughout the life span (Wallace & Frankenfeld, 2017).

 

The Nutritional Origins of Complex Chronic Disease

Rather than prevent bone deterioration by ensuring optimal intakes of all essential nutrients, current practice is to wait until osteoporosis or its precursor, osteopenia, becomes clinically obvious, then treat with pharmaceuticals. The bisphosphonates, currently the drugs of choice for osteoporosis, potentially damage the gastrointestinal tract, and their regular use can cause gastritis, gastric ulcers and worsening of pre-existing inflammatory bowel disease. So to protect the health of the gut, acid suppressing drugs such as proton pump inhibitors (PPIs) are commonly co-prescribed (Itoh, Sekino, Shinomiya & Takeda, 2013)

However, PPIs are known to deplete magnesium (Pisani et al., 2016). Magnesium is a basic requirement for bone health. Studies have shown that a higher dietary intakes and/or supplementation with magnesium is linked to greater bone mineral density (Kunutsor, Whitehouse, Blom & Laukkanen, 2017), and low dietary magnesium intakes have been shown to increases fracture risk (Veronese et al., 2017). Paradoxically, then, if bisphosphonates are given together with PPIs, bone health is unlikely to improve, and may even worsen. Blocking acid secretion in the stomach will also increase the risk of vitamin B12 deficiency which requires adequate gastric acid for absorption, and also decrease the absorption of iron and zinc (Ito & Jensen, 2010).

Furthermore, the symptoms of magnesium depletion induced by PPIs include arrhythmias and high blood pressure (Pisani et al., 2016). If these are not recognized as signs of magnesium depletion, additional medications will be prescribed, which may have their own nutrient depletion profile. For example, the use of some medications commonly

used to control blood pressure can deplete magnesium and zinc (Koren-Michowitz et al., 2005). In turn zinc depletion will adversely affect not only bone health but also undermine immunity. Zinc deficiency has recently been suggested as a high risk factor for the development of chronic obstruction pulmonary disease (COPD) (Roscioli et al., 2017)

Since all tissues need all nutrients all the time, continuing to ignore the nutritional inadequacies that underlie osteoporosis will inevitably compromise the health of other tissues. Today, the emergence of Complex Chronic Disease (CCD) – that is, more than two chronic diseases in the same individual – is a major public health challenge. Using osteoporosis as an example it is clear that failure to incorporate nutritional strategies into treatment and prevention of this common condition, exacerbated by the use of nutrient depleting medication, could ultimately lead to the development of CCD.

Support for this concept comes from evidence linking osteoporosis to increased risk of other chronic conditions, including Type 2 diabetes (Rubin & Patsch, 2016), cardiovascular disease (Frysz et al., 2016), stroke (Pedersen et al., 2017), COPD (Liao, Liang & Li, 2016), and dementia (Chang et al., 2014).

 

Recommended Daily Intakes Are Not Optimal

Current nutritional policies set Dietary Reference Intakes (DRIs) for each individual nutrient, which are presumed to provide for the daily needs of most healthy individuals. Although ostensibly evidence-based, the data used to derive DRIs are often scanty, or drawn from studies that have serious limitations and/or methodological flaws (Spedding, 2014).

Nutritional research has historically relied on a reductionist approach, where individual nutrients are studied at the cellular and molecular level. While this approach may have made sense at the beginning of the 20th century when fatal deficiency diseases like scurvy were major determinants of shortened life expectancy, it ignores the web like interactions and inter-dependencies of nutrients, and the fact that deficiencies of any one of a range of essential nutrient can lead to chronic conditions like osteoporosis.

Unfortunately today the ‘single nutrient’ approach has led to drug-style randomized controlled trials (RCTs) being considered the gold standard for vitamin research. Such studies extrapolate from epidemiological data linking low blood levels or intakes of certain nutrients to particular diseases, and then attempt to show whether or not supplementing with that particular nutrient can reverse major diseases like heart disease, or prevent others, like cancer. When these ‘magic bullet’ trials fail to show benefit, the simplistic conclusion is drawn that the nutrient under study is irrelevant to treatment or prevention.

Moreover, committees that establish DRIs insist that RCTs provide the highest level of evidence and observational studies are insufficient to modify DRIs without the support of RCTs. However, diet-derived vitamins are ingested with a host of other nutrients that interact in complex ways and whose presence or absence is almost impossible to capture in RCTs. So, for example, increased risk of heart disease is linked to low intakes of the B-vitamins, especially folic acid and vitamin B12 (Ma et al., 2017). But heart disease is also linked to suboptimal intakes of vitamins D and E (Rashidi, Hoseini, Sahebkar, & Mirzaei, 2017), magnesium (Gröber, Schmidt, & Kisters, 2015), and omega 3 fatty acids (Watanabe & Tatsuno, 2017), as well as excess intakes of iron (Kraml, 2017), and calcium (Tankeu, Ndip, & Noubiap, 2017). So a study focused on just one of these nutrients, vitamin E and heart health, for example, would need to control for all these other dietary variables for the results to be meaningful.

 

Personal Genetics Changes Nutritional Needs

Another reason that DRIs based on current research might not be adequate for optimal health is that they are intended to apply to all healthy individuals in a particular demographic. With the advent of new sciences like nutritional genetics and genomics, it is clear that personal genetics influences the need for individual nutrients, and confirms observations made by early vitamin researchers that, as individuals, we vary greatly, one from another, in our needs for any particular nutrient.

A well-known example is the MTHFR gene, 677TT variant genotype, which influences serum folate concentrations. Folate is required for DNA methylation, abnormalities of which are associated with numerous pathologies, including cancer. The offspring of women carrying this gene are at increased risk of neural tube defects unless the mother is supplemented with higher than average intakes of folic acid (Axume et al., 2007). Similar genetic dependencies have been shown for magnesium (Stuiver et al., 2011), vitamin C (Michels, Hagen, & Frei, 2013), and vitamin B12 (Froese & Gravel, 2010).

An extreme example of what renowned vitamin researcher Roger Williams called “biochemical individuality” comes from clinical studies of iron absorption and excretion in men and pre- and post-menopausal women, which have shown up to a 40-fold variation in individual needs for iron that are unrelated to age, sex or life stage (Hunt, Zito, & Johnson, 2009). Physiologically, it would seem impossible that this wide degree of individual requirement could be accommodated by a single recommended daily intake.

 

Genetic Dependencies: Only Part of the Puzzle?

So will universal genetic testing for nutrient dependencies be the ultimate answer to optimal nutrition? Some clinicians believe so, and are already relying on genetic biomarkers to modify supplement recommendations to patients. In addition, commercial nutrigenomics websites now provide testing directly to patients. At least 8 million single-nucleotide polymorphisms contribute to individual variation in genetic responses to nutrients and uncovering these dependencies shows promise as a tool for tailoring nutrient intakes to individual needs (Zeisel, 2007).

Such tests do provide valuable information on whether an individual might need life-long supplementation with particular nutrients and can be a useful motivator for patients. But knowing for example that someone requires methyltetrahydrofolate if they possess certain variants of the MTHFR gene is helpful, but will not be the entire solution for a healthy pregnancy. Since all the essential components of nutrition unite to direct and control fetal development, identifying needs for one nutrient and supplying it in no way guarantees that other non-genetic nutrient needs are addressed, which may be inadequate due to concurrent dietary practices, medication use or stress levels.

 

When More is Better

If DRIs are adequate, they are certainly not optimal. For example, the DRI for vitamin D in North America is set at 600 IU/day for children from 1 year of age and up, as well as adults up to the age of 70, after which the DRI increases to 800 IU/day. These estimates are based on what is assumed to be sufficient for bone building and maintenance, and no other clinical indication. Yet we know that vitamin D plays a critical regulatory role in brain health (Patrick & Ames, 2014). When otherwise healthy Canadian adults were given either 400 IU or 4000 IU of vitamin D for 18 months, nonverbal (visual) memory and executive function significantly improved, but only in those taking the higher dose (p=0.005) (Pettersen, 2017).

All members of the water-soluble B-vitamins preform closely related roles in cellular metabolism, and are particularly important for optimal brain function. When fit, healthy young men were given either a placebo or B-vitamins at doses 10-15 times in excess of the current governmental recommendations and then subjected to mental and physical stress, supplementation led to improved cognitive performance, mood and stamina (Kennedy et al., 2010).

Another example of the benefits of higher than recommended daily intake comes from studies of vitamin C and mood. The adult DRI for vitamin C is set at 90 mg/day for men and 75 mg/day for women, based on the amount of vitamin C needed to maintain near-maximal concentrations of vitamin C in neutrophils and support immunity (“Vitamin C Fact Sheet.” 2016). However, vitamin C is required for multiple functions other than immune support, including the synthesis of neurotransmitters that control mood. When a group of high school students were given either 500 mg vitamin C or placebo, vitamin C supplementation measurably reduced anxiety levels compared with placebo (de Oliveira, de Souza, Motta & Da-Silva, 2015).

 

Determining Optimal Nutrition

While we can say with confidence that DRIs are in many cases suboptimal, we do not as yet know what optimal intakes might be. Indeed, the whole concept of optimal nutrition is very new and nutritional sciences are still generally focused on the minimal target for a general population that will prevent the classic nutritional deficiency diseases (Shao et al., 2017)

Suboptimal intakes have been defined as those associated with abnormalities of metabolism that can be corrected by supplementation with that vitamin (Fletcher, & Fairfield, 2002). Those abnormalities can be quite subtle, and not necessarily associated with obvious health problems. If it is possible, as some recent studies have shown, to beneficially change basic physiological processes like energy metabolism or cerebral blood flow simply by giving higher than DRIs of vitamins and other micronutrients to ostensibly healthy members of the population, then it must be that their nutritional status is inadequate for optimal functioning, and by extension, the nutritional status of the population from which they were drawn (Kennedy et al., 2016).

Indeed some researchers have suggested that when attempting to determine optimal nutrition, psychological response to nutritional supplementation is the ultimate indicator of nutritional adequacy. This is because the brain is the most complex and metabolically active organ of the body, and as such might be the first organ to display a negative response to minor nutritional inadequacies. Meta-analyses consistently show that cognition in children and mood and memory in adults can be improved with high dose multivitamin and mineral supplementation (Benton, 2013).

If in future iterations of DRIs reviewers considered studies of nutritional requirements for optimal mental processing and cognitive health the most sensitive indicators for establishing new nutritional guidelines, we would, in my opinion, have made a major step towards defining optimal intakes.

 

Tolerable Upper Limits

In the absence of reliable DRIs to guide nutritional supplement advice at present, should we be contemplating the use of tolerable upper limits of intake to guide micronutrient supplementation.

The tolerable upper limit (UL) of a nutrient is defined as the largest daily intake that can be taken continuously without causing harm. In the absence of more specific guidance it is reasonable to consider using upper limits appropriate to age, sex and life stage for all nutrients in all patients. Although it is generally assumed that no benefits are to be had from consuming levels of nutrients above the DRIs and that ULs are safety guidelines only and not acceptable intake levels (Zlotkin, 2006), current research, some of which is outlined in this paper, shows otherwise.

Comprehensive high dose multi-nutrient formulations have been used safely in children (Kaplan, Tsatsko & Hilbert, 2015). and adults (Rucklidge, & Kaplan, 2014). However, given the frequency with which concerns are raised that high dose micronutrients supplementation could have adverse effects, clinical trials are warranted. If such trials are to be carried out, changes in psychological and cognitive parameters verified by brain imaging and the use of established standardized tests are likely to be the most sensitive indicators of benefit.

 

Competing Interests

The author declares that she has no competing interests.

 

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