The Future of Personalized Lifestyle Medicine
Where We Have Been and Where We Are Going
(Keynote Speaker at Nutri Advanced’s The Science of Health, London June 2019)
Chronic conditions such as type 2 diabetes, cardiovascular disease, metabolic syndrome, and obesity are, in varying degrees, associated with unhealthy lifestyle and behaviour, including tobacco use, nutritional excesses, lack of physical activity, and heightened exposure to stress (Figure 1). Egger et al.  reported that most (about 60%–70%) health care visits in industrialized countries are correlated with these lifestyle-induced, preventable diseases. Therefore, due to the exorbitant cost and lack of resources to deal with the rising tide of illness, the importance of lifestyle factors in the origin and progression of disease can no longer be ignored. In fact, Dysinger  documented that in 2012, the American Medical Association issued a call to action for physicians to “acquire and apply the 15 clinical competencies of lifestyle medicine, and offer evidence-based lifestyle medicine interventions as the first and primary mode of preventing and, when appropriate, treating chronic disease within clinical medicine.”
In 2010, Lianov and Johnson  published an article in the Journal of the American Medical Association that strongly advocated physician education and training in lifestyle medicine: “Physician educators at both the undergraduate and graduate medical education levels should consider incorporating the relevant lifestyle medicine competencies into education and training programs.” The need for education in lifestyle medicine is so profound that prominent universities like Harvard, Stanford, and Yale have implemented the inclusion of lifestyle medicine into their curriculum, ranging from postgraduate courses to the development of separate institutes devoted to the cause. Additionally, the American Journal of Lifestyle Medicine is a peer-reviewed journal that was launched in 2007 for the purpose of educating practitioners on how to incorporate lifestyle medicine into clinical practice.
Lifestyle medicine is not a new or alternative medical discipline. The value of food as medicine was acknowledged several centuries ago by Hippocrates. Despite the fact that lifestyle recommendations have been recognized in ancient healing traditions over centuries, there are several modern day definitions of lifestyle medicine that have been proposed. Dysinger  states it succinctly that lifestyle medicine is “the application of simple, natural healing approaches to chronic disease and prevention.” In his textbook on lifestyle medicine, Egger refers to lifestyle medicine as “the application of environmental, behavioural, medical and motivational principles to the management of lifestyle-related health problems in a clinical setting .” The Lifestyle Medicine Competency Development Panel defines it as “the evidence based practice of helping individuals and families adopt and sustain healthy behaviours that affect health and quality of life .” Dean Ornish, touted as the most well-recognized pioneer in lifestyle medicine, states that it is composed of nutrition, physical activity, stress reduction and rest, and social support systems .
For the purposes of this review, lifestyle medicine is considered in the broadest sense as follows:
(i) nutrition, as it relates to dietary supplements, medical foods, and functional foods;
(ii) physical activity as defined by the entire spectrum of movement, from anaerobic to aerobic, and from mild to vigorous in intensity;
(iii) stress management and behavioural modification, as needed, and all the aspects that modulate behaviour such as mind-body medicine, psychosocial influences, and social networks;
(iv) environmental exposure to contaminants found in air, food, water, and radiation, due to the ubiquitous nature of toxins and their compounding concentration in the environment, leading to the well-recognized increasing toxin burden in physiological systems that relates directly to chronic disease.
Aspects of lifestyle medicine are as follows:
(i) whole foods and dietary patterns;
(ii) specific food-derived bioactives;
(iii) liquids and hydration;
(iv) dietary supplements;
(v) medical foods;
(vi) functional foods;
(vii) physical activities (aerobic or anaerobic);
(viii) mental fitness;
(ix) emotional regulation;
(x) mind-body medicine modalities for stress modulation;
(xi) social networks and support groups;
(xii) rest and sleep;
(xiii) environmental exposures (air, food, water or radiation).
Perhaps most importantly, lifestyle medicine is intended to be patient focused, enabling and requiring patients to be intimately involved in their health trajectory with the accompaniment of healthcare professionals. The system of mainstream medicine is designed for the “typical” patient with lab biomarkers within specific ranges; however, there is a subset of patients who tend to be outliers in this distribution of the population. In fact, these outliers may occur more frequently than is perhaps acknowledged, and, at the same time, they may experience increased difficulty with navigating the healthcare system. Even genetic variants with low penetrance can have significant effects in one’s physiology, resulting in low tolerance to certain environmental influences. Furthermore, laboratory values in the low or high normal range may signify the onset of subclinical pathological syndromes, and, ultimately, these individuals may become excellent candidates for what personalized lifestyle medicine has to offer (Figure 2).
In conjunction with being a compelling solution to the chronic disease epidemic and allowing the patient to have control of their health, lifestyle medicine therapies have been shown to be cost effective. Herman et al.  assessed both lifestyle intervention and metformin against placebo intervention in the prevention of type 2 diabetes in individuals with impaired glucose intolerance. Lifestyle delayed the onset of type 2 diabetes by 11 years and metformin by 3 years compared with placebo. Additionally, the cost per quality-adjusted life-years (QALYs) was much lower for the lifestyle intervention relative to the implementation of metformin therapy (cost per QALY: $1,100 versus $31,300, resp.).Thus, lifestyle costs less and performs better in one of the largest, growing chronic diseases in developed countries, type 2 diabetes.
The Personalization of Nutritional Care
It is worthwhile to question whether standardized public health positioning statements are sufficient to meet the diversity of the average individual, including addressing the multitude of variables such as age, lifecycle, gender, medical history, family history, vitamin and mineral status, ethnic background(s), lifestyle habits, genetics, single nucleotide polymorphisms (SNPs), mutations, and epigenetics. The following are the patient characteristics to consider in establishing a personalized lifestyle medicine therapeutic protocol:
(iv) past medical history,
(v) family history,
(vi) ethnic background and ancestry,
(vii) lifestyle habits (e.g., smoking, activity, and stress reduction practices),
(viii) nutritional status (e.g., macronutrients, micronutrients, phytonutrients, and vitamins),
(ix) medication use,
(x) dietary supplement use,
(xi) physical location and frequency of travel,
(xii) home and environment,
(xiii) genetics and mutations,
(xiv) single nucleotide polymorphisms (SNPs),
(xv) epigenetic patterns.
Xie et al.  illustrate the complexity of the individual by suggesting the role of metabonomics in personalized nutrition. Metabonomics, or assessment of metabolic responses based on nutrient sufficiency or deficiency, is a way to characterize the metabolic phenotype of individual and predict their corresponding interactions with gut microbiota, environment, and behaviour. In addition, Xie et al.  discuss advances in the role of phytochemical modulation of cellular physiology and propose phytochemical profiling, or phytoprofiling, to assist in the facilitation of determining phytonutrient requirements with more effective interventions with plant-derived compounds. Hence, the needs of the individual can be complex and require in-depth assessment before interventions can be confidently applied.
In much the same way, determining how the food intake as part of a dietary intervention meets the needs of an individual can be equally daunting. The challenge in understanding the integration of the many facets of the individual with the diversity of food constituents is supported by Jacobs and Tapsell  who state that reducing dietary recommendations to individual nutrients without considering the whole food and its multitude of constituents, including phytonutrients, may not be accounting for “food synergy.” Certainly, it would seem that the mere presence and interplay of complex constituents in food would be important to acknowledge in the formulation of dietary recommendations. Improved quantitation of phytochemicals, secondary metabolites, bacterial species, and micronutrients would be useful in positioning of plant foods for their antioxidant, anti-inflammatory, and anticancer properties. Along similar lines, Minich and Bland  discussed the importance of phytochemicals from cinnamon, hops, green tea, berberine, ginseng, quercetin, and resveratrol, in the modulation of the intracellular signals related to metabolic processes specific to insulin sensitivity, referred to as selective kinase response modulators, since these phytochemicals amplify signals through the cell selectively via protein kinases and to the degree required to restore intracellular function. Therefore, dietary recommendations for a variety of high phytonutrient-dense foods might be beneficial as part of individually tailored advice due to the specific roles of these compounds in various organ systems and how they impact intracellular physiology.
The recognition of the complexity of both an individual and a food may relate to the plethora of conflicting research studies on dietary components and food consumption, whether saturated fat, cholesterol, eggs, coconut oil, or caffeine. It is difficult for nutrition researchers to take into account the complexity of how a food interacts with the multitude of variables in a single individual, including, but not limited to, genotypic or epigenetic stratification, two aspects closely associated with an individual’s requirements. Part of the reason for this omission may be due to the lack of adequate diagnostics, difficulty with interpretation, or the paucity of long-term, prospective studies to demonstrate how to clinically integrate this information with therapeutics.
Despite the opportunities that lie ahead for developing a sophisticated interface between technology, metrics, and nutritional interventions, several instances of personalized nutrition approaches have begun to emerge in the literature, suggesting that the introduction of personalized lifestyle medicine is perhaps timely and appropriate at this point in the evolution of medicine.
(i) Iron Need and Iron Transport Polymorphisms. Most individuals with hereditary hemochromatosis could theoretically be evaluated for mutant genotypes that are associated with primary iron overload and increased transferrin saturation and/or serum ferritin levels for better and faster treatment .
(ii) Zinc Need and Polymorphisms. Select polymorphisms in interleukin-6 and metallothionein may alter one’s need for dietary zinc .
(iii) Vitamin D Requirement for Diabetics with Polymorphisms in the Vitamin D Receptor. Variations in the vitamin D receptor may influence vitamin D requirement and utilization in individuals with type 2 diabetes .
(iv) The Influence of Polymorphisms on Coenzyme Q10 (CoQ10) Need for Energy Production and Its Role in Cerebellar Ataxia. Genetic variants in the biosynthesis, reduction, and metabolism have been shown to be correlated with plasma CoQ10 levels . CoQ10 deficiency genes were sequenced in patients with unexplained ataxia. CABC1/ADCK3 mutations were identified in symptomatic patients along with decreased muscle concentrations of CoQ10 .
(v) Folate, MTHFR Polymorphisms, and Depression. A number of studies have demonstrated the association between low serum folate levels and incidence of depression with a higher frequency of genetic variations in the methylene tetrahydrofolate reductase (MTHFR) enzyme in depressed versus nondepressed individuals . It has been suggested that MTHFR genotyping may be helpful in determining which patients would benefit from L-methylfolate supplementation to override the limitation of reduced conversion of folic acid to this biologically active form due to the polymorphisminMTHFR .
(vi) B Vitamin Gene Variants and Risk to Smoking-Induced Lung Cancer. Identification of polymorphisms in B vitamin metabolism, particularly folate, has been associated with lung cancer risk, thereby potentially providing an individualized strategy to nutritional interventions for smokers .
(vii) Antioxidants and Polymorphisms in Glutathione STransferases (GST). Propensity towards increased oxidative stress and inflammation can be partially determined by GST genotype. Of all the nutritional factors measured, serum vitamin C was the most consistent nutrient associated with genetic variants of GST .
(viii) Bitter Tasting and Body Composition Differences. The individual’s ability to taste bitter compounds is highly variable and depends on structural and genetic differences in 25 human bitter receptors, termed T2Rs . Since there appears to be a relationship between bitter tasting ability and body mass index (BMI) , assessment of a patient’s ability to taste bitter may be a useful individualized tool for understanding modifications in metabolism and determining whether inclusion of bitter compounds in the diet or through supplemental means is warranted.
Transition into a Global System of Personalized Lifestyle Medicine
Several systems and medical delineations have been conceptualized in the past decades (Table 1). Personalized lifestyle medicine presents a system of medicine which merges technological advances with the traditional foundation of lifestyle through the psychosocial-behavioural interface (Figure 3). It would seem that with the advent of personalized medicine and the emergence of diagnostics to assess one’s genotype and moment-by-moment biomarkers that dietary and lifestyle recommendations will inevitably become individualized to the patient. There have been differing views expressed on whether or not offering personalized nutritional advice based on an individual’s genes and SNPs is welcomed by the public at large . As Görman et al.  suggest, the evidence for sufficient guidance based on genes and even epigenetics is rather limited and gaps in knowledge need to be overcome; however, the merit in this approach, when scientific data are available, is that it may result in improved compliance and support the individuality and inherent choices to be made by the patient.
As increasing recognition for the use of biomarkers as indirect or direct indicators of not just symptoms, but the underlying causes related to an individual’s genotypic profile, there will be greater emphasis on a personalized approach to health. Additionally, with the advent of technologies to assist in these types of laboratory measures in becoming mainstream, lifestyle medicine areas, including diet, physical activity, stress responses, and environmental factors, will begin to merge with the outcomes of these tests, resulting in clinically applied personalized lifestyle medicine approaches to most favourably address a patient’s condition. In so doing, the patient will be able to regain control of their health and feel empowered in their decisions concerning their outcomes.
For several years before disease onset, a patient may have subclinical manifestations of a disease, indicated by low and/or high normal laboratory values, and the presence of ill-defined symptoms which do not classically qualify for a determined diagnosis. Personalized lifestyle medicine can be integral throughout a patient’s life, from prevention to preclinical symptoms to disease manifestation and progression.
 G. J. Egger, A. F. Binns, and S. R. Rossner, “The emergence of “lifestyle medicine” as a structured approach for management of chronic disease,” Medical Journal of Australia, vol. 190, no. 3, pp. 143–145, 2009.
 W. S. Dysinger, “Lifestyle medicine competencies for primary care physicians,” Virtual Mentor, vol. 15, no. 4, pp. 306–310, 2013.
 L. Lianov and M. Johnson, “Physician competencies for prescribing lifestyle medicine,” Journal of the American Medical Association, vol. 304, no. 2, pp. 202–203, 2010.
 G. Egger, A. Binns, and S. Rossner, Lifestyle Medicine, McGraw- Hill, Sydney, Australia, 2008.
 W. H. Herman, T. J. Hoerger, M. Brandle et al., “The cost effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance,” Annals of Internal Medicine, vol. 142, no. 5, pp. 323–332, 2005.
 G. Xie, X. Li, H. Li, andW. Jia, “Toward personalized nutrition: comprehensive phytoprofiling and metabotyping,” Journal of Proteomic Research, vol. 12, no. 4, pp. 1547–1559, 2013.
 D. R. Jacobs and L. C. Tapsell, “Food synergy: the key to a healthy diet,” Proceedings of the Nutrition Society, vol. 72, no. 2, pp. 200–206, 2013.
 D. M. Minich and J. S. Bland, “Dietary management of the metabolic syndrome beyond macronutrients,” Nutrition Reviews, vol. 66, no. 8, pp. 429–444, 2008.
 P. C. Santos, J. E. Krieger, and A. C. Pereira, “Molecular diagnostic and pathogenesis of hereditary hemochromatosis,” International Journal of Molecular Sciences, vol. 13, no. 2, pp. 1497–1511, 2012.
 E.Mocchegiani, R.Giacconi, L.Costarelli et al., “Zinc deficiency and IL-6 -174G/C polymorphism in old people from different European countries: effect of zinc supplementation. ZINCAGE study,” Experimental Gerontology, vol. 43, no. 5, pp. 433–444, 2008.
 T. R. Neyestani, A. Djazayery, S. Shab- Bidar et al., “Vitamin D receptor Fok-I polymorphism modulates diabetic host response to vitamin D intake: need for a nutrigenetic approach,” Diabetes Care, vol. 36, no. 3, pp. 550–556, 2013.
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 R. Horvath, B. Czermin, S. Gulati et al., “Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 83, no. 2, pp. 174–178, 2012.
 M. H. Lizer, R. L. Bogdan, and R. S. Kidd, “Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in depressed versus nondepressed patients,” Journal of Psychiatric Practice, vol. 17, no. 6, pp. 404–409, 2011.
 M. D. Swartz, C. B. Peterson, P. J. Lupo et al., “Investigating multiple candidate genes and nutrients in the folate metabolism pathway to detect genetic and nutritional risk factors for lung cancer,” Plos One, vol. 8, no. 1, article e53475, 2013.
 G. Block, N. Shaikh, C. D. Jensen, V. Volberg, and N. Holland, “Serum vitamin C and other biomarkers differ by genotype of phase 2 enzyme genes GSTM1 and GSTT,” The American Journal of Clinical Nutrition, vol. 94, no. 3, pp. 929–937, 2011.
 K. Maehashi and L. Huang, “Bitter peptides and bitter taste receptors,” Cellular and Molecular Life Sciences, vol. 66, no. 10, pp. 1661–1671, 2009.
 E. Feeney, S. O’Brien, A. Scannell,A.Markey, and E. R.Gibney, “Genetic variation in taste perception: does it have a role in healthy eating?” Proceedings of the Nutrition Society, vol. 70, no. 1, pp. 135–143, 2011.
 U. Görman, J. C. Mathers, K. A. Grimaldi, J. Ahlgren, and K. Nordström, “Do we know enough? A scientific and ethical analysis of the basis for genetic-based personalized nutrition,” Genes and Nutrition. In press.
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