12th INTERNATIONAL HOLISTIC HEALTH CONFERENCE August 3-6, 2006
Rydges Lakeland Resort - Queenstown NEW ZEALAND

Plenary Session Presentation: Nutrition Medicine: genes, nutrition and health
Dr Melvyn A Sydney-Smith. KGSJ.

The interplay between genetic inheritance and the environment is the major factor that determines health maintenance or disease development. From early history, doctors have long recognised the import of genetics, diet and regular exercise, with Hippocrates writing in 480 B.C. that:

"Positive health requires a knowledge of man's primary constitution and of the powers of various foods, both those natural to them and those resulting from human skill. But eating alone is not enough for health. There must also be exercise, of which the effects must likewise be known. The combination of these two things makes regimen, when proper attention is given to the season of the year, the changes of the winds, the age of the individual and the situation of his home. If there is any deficiency in food or exercise, the body will fall sick." 1

Following unscrambling of the human genetic code, genomics has generated much research effort to determine the functional metabolic effects and interactions regulated by organisms' genes and their products. Nutrigenomics more specifically focuses on how genetic inheritance affects nutrient requirements; how diet and nutrient intake affects gene expression and tissue metabolism; and how common dietary chemicals affect the propensity towards health or disease. The exciting vision of nutrigenomics is that greater understanding of human genetic variations and their impact on health status will improve nutritional intervention therapy in the prevention and treatment of disease 2,3 .

Gene expression contributes to disease

Though still in its infancy nutrigenomic research has already defined multiple gene allelic polymorphisms that reportedly contribute to disease 4 . Thus in review papers, Simopoulos 4 and Schaefer 5 discuss how common polymorphisms (7-16% of population) in genes that regulate expression and activity of apolipoproteins (APO A-IV, APO- A, APO-B, APO E), lipoprotein lipase and cholesterol ester transfer protein impact on blood lipid levels and responses to recommended dietary interventions in a manner that runs counter to that expected. However, though various lipoprotein and other genetic polymorphisms have been reported to alter responsiveness to dietary fat and cholesterol, no consistent influence has been yet reported for any specific genetic polymorphism and contradictory results commonly abound 6 . Thus, it would appear that the genetic influence on blood lipid disorders remains ill-defined, possibly related to confounding effects from competing gene activities or epigenetic environmental factors.

Simopoulos 4 further discusses other genetic polymorphisms that contribute to increased risk of: hypertension (Glycine 460 Trp in the gene coding for adducin); osteoporosis (Vitamin D Receptor variants); hyperhomocystinaemia (a 677C à T methylenetetrahydrofolate reductase enzyme (MTHFR) variant present in 5-15% of population) that contributes to increased risk of CHD, neural tube defect and dementia and signifying an increased need for dietary folate. Moreover, Simopoulos highlights the highly variable incidence of genetic polymorphisms and mutations between different ethnic populations that alters population disease incidence. For example, coeliac disease triggered by gluten consumption has an incidence of 1/3000 live births in European communities, whereas the incidence in Ireland approximates 1/200 live births. Similarly, APO E4 exhibits a mean frequency of about 15% in Caucasians, whilst extremely high frequencies have been reported for populations of New Guinea (35%) and Nigeria (30%). Also, even within Europe, APO E4 expression varies from a high frequency in Finland (22.7%) and Sweden (20.3%) to a low frequency in Italy (9.4%) 4 .

Though the disease propensity of many single gene polymorphisms has been relatively clearly defined, specific genomic involvement in chronic disease processes remains poorly defined, most likely due to the multiple and often competing genetic interplay that characterises complex disease, as discussed above. However, recent identification of the gene coding for carbohydrate responsive element-binding protein (ChREBP) shows promise as being of key importance in the development of modern chronic diseases. ChREBP activation by high dietary carbohydrate intake has been reported to induce increased transcription of multiple genes involved in the metabolic conversion of glucose to fat, upregulating lipogenic gene activity whilst reducing glucose utilisation, thus contributing to obesity, insulin resistance and diabetes 7 . With further research, it is expected that the genotypic contribution to the modern epidemic of obesity, diabetes and CHD, though currently elusive, may soon become more clearly defined.

Nutritional modulation of gene expression

Importantly, it is apparent that genotype is not an immutable prescription for disease but is strongly modulated by environmental and developmental factors particularly diet, nutrient status, exercise, maternal nutrition and aging 8 . Conversely, gene polymorphisms that promote deleterious metabolic changes that contribute to disease may well be countered by beneficial nutritional status, physical conditioning and lifestyle practices.

Thus, it is now known that gene expression and impaired metabolism may be beneficially modulated by specifically changing host nutritional status. Ames et al 9 highlight the impact of genetic polymorphic variants on the activity of their corresponding specific enzymes, often due to decreased binding affinity (increased Km) of the enzyme for its vitamin-derived cofactor. The authors conclude that "As many as one-third of mutations in a gene result in the corresponding enzyme having an increased Michaelis constant, or Km, (decreased binding affinity) for a coenzyme, resulting in a lower rate of reaction. About 50 human genetic diseases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity. Several single-nucleotide polymorphisms, in which the variant amino acid reduces coenzyme binding and thus enzymatic activity, are likely to be remediable by raising cellular concentrations of the cofactor through high-dose vitamin therapy."

Whilst much genomic research has focused on nuclear genes, evidence of mitochondrial DNA mutations capable of altering tissue metabolism and function has also been reported. Liu et al 10 have shown that, in elderly rats, age-related memory dysfunction is associated with mitochondrial decay and oxidative RNA/DNA damage in the brain. Moreover, the authors state that these changes are ameliorated by high-dose Acetyl-carnitine and/or Lipoic acid therapy, which improved the Km binding affinity for carnitine acetyltransferase and partially reversed memory dysfunction.

Inadequate vitamin and mineral status (below 50% RDA and each occurring in about 10% of the population) also impacts on genomic activity, causing DNA damage, mitochondrial decay, and other pathologies. Folate, B12, or B6 deficiency causes DNA incorporation of uracil, resulting in chromosome breakage, similar to radiation damage 11 . Zinc deficiency promotes increased release of oxidants, with resultant DNA oxidation, and inactivation of p53 and other zinc enzymes involved in oxidant defense and DNA repair 12 . Whilst iron deficiency reportedly inactivates mitochondrial Complex IV, thereby increasing oxidant release and mitochondrial decay and mimicking age-induced neurodegeneration in the brain 13 .

However, arguably the major influence on disease-promoting genomic expression is the gross discrepancy between current dietary macronutrient and micronutrient intake and the human ancestral diet of the paleolithic period, during which the human genome was subject to strict Darwinian selection. Eaton 14 proposes that modern human evolution, initially occurring in East Africa 100,000 years ago, resulted in a genome adapted to the nutrient intake of those times, which has remained essentially unchanged since then.

Anthropological best estimates suggest that paleolithic human ancestors obtained about 30% of dietary energy from protein, 35% from carbohydrates and 35% from fats, with saturated fats approximating 7.5% total energy and a substantial cholesterol (about 480mg/d) but negligible trans-fatty acid intake. Polyunsaturated fat intake was high, with an omega-6/omega-3 EFA ratio approximating 2:1 (v. 10:1 today). Carbohydrate intake derived from fruits and vegetables was about 3-fold that consumed in the modern diet, with sugar intake from honey approximating 2-3% total energy compared to the 15% in today's diet. Fruit and vegetable intake greatly exceeded grain intake, estimated at about 1%, whilst dairy consumption was non-existent. Fibre consumption was high, perhaps 100 g/d, but with minimal phytate content, due minimal consumption of grains and legumes. Micronutrient intake was typically 2 - 8 fold higher than that in the modern diet, except for low sodium intake (estimated at <1000 mg/d) with a high potassium/sodium ratio.

Eaton 14 contends that the Neolithic evolution of farming and animal husbandry, followed by commercialisation of food production since the Industrial Revolution, has resulted in a modern Western diet that is unduly high in carbohydrates (60-70% total energy) and saturated fats (15-20%) but low in protein (15%), with an extremely high omega-6/omega-3 EFA ratio, elevated trans-fatty acid consumption and high grain intake. The discrepancy between the nutrient balance of the modern diet and that to which the human genome is adapted is proposed as a major influence on human genome activity, promoting marked changes in DNA/RNA transcription, signalling molecules and regulatory chemicals (hormones, cytokines and eicosanoids) that adversely affect cellular, tissue and organ function and biochemical integration.

Eaton's contention is supported by contemporary research, as reviewed by Simopoulos 15 . This review reports that both elevated dietary omega-6-/omega-3 EFA ratios and high saturated fat intake adversely modulate expression of genes and gene promoters which code for multiple intracellular and intercellular signalling molecules and transcription factors that enhance the pro-inflammatory potential within body tissues. Also, the deleterious effect on ChREBP activation by the high carbohydrate intake of the modern diet 7 lends further support to the Paleolithic diet concepts proposed by Eaton.

Currently nutritional scientists are favourably inclined towards the Paleolithic diet, which compares favourably to the pre-1960 Cretan cultural diet that has been associated with low prevalence of cardiac disease, diabetes and autoimmune disease. Simopoulos 16 , in her analysis of the Cretan diet, points out its similarity to the Paleolithic diet (apart from the grain intake), particularly relative to the micronutrient and antioxidant intake and the relatively low omega-6/omega-3 EFA ratio.

Clinical nutrition practice

So exciting times lie ahead with regard to our understanding of the genotypic influence on disease processes and how environmental factor modulation may improve body metabolism and disease development.

Sadly, however, from a clinical practice perspective, assessment and management of genotypic disease must perforce remain limited to data gleaned from apolipoprotein phenotype analysis and extrapolated from family history, ethnicity and careful nutritional assessment married to the knowledgeable implementation of dietary and nutrient interventions on a clinical trial basis, supported by regular monitoring of clinical progress. In other words, for the nutritional practitioner clinical practice must continue unchanged, for now, until clinical access (laboratory testing) to genomic analysis lives up to its promised future.

References

1. Simopoulos AP, Pavlou KN. The Hippocratic Concept of Positive Health in the 5th Century BC and in the New Millennium. In: Nutrition and Fitness: Metabolic Studies in Health and Disease. World Rev Nutr Diet. Basel , Karger, 2001, vol 90, pp 1-4

2. Kaput J, Rodriguez RL. Nutritional genomics: the next frontier in the postgenomic era. Physiol Genomics 2004;16: 66-177.

3. L Afman, M Muller. Nutrigenomics: From Molecular Nutrition to Prevention of Disease. J Am Dietetic Assoc 2006;106:569-76

4. Simopoulos AP. Genetic variation and nutrition. Nutr Rev 1999;57(5): S10.

5. Schaefer EJ. Lipoproteins, nutrition and heart disease. Am J Clin Nutrit 2002;75:191-212.

6. Ye SQ, Kwiterovich PO . Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol. Am J Clin Nutrit 2000;72(Suppl):1275S-84S.

7. Uyeda K, et al. Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochem Pharmacol 2002;63:2075-80.

8. Sing CF, et al. Genes, Environment, and cardiovascular Disease. Arterioscleros ThrombVasc Biol 2003;23:1190-96.

9. Ames BN, et al. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. Am J Clin Nutrit 2002;75(4):616-658.

10. Liu J, et al. Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-a-lipoic acid. Proc Natl Acad Sci 2002;99:1876-1881

11. Ames BN. Increasing Longevity by Tuning-up Metabolism. EMBO Reports 2005;6:S20-4.

12. Ho E, Ames BN. Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkB, and AP1 DNA-binding, and affects DNA repair in a rat glioma cell line. Proc Natl Acad Sci 2002;99:16770-16775

13. Atamna H, et al. Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc Natl Acad Sci 2002; 99:14807-14812.

14. Eaton SB. The ancestral human diet: what was it and should it be a paradigm for contemporary nutrition?
Proc Nutr Soc 2006;65(1):1-6.

15. Simopoulos, AP. Evolutionary aspects of diet, essential fatty acids and cardiovascular disease. Eur Heart J 2001;3 (Suppl D):D8-D21.

16. Simopoulos AP.The Mediterranean Diets: What Is So Special about the Diet of Greece ? The Scientific Evidence. J Nutr 2001;131:3065S-73S.

Nutrition Medicine in Health & Disease

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