Diet and Dementia: Approaches to Risk-Minimisation through Nutrition and Lifestyle Management of Neurodegenerative Diseases.

My gorgeous and loving Father. Alzheimer's.

Introduction

Dementia is characterized as an irreversible progressive decline in the ability to remember, learn, understand and communicate (Coppedé et al. 2012, Ramirez-Bermudez 2012). Alzheimer’s disease is by far the most common form of dementia in the elderly, with other dementia types including vascular dementia (usually resulting from minor strokes), dementia with Lewy bodies, and dementia associated with conditions like Huntington’s and Parkinson’s disease (Philpott 2014).

Currently over 46 million people worldwide are living with dementia, with the numbers expected to double by 2030, and reach 131.5 million by 2050 (Prince et al. 2015), primarily as a result of increased life-span expectancy in developed and developing countries (Brookmeyer et al. 2007).

Despite a vast number of randomized controlled trials involving single-nutrient nutrition interventions (Alves et al. 2013, Van der Zwaluw et al. 2014, Ngandu et al. 2015), Alzheimer’s Disease International’s Review of Nutrition and Dementia Research found no clear evidence to support a protective or curative effect of the various individual nutrients focused on by current and recent research (Philpott 2014). Following, a ‘whole diet’ paradigm is beginning to dominate in nutritional epidemiology (Valls-Pedret et al. 2013). Although cost-effective and easy to implement (Saulle, Seymyonov and la Torre 2013), the shift in methodology to include non-biomedical parameters makes clinical meaningfulness and the hierarchy of supporting evidence difficult to establish and controversial within the research community.

With methodological issues and a consensus that future trials and research establish more cohesive parameters (Morris 2016), newer epidemiological approaches to “whole diet/whole person” intervention, as well as alternative assumptive frameworks and cognitive models are now questioning whether the “hierarchy of evidence”(used to create relevant dietary guidelines), giving greatest weight to randomized controlled trials, is definitively the best choice for addressing the complexity of human diet and health relationships (Hassel 2014).

Whole diet strategies (The Mediterranean Diet), the gut microbiome, epigenetics and a concert of psychosocial interventions offer alternative multi-disciplinary models to the complex study of relationships between food ingestion and neurological degeneration. These strategies accept as a central tenet that dementia may not just be a matter of a technical fix with targeted pharmaceuticals, but is instead a complex social, psychological, medical, nutritional, ethical and spiritual condition (Hughes 2011) that may defy deterministic cause/effect paradigms.

Dietary approaches to prevention.

In the early 1950’s Ancel Keys observed that the poor populations of small towns in Crete and Southern Italy were much healthier than the wealthy citizens of New York. He theorized that this was due to their simple, fresh and regional/traditional dietary choices and went on to scientifically prove the nutritional value of this ‘Mediterranean Diet’ in the famous “Seven Countries Study” (Wright 2011).

The diet is dominated by consumption of plant foods (vegetables, fruits, legumes and cereals) and olive oil, a moderate intake of fish, a low to moderate use of dairy products (mostly goat-milk derived), low consumption of meat and poultry, very little saturated fat and wine consumed in low to moderate amounts, usually with a meal (Willett et al. 1995). This “whole diet” framework encompasses beneficial levels of specific micronutrients associated with protection against cognitive decline and aging such as Vitamin E, vitamin B12, folate, choline and Vitamin C (Morris 2012, Perez et al. 2012, Meck et al. 2007, Caudill 2010).

This food combination’s cited biological basis for physical benefit lies in a decrease in oxidative stress, inflammation and vascular disease, -all recognised as valid participants in the pathophysiology of neurodegenerative disease (Féart et al. 2009, Morris 2012, Perez et al. 2012). Strict adherence to the diet may lower the risk of Alzheimer’s by as much as 50% (Liu et al. 2010), although its beneficial effects are more likely during the long prodromal phase of dementia, rather than in the years immediately preceding diagnosis.

One of the least studied but most fascinating components of the Mediterranean diet is its very nature. We know its basic food-parameters, -for example, ‘high consumption of plant foods’ (Morris 2012), but what does this mean? Do the ‘plant foods’ themselves contribute more than we suspected beyond general health parameters?

The traditional Mediterranean diet is characterized by certain food combinations that have an over-arching theme: Fresh, seasonal, local, accessible and economically affordable (Gerber & Hoffman 2015). It was a diet adjusted to the cultural, climatic and environmental characteristics of the region and its people (Naska & Trichopolou 2014), and included not only the extensively studied Virgin Olive Oil (Hoffman & Gerber 2014, Servili et al. 2014) but an extraordinary variety of wild plant and animal foods.

Wild greens for example, were a winter staple. They start growing after a good autumn rainfall and are mostly available up until early summer when more traditional cultivated vegetable crops became available (Dymiotis 2015). An enormous variety of wild plant foods were regularly harvested by women and children and are the central feature in many iconic regional dishes (Kochilas 2016). The harvesting itself requiring cardiovascular exercise and sunlight exposure. Many, if not all of these wild foods provided not only caloric nutrition, but an enormous range of pharmacological benefits. Greens in common use included: Bitter dock (Rumex obtusifolius), Arugula (Eruca sativa), Black bryony (Tamus communis), Blue Mallow (Malva silvestris), Golden thistle (Scolymus), Garden cress (Lepidium sativum L.), Grass Lily (Ornithogalum), Nettles (Urtica dioica), Purslane (Portulaca oleracea L.), Wild Fennel (Foeniculum vulgare) and Yellow salsify (Tragopogon) (Kochilas 2016).

Blue Mallow (Malva silvestris) for example is well documented as a potent periodontal disease inhibitor, which itself is related to many systemic diseases known as contributing markers to Alzheimer’s (including cardiovascular disease and diabetes) (Benso et al. 2015, Negrato et al. 2013, Rautemaa et al. 2007). Purslane (Portulaca oleracea L.) contains pancreatic lipase inhibitors, reduces triglycerides, LDL-cholesterol, vascular tension and systolic blood pressure (Lee et al. 2012, Farzei et al. 2015). Nettles (Urtica dioica) are a rich source of minerals and essential elements like Calcium, Magnesium, Iron, Manganese, Zinc, and copper (Mahlangeni, Moodley & Joannalagadda 2015).

The use of local, seasonal, minimally processed foods is not exclusive to the Mediterranean Diet, and has been observed in numerous societies to promote healthful longevity and minimise the neurological degeneration associated with aging. Buettner’s ‘Blue Zones’ exhibit this dietary pattern (Carter 2015) as did the Okinawan’s made famous in 2001 for their extraordinary longevity and freedom from disease (Willcox, Willcox & Suzuki 2001). Indeed, the human species has created a huge diversity of uninvestigated non-biomedical models for understanding diet and health. Cross-cultural engagement (Hassel 2005, 2006) could be utilised to a much greater extent in seeking out traditional food and health understandings that developed beyond the scope and a priori of biomedical science. The first American Pharmacopeia, published in 1820 listed more than 200 food-medicines coming from indigenous inhabitants (Moerman 1998). Although these food cures and medicines come from a different cognitive orientation that do not share the rigid subject/object separation of Western biomedicine, they were nonetheless developed with a rigorous empiricism (Elk 2016) that seems foolish to dismiss ‘out of hand’ as non-scientific.  The well-researched health benefits of minimally processed plant food diets utilized by so many cultures exhibiting exceptional longevity and physical/mental health are also beginning to gain traction within the mainstream medical communities, with plant-based dietary medicine being offered in Hospital residency programmes (Kamila 2016).

In addition to these concerns, we are now also presented with new research on the gut microbiome and epigenetics, and their influence on neurological processes. Although research is in its infancy, it appears that what we ingest and the resulting composition and expression of the gut microbiome has pronounced effects on both mood and behaviour (Cryan & Dinan 2012, Mayer et al. 2014). Recent research has linked microbial dysbiosis to neurological disorders like Parkinson’s and Alzheimer’s Diseases with disruptions in bacterial populations of Clostridia, Bacteriodetes and Verrucomicrobia implicated particularly for Alzheimer’s disease (Ghaisas, Maher & Kanthasamy 2016). In support of the aforementioned plant-based diet, it has been found that a diet rich in complex carbohydrates, fermented vegetables and pre-biotic containing foods decrease toxin-producing bacteria and increase beneficial bacteria in the gut microbiome (Hvistendahl 2012). With 70% of genes that code for health and longevity under epigenetic control, Dr Perlmutter of the University of Michigan, Miller School of Medicine says that when it comes to physical and mental health, Hippocrates was right: “Let food be your medicine and medicine be your food” (Perlmutter 2015).

 Prevention through nutrition is only one part of the complex human puzzle that is neurodegenerative disease, and despite the encouraging findings of many epidemiological studies in dietary intervention and the support of published Dieticians and Nutritionists (Campbell 2013, Jacobs & Tapsell 2013, Slavin 2012), the clinical meaningfulness of such findings remains controversial within medical science, with supporting evidence cited as ‘weak’ and further studies required before these approaches can be supported as recommendations (Richard et al. 2012, Valls-Pedret & Ros 2013, Canevelli et al. 2016). What is certain, is that despite “magic bullet” thinking still very much apparent in mainstream media nutrition reporting (‘Best Odds Diet to beat Dementia’, The London Sun, 2016), as each individual that develops dementia is unique, so will be the optimal ‘preventive’ diet pattern. Equally, as individuals are comprised of far more than a digestive system, a multi-disciplinary approach to dementia care and prevention is essential (Wolfs et al. 2008).

Lifestyle management, nutrition and care: Living with dementia

‘Cures may emerge; but they should do so against the fundamental background of solicitude’

                                                                                                                    (Hughes 2011)

People with dementia, and indeed any cognitive disorder are as different from each other in likes, needs, memories, culture, beliefs and world-views as any other human being. Reducing behavioural aspects of neurodegeneration to merely ‘disease symptoms’ engenders a depersonalisation that adversely affects therapeutic intervention (Barak 2014). Unfortunately, traditional nursing home structures and practises all too often contribute to this depersonalisation leading to sub-optimal or even unacceptable patient outcomes (Alfredson & Annerstedt 1994, Boekharts et al. 2009).

Recent figures estimate that 85% of patients with advanced dementia have eating difficulties, and that the six-month mortality for such patients is almost 40% (Lam & Lam 2014). Despite these sobering estimates, Australian aged-care residential facilities spend an average of only $9.07 per person, per day on ‘food costs, a figure that incorporates consumables, cutlery, crockery and supplements (Rowe 2014). Nutrition and appetite decline with age, usually accompanied by weight loss (Perez et al. 2012), and in advanced dementia feeding problems can become critical, requiring families and physicians to assess the risks and benefits of artificial (tube) nutrition and hydration.  Up to one third of nursing home residents with advanced cognitive impairment are currently fed with feeding-tubes (Sherman 2003) despite tube feeding being associated with agitation, increased use of restraints and worsening pressure ulcers (Lam & Lam 2014).

One of the key findings in the recent review of nutrition and dementia by Alzheimer’s Disease International was that the eating environment in aged care facilities had a substantial impact on appetite stimulation and food intake. Smaller, well-lit dining rooms decorated in warm, cheerful colours including side-boards and objects d'art were associated with increased food intake and reduced agitation (Philpott 2014), as was a dining area linked to a kitchen that allowed food preparation sounds and smells to cue meal times and stimulate appetite. Familiar, relaxing background music was also linked to increased calorie consumption. A substantial body of research also demonstrated that interacting with food via gardening-based interventions enhances emotional well-being, social function and improved physical health parameters (Clatworth, Hinds & Camic 2013). In short, people are happier and more likely to eat according to their needs in an environment that reflects ‘home’.

Australia’s answer to ‘Mrs Caldicot’ (Arrow Film Distributors 2002), Maggie Beer along with Brisbane-based dietician Cherie Hugo and Flinders University are currently utilising these findings in a series of ‘test case’ aged care homes in South Australia. Through the Maggie Beer-A Good Food Life for All foundation (established in April 2014), they aim to benchmark best practise in Australia and develop a framework for aged-care homes to provide flavoursome, nutritious meals that foster an enjoyment of food, from garden to plate (Rowe 2014). Internationally, Geriatrician William H. Thomas has established more than 100 ‘Green House Projects’ with similar objectives. Thomas’s facilities focus on the natural rhythms of the day and not the staff’s tasks.

“Most of them are serving life sentences, stripped of privacy, independence and choice. The fact that so many people, whose only crime is frailty, are confined in this way is powerful evidence that we live in a deeply ageist society”  (pp 3, Drevitch 2012).

 ‘Patients’ are titled ‘Elders’ and afforded the respect and courtesies that accompany the new nomenclature. Meal times are not determined by management, but by the individual’s personal sleep/wake and hunger cues (Drevitch 2012). Neither initiative will tolerate the serving of ‘eggs that bounce’! (Morgan-Jones 2014).

Conclusions

Whether promoting continued research into biomedical models of dietary prevention strategies, adopting alternative cognitive frameworks embracing non-Western approaches to diet and disease or addressing the quality and systems-based nutrition interventions of people with dementia, Dieticians and Nutritionists have a crucial role in the future directions of dementia care both in Australia and as part of the International community. As new research and initiatives continue to emerge, it is essential that nutrition professionals continue to embrace a broader definition of both ‘disease’ and ‘care’, and to continue to recognise the rich tapestry of ‘person’ beyond disease.

REFERENCES

Alfredson, B.B. & Annerstedt, L. (1994). Staff attitudes and job satisfaction in the care of demented elderly people: group living compared with long-term care institutions. Journal of Advanced Nursing, 20. 964-974

Alves, C.R.R., Merege Filho, C.A.A., Benalti, F.B., Brucki, S….Gualano,B. (2013). Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women. A randomised double-blind study. PLoSONE, 8. E76301

Barak, Y. (2014). Neurodegenerative Diseases –Laboratory and Clinical Research: Preventing Alzheimer’s Disease– Personal Responsibility: Personal Responsibility. Hauppauge, US; Nova. Retrieved from http://www.ebrary.com.ezyproxy.csu.edu.au

Benso, B., Rosalen, P.L., Alencar, S.M., Murata, R.M. (2015). Malva sylvestris Inhibits Inflammatory Response in Oral Human Cells. An In Vitro Infection Model. PLosONE, Oct 19. 2015. DOI: http://dx.doi.org/10.1371/journal.pone.0140331

Boekharts, S., Depla, M.F.I.A., De Lange, J., Pot, A.M., Eefsting, J. (2009). The effects of group living homes on older people with dementia: a comparison with traditional nursing care. International Journal of Geriatric Psychiatry, 24. 970-978

Brookmeyer, R., Johnson, E., Ziegler-Graham, K. & Arrighi, H.M. (2007). Forecasting the global burden of Alzheimer’s Disease. Alzheimer’s and Dementia, 3(3). 186-191

Canevelli, M., Lucchini, F., Quarata, F., Bruno, G. & Cesari, M. (2016). Nutrition and dementia” Evidence for preventive approaches? Nutrients, 8(3). 144. Retrieved from http://serach.proquest.com.ezproxy.csu.edu.au/docview.1802750487?accountid=10344

Campbell, T.C. (2013). Whole. Rethinking the science of nutrition: BenBella Books, Inc. Retrieved from http://www.ebrary.com.ezproxy.csu.edu.au

Carter, E.D. (2015). Making the Blue Zones: Neoliberalism and nudges in public health promotion. Social Science and Medicine, 133. 374-382. DOI: 10.1016/j.socscimed.2015.01.019

Caudill, M.A. (2010). Pre- and postnatal health: evidence of increased choline needs. Journal of the American Dietetic Association, 110(8). 1198-1206

Clatworth, J., Hinds, J. & Camic, P.M. (2013). Gardening as a mental health intervention: a review. The Mental Health Review, 18(4). 214-225. DOI: http://dx/doi.org.ezproxy.csu.edu.au/10.1108/MHRJ-02-2013-0007

Coppedé, F., Bosco, P., Fuso, A., & Traen, A.M. (2012). Nutrition and Dementia. Current Gerontology and Geriatrics Research, 2012(2012). Article ID: 9260832. DOI: 10.1155/2012/926-82

Cryan, J.F., & Dinan, T.G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature Reviews neuroscience, 13. P 701. DOI: 10.1038/nrh.3346

Drevitch, G. (2012). Not Your Father’s Nursing Home: A Visit to the Urban Green House. September 21, 2012. www.nextavenue.org/not-your-fathers-nursing-home-visit-urban-green-house-O/

Dymiotis, M. (2015). www.markdymiotis.com/food/wild-greens/wild-greens-2/

Elk, L.B. (2016). Native Science: Understanding and Respecting Other Ways of Thinking. Rangelands, 38(1). 3-4. DOI: 10.1016/j.rala.2015.il.003

Farzei, M.H., Roja, R., Farzei, F., Abdollahi, M. (2015). Traditional Medicinal Herbs for the Management of Diabetes and its Complications: An Evidence-Based Review. International Journal of Pharmacology, 11(7). 874-877

Féart, C., Samieri, C., Allés, B., Barberger-Gateau, P. (2012). Potential benefits of adherence to the Mediterranean diet on cognitive health. Proceedings of the Nutrition Society, 72. 140-152. DOI: 10.1017/S0029665112002959

Gerber, M. & Hoffman, R. (2015). The Mediterranean Diet: health, science and society. British Journal of Nutrition, 113. S4-S10. DOI: 10.1017/S0007114514003912

Ghaisas, S., Maher, J. & Kanthasamy, A. (2016). Gut microbiome in health and disease: Linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases. Pharmacology and Therapeutics, 158. 52-62. DOI: 10.1016/j.pharmthera.2015.11.012

Hassel, C. (2005). The craft of cross-cultural engagement. Journal of Extension, 43(6). www.joe.org/joe/2005december/a1.php

Hassel, C.A. (2006). Woodlands Wisdom: A Nutrition Program Interfacing Indigenous and Biomedical Epistemologies. Journal of Nutrition Education and Behaviour, 38(2). 114-120. DOI: 10.1016/j.jneb.2005.11.033

Hassel, C. (2014). Reconsidering nutrition science: critical reflection with a cultural lens. Nutrition Journal, 13(42). DOI: 10.1186/1475-2891-13-42

Hughes, J.C. (2011). What do people with dementia and their carers really need? Neurodegenerative Disease Management, 1(1). 37-42. DOI: http://dx.doi.org.ezproxy.csu.edu.au/10.2217.nmt.11.3

Hoffman, R. & Gerber, M. (2014). Can rapeseed oil replace olive oil as part of a Mediterranean style diet? British Journal of Nutrition, 112(11). 1992-1895. DOI: 10.1017/S0007114514002888

Hvistendahl, M. (2012). My microbiome and me. Science, 336(6086). 1248-1250. DOI: 10.1126/science.336.6086.1248

Jacobs, D.R. & Tapsell, L.C. (2013). Food Synergy: The key to a healthy diet. The Proceedings of the Nutrition Society, 72(2). 200-206. DOI: 10.1017/S0029665112005011

Kamila, A.Y. (2016). Maine med plants seeds for doctors to focus on health impact of food. Portland Press Herald. April 14, 2016. www.pressherald.com/2016/04/13/vegetarian-kitchen-maine-med-plants-seeds-for-doctors-to-focus-on-health-impact-of-food/

Kochilas, D. (2016). www.dianekochilas.com/glossary-of-edible-wild-greens-2/

Lam, R.E. & Lam, P.J. (2014). Nutrition in dementia. Canadian Medical Association Journal, 186(17). 1319-1320

Lee, A.S., Lee, Y.J., Lee, S.M., Yoon, J.J., Kim, J.S., Kang, D.G., Lee, H.S. (2012). Portulaca oleracea ameliorates diabetic vascular inflammation and endothelial dysfunction in db/db mice. Evidence-Based Complementary and Alternative Medicine, 2012. Article ID: 741824, 9 pages. http://dx.doi.org/10.1155/2012/741824

Liu Y., Nieves, J.W., Stem, Y., Luchsingen, J.A., Scarmeas, N. (2010). Food combination and Alzheimer’s disease risk: a protective diet. Archives of Neurology, 67. 699-706

The London Sun. 2016. April 26. Best Odds Diet to Beat Dementia. [scot region]. Retrieved from http://search.proquest.com.ezproxy.csu.edu.au/docview/1784028946?accountid=10344

Mahlangeni, N.T., Moodley, R. & Jonnalagadda, S.B. (2015). The distribution of macronutrients, antinutrients and essential elements in nettles, Laportea peduncularis susp.peduncularis (River nettle) and Urtica dioica (Stinging nettle). Journal of Environmental Science and Health, 51(3). DOI: 10.1080/03601234.2015.1108806

Mayer, E.A., Knight, R., Mazmanian, S.K., Cryan, J.F., Tilisch, K. (2014). Gut Microbes and the Brain: Paradigm Shift in Neuroscience. The Journal of Neuroscience, 34(46). 15490-15496. DOI: 10.1523/JNEUROSCI.3299-14.2014

Meck, W.H., Williams, C.L., Cermak, J.M. & Blusztajn, J.K. (2007). Developmental periods of choline sensitivity provide an antogenic mechanism for regulating memory capacity and age-related dementia. Frontiers in Integrative Neuroscience, 1(7). 1198-1206

Moerman, D. (1998). Native American Ethnobotany. Portland. Timber Press

Morgan-Jones, P. (2014). Don’t give me eggs that bounce! HammondCare media. Australia.

Morris, M.C. (2012). Nutritional determinants of cognitive aging and dementia. Proceedings of the Nutrition Society, 71(1). 1-13

Morris, M.C. (2016). Nutrition and risk of dementia: overview and methodological issues. Annals of the New York Academy of Sciences, 1367. 31-37. DOI: 10.1111/nyas.13047

Mrs Caldicot’s Cabbage War (2002). Arrow Film Distributors. United Kingdom. https://en.wikipedia.org/wiki/Mrs-Caldicot%27s_Cabbage_War.

Naska, A. & Trichopolou, A. (2014). Back to the future: The Mediterranean diet paradigm. Nutrition, Metabolism and Cardiovascular Diseases, 24(3). 216-219. DOI: 10.1016/j.numecd.2013.11.007

Negrato, C.A., Tarzia, O., Jovanovič, L., Chinellato, L.E. (2013). Periodontal disease and diabetes mellitus. Journal of Applied Oral Science, 21(1). 1-12. DOI: 10.1590/1678-7757201302106

Ngandu, T., Lehtisalo, J., Solomon, A., Levalahti, E. … Laatikainen, T. (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial. Lancet, 385. 2255-2263

Perez, L., Heim, L., Sherzai, A., Jaceldo-Siegl, K., Sherzi, A. (2012). Nutrition and vascular dementia. Journal of Nutrition, Health and Aging, 16(4). 319-324

Perlmutter, D. (2013). Epigenetics as Fuel for Brain Health. Alternative and Complementary Therapies, 19(1). 9-12. DOI: 10.1089/act.2013.19103

Philpott, G. (2014). Nutrition and Dementia: Pooling Global Knowledge. INsite, 8(6). 14-15. www.insitemagazine.co.nz/issues/august-2014/nutrition-and-dementia-pooling-global-knowledge/#.V6fngbh96Uk. Accessed 08.08.2016

Prince, M., Wimo, A., Guerchet, M., Ali, G.C., Wu, Y., Prina, M. (2015). World Alzheimer Report, 2015. The Global Impact of Dementia: An Analysis of prevalence, Incidence, Cost and Trends. Alzheimer’s Disease International (ADI), London. https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf Accessed 08.08.2016

Ramirez-Bermudez, J. (2012). Alzheimer’s Disease: Critical Notes on the History of a Medical Concept. Archives of Medical Research, 43(8). 592-599. DOI: 10.1016/j.arcmed.2012.11.008

Rautemaa, R., Lauhio, A., Cullinan, M.P., Seymour, G.J. (2007). Oral Infections and systemic disease –an emerging problem in medicine. Clinical Microbiology and Infection, 13(11). 1041-1047. DOI: 10.1111/j.1469-0691.2007.01802.x

Rowe, M. (2014). Maggie Beer’s campaign to improve the meals in aged-care homes. The Australian, July 5, 2014. www.theaustralian.com.au/archive/executive-living/maggie-beers-campaign-to-improve-the-meals-agedcare-homes/news-story/C6d64dc761698836ecacf300ce1e6603

Saulle, R., Seymyonov, L., La Torre, G. (2013). Cost and cost-effectiveness of the Mediterranean Diet: Results of a systematic review. Nutrients, 5(11). 4566-4586. DOI: 10.3390/nu.5114566

Servili. M., Sordini, B., Esposto, S., Urbani, S. … Taticchi, A. (2014). Biological Activities of Phenolic Compounds of Extra Virgin Olive Oil. Antioxidants, 3(1). 1-23. DOI: 10.3390/antiox3010001

Sherman, F.T. (2003). Nutrition in advanced dementia. Geriatrics, 58(1). 11-12.

Slavin, J. (2012). Dietary Guidelines: Are we on the right path? Nutrition Today, 47(5). 245-251. DOI: 10.1097/NT.0b013c31826c50af

Van der Zwaluw, N.L., van de Rest, O., Tieland, M., Adam, J.J., Hiddink, G.J., van Loon, L.J.C., de Groot, L.C. (2014). The impact of protein supplementation on cognitive performance in frail elderly. European Journal of Nutrition, 53. 803-812

Willett, W.C., Sacks, F., Trichopolou, A., Drescher, G. & Al, E. (1995). Mediterranean diet pyramid: A cultural model for healthy eating. The American Journal of Clinical Nutrition, 61(6). Retrieved from http://serach.proquest.com.ezproxy.csu.edu.au/docview/231918341?accountid=10344

Wolfs, C.A.G, Kessels, A., Dirksen, C.D., Severens, J.L. & Verhey, F.R.J. (2008). Integrated multidisciplinary diagnostic approach for dementia care: randomised controlled trial. The British Journal of Psychiatry, 192(4). 300-305. DOI: 10.1192/bjp.bp.107.035204

Wright, C.M (2011). Biographical notes on Ancel Keys and Salim Yusuf: origins and significance of the Seven Countries Study and the INTERHEART Study. Journal of Clinical Lipidology, 5(6). 434-440. DOI: 10.1016/j/jcd.2011.09.003

Willcox, B., Willcox, C. & Suzuki, M. (2001). The Okinawa Way: How to improve your health and longevity dramatically. Penguin Books, London. England. ISBN: 0-718-14494-5

Valls-Pedret, C., Sala-Vila, A., Serra-Mir, M., Corella, D., de la Torre, R. … Rose, E. (2015). Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. JAMA Internal Medicine, 175(7). 1094-1103. DOI: 10.1001/jamainternmed.2015.1668

Why have I chosen to pursue a career in Food & Nutrition?

It’s such a small word, ‘why’ isn’t it? Three little letters. It’s not Latin or Greek, it doesn’t belong exclusively to any discipline. In fact it’s a rather special relative pronoun that pertains to reason. It is also the biggest small word known to humanity, and is rarely, if ever, a question with a one-dimensional answer. The reasons behind our eventual choices and actions are rarely neatly empirical and the threads linking the reasons as complex and individual as people themselves. On that note, I want you to think of my ‘Why’ as a tapestry. It’s a rich and detailed story-image with thousands of individual threads. From a distance you will see blocks of obvious colour and familiar images. If you step closer, -nose right up to the tapestry itself, you will see tiny flecks of gold thread, a whisper of a purple that serves to highlight, a sky-blue that wasn’t visible only a step away. You will also notice that each thread contains further winding strands and fibres, almost like a DNA helix. Because you know your basic genetics, you will also know (although you won’t see this without your microscope) that this fine helix can be further broken down on a molecular and even atomic level. So as I use the somewhat clumsy broad strokes of language to attempt an answer to ‘Why’, remember the tapestry and look for those intrinsic but perhaps hidden threads. Like the mycelium in the forest floor, each thread is connected and reliant on the network itself to produce the precise conditions for growth and development. I am the sapling.

Let us begin with a distant view. This is the image that is likely to be obvious to anyone observing this tapestry. It’s all plants. Vegetables, fruits, grains, nuts, seeds. An abundant cornucopia of micro and macronutrients in a riot of colours and textures. This picture tells you that I am a vegetarian, or one that follows a plant-based diet. As a freckly, spindly girl I visited my uncle’s farm in Armidale one summer. I was excited to learn that we would be allowed to help that day with ‘dingo-baiting’. This was in the 1980’s when Dingoes had attained an almost mystical status in the public perception as vicious outback baby-killers. The adults around me assured me that we must poison these terrifying beasts in order to safeguard the new lambs and calves. Fair enough. You don’t question authority to any great extent at 10 years old. I think I imagined the ‘bait’ would be a bit like the plastic squares we put down to kill cockroaches at home. I did not expect to see a calf shot point-blank in the head and then chopped up into bloody pieces under a large circular timber saw. I never ate meat again. The next 10 years involved a great deal of research on my part regarding the benefits of Vegetarian diets and their suitability for health. My food choices were questioned daily by well-meaning elders and friends convinced I would fade away from protein, B12 or iron deficiency. Eventually, I surmised that a qualification in Nutrition was necessary, if my informed ‘opinion’ was ever to be taken seriously. I was also quite prepared to be proven wrong, but only by the weight of scientific evidence!

Another thread, and one that links every other in this picture is my genuine Love (yes, big ‘L’) of growing, harvesting and preparing food. To my mind, there is nothing in the world more beautiful to the senses: my eyes, my heart and my soul than a heavily laden apple tree glistening in the autumn mist. Plucking and biting into that red orb lights up neural pleasure pathways usually associated with the other big ‘L’…as does walking through a verdant vegetable garden, or spotting a knobbly heirloom squash nestled secretly beneath a canopy of leaves. The shared pleasure and extraordinary flavour of a lovingly prepared garden-to-plate meal is one that our industrialised food systems cannot match. Food has become a commodity, a set of nutrients, a conveniently packaged means of getting through each day. We have lost our connection to the soil, to its teeming army of microorganisms and to the food we wrest from its bosom. To me, this is not just a shame, it is a broken system. My studies scream that our mental, physical, social and planetary health cry out for a serious system adjustment. Food biodiversity, availability and sustainability have become questions we can no longer ignore, and as farming practise becomes more and more regulated and defined by corporate need, our population becomes sicker and increasingly disillusioned with the status quo. Yes, I have a burning need to be one of those at the vanguard of a solution.

This 'reality' makes me both sad and angry. Health: As a society, we are obsessed with it (and its less-quantifiable sister ‘wellness’) and yet the prevalence of diet-related disease climbs steadily with every passing year. In the 2008 Health Impact Assessment Report, the Sydney West Area Health Service identified The Lithgow LGA (my current home and area of future practise) as well above the NSW State average for obesity, diabetes, hospitalization due to digestive disorders, colorectal and prostate cancer incidence, and cardiovascular disease and urged the Lithgow City Council to develop initiatives to protect and promote community health¹ . The statistics say it, and I see it. Every day. As a University trained Nutritionist I can positively affect these outcomes. With my upcoming Masters in Gastronomy & Tourism I hope to approach food from another angle entirely, -that of the human need for pleasure/hedonism/beauty. As a gardener and qualified agroecologist, and passionate local food activist, I can pull further threads into this tapestry via initiatives like the Portland CSAI² 

 Current research into the crucial composition of the gut microbiome and its epigenetic effects shows more than ever the enormous impact of food choices and contact with the soil/animal microbiomes on human health^3,4,5. Like most people, I want my time on this earth to have been meaningful and useful. A career in Food, Nutrition and Public health is the picture painted by my own personal tapestry of ‘whys’…and it excites me every single day.

1.       1. SWAHS. Sydney West Area Health Service, NSW Health (2008). Health Impact Assessment Report of Lithgow City Council Strategic Plan 2007.  hiaconnect.edu.au/wp-content/uploads/2013/04/Lithgow_HIA_Report.pdf

2.       http://www.abc.net.au/news/2015-11-30/call-to-transform-old-portland-cement-works-site-into-market-ga/6984874

3.       Konkel, L. (2013). The environment within: Exploring the role of the gut microbiome in health and disease. Environmental Health Perspectives (Online), 121(9) Retrieved from https://search-proquest-com.ezproxy.csu.edu.au/docview/1661374987?accountid=10344

4.       Rehman, A., Rasuch, P…Ott,S (2016). Geographical patterns of the standing and active human gut microbiome in health and IBD. British Medical Journal, 65 (2)

5.       Qin, J., Li, R., Raes, J. et al (2010). A human gut microbial gene catalogue established by metagenomics sequencing. Nature, 464. Pp 59-65 doi: 10.1038/nature08821

GENETIC TESTING FOR INDIVIDUAL MTHFR POLYMORPHISMS: CLINCAL RELEVANCE AND ETHICAL CONSIDERATIONS IN THE TOP 3 WORLDWIDE CAUSES OF MORBIDITY AND MORTALITY.

INTRODUCTION

According to the World Health Organization Cancer, Type II Diabetes and Cardiovascular Disease represent the world’s leading causes of morbidity and mortality. Cancer accounted for 7.6 billion, or 13% of all deaths, 346 million people have diabetes with 3.4 million of those dying as a direct result of high blood sugar, and 17.3 million people died from Cardiovascular disease in 2008, representing 30% of all global deaths (Worldwide death rates from cancer, 2014; Worldwide death rates from diabetes, 2014; Worldwide death rates from cardiovascular disease, 2014). Population-based epidemiological evidence has clarified the role of diet in preventing and controlling morbidity and mortality resulting from these NCDs  (non-communicable diseases) (WHO 2003, Hobbs et al. 2014; McMahon & Amaya, 2013; Hosking & Danthiir, 2013; Annema et al., 2011). Stemming from the overwhelming evidence regarding dietary intake and disease risk, International Government bodies have focused on encouraging higher relative consumption of fruits, vegetables and whole grains within the population’s daily food intake via evidence-based macro and micronutrient recommendations (Rodriguez & Miller, 2015; Australian Dietary Guidelines, 2013). The Recommended Daily Intake (RDI) value, for example, reflects the levels of essential nutrients considered adequate to meet the nutritional needs of most healthy people and are based on age, gender, level of physical activity, and pregnancy/lactation status (Brownie, Muggleston & Oliver, 2015).  Recent genetic research however. indicates that individual genetic polymorphisms, such as those on the MTHFR gene may result in substantial relative risk changes for the aforementioned diseases through epigenetic mechanisms (Kasapoglu et al, 2015; Huemer et al., 2016), requiring a far more individualised approach to recommended nutrient intake and overall dietary pattern. Despite these emerging variations in individual vs population genetic responses to diet and nutrient intake, the application of Nutrigenetics and Nutrigenomics to individual nutrition consultation and dietary recommendation remains ethically controversial (Paulidis, Patrinos & Katsila, 2015; Ferguson, 2014). This paper elucidates the relationship between the aforementioned NCDs and MTHFR gene mutations and addresses both sides of the argument regarding current and potential therapeutic applications, however, until definitive evidence is presented supporting these therapeutic interventions, the usage is not recommended .

CURRENT DIAGNOSIS AND TREATMENT

Cancer, Type II Diabetes and Cardiovascular Disease are all recognised as having both genetic and dietary/lifestyle aetiologies (Eng, 2011; Printz, 2013; Nankervis, 2015; Dupas et al. 2016; Yu, 2016). Hereditary breast and ovarian cancers are linked to BRCA1 and BRCA2 genes, while MLH1 and MSH2 are linked to hereditary colon cancer (Eng, 2011). Type II Diabetes is associated with 70 genomic regions that commonly involve mutations in transcription factors HNF1á and HNF4á that affect insulin secretion (Nankervis , 2015). Cardiovascular disease has been associated with alcohol dehydrogenase, aP2, CCR2 and CCR5, PPARG2, lymphotoxin-a, ABCA1, a common variant at 9p21, NFKB1 and ADRb1 (Yu et al., 2016). More recently, mutations on the MTHFR gene have been linked to all of these diseases in both homozygotic and heterozygotic individuals. Pathogenic mutations associated with an autosomal recessive error of folate metabolism lead to increased homocysteine levels and alteration of gene expression via methylation (Levin & Varga, 2016).

Genetic predisposition is only one of many non-dietary factors at play in the development and emergence of NCDs. Economic, social, climatic, cultural, psychological and even polymorphisms in circadian genes influence the hereditability of these diseases (Almon et al. 2012; Shanmugam et al. 2013). As a result the global health community has recognised that social, economic and political environments drive disease emergence just as, or more strongly, than genetics, biology and individual choice. Combating the major causes of chronic NCDs, rather than new symptom management in an acute care setting is the major focus of the WHO’s Global Coordination Mechanism for NCDs. Prevention is prioritized (Allen, 2016). It is precisely this focus on prevention however that is driving frantic research into the MTHFR gene mutations implicated in chronic NCDs. Identifying at-risk individuals and adjusting specific nutrient values according to their individual polymorphism has been strongly embraced by both the scientific research community and the allied health internet communities as a potentially powerful prevention strategy (Kasapoglu et al. 2015; Shiao et al. 2016; Clarke et al. 2016; Culson et al. 2015; Lynch 2016; Skeptical Raptor’s blog 2015). The multi-system effects of genetic methylation variation due to MTHFR polymorphisms do suggest that a greater understanding of these mutations and the epigenetic effects of diet and lifestyle on the phenotype may be key to targeted prevention of NCDs, however individual genetic testing and its application to disease prevention is still mired in controversy.

MTHFR COMMON MUTATIONS AND PHENOTYPIC EXPRESSION

MTHFR, the methylenetetrahydrofolate reductase gene has been widely investigated regarding epigenetics and human disease (Mcbride & Koehly 2017; Wade, Mcbride, Kardia & Brody, 2010). Showing an autosomal recessive inheritance pattern, the two most common loci exhibiting polymorphism mutations on the gene  are C677T and A1298C. These two single nucleotide polymorphisms are about 2,000 base-pairs apart  (http://ghr.nlm.nih.gov/gene/MTHFR). The MTHFR enzyme, coded by the MTHFR gene is responsible for homocysteine remethylation to methionine. It catalyzes reduction of 5,10- methylenetetrahydrofolate to 5-methylenetetrahydrofolate, the most common form of folate in blood, tissues and cerebrospinal fluid. This folate form  acts as a methyl donor for the methylation of homocysteine to methionine. In those with MTHFR deficiency, this methylation is decreased so plasma levels of homocysteine remain elevated while methionine levels are at low concentrations (Burda et al. 2015). Low methionine then leads to a lack of S-adenosylmethionine which is the primary donor for many important methylation reactions including creatine synthesis and RNA and DNA methylation (Huemer et al. 2016 ).

Figure 1: Simplified metabolic pathways involving 5,10-methylenetetrahydrofolate reductase (MTHFR) adapted from Botto & Young, 2000.

Enzyme function in affected individuals varies according to hereditability patterns. With an MTHFR 677TT homozygous mutation, 70% of enzyme function is lost compared to 35% in a heterozygous mutation. In MTHFR 1298CC mutations the respective loss of function is 30% (homozygous) and 15% (heterozygous). In rare cases, individuals can exhibit compound polymorphisms or mutations at both loci and will be at increased risk of developing health problems with both neurological and vascular symptoms (Shiao & Yu, 2016).

The resulting low plasma folate/high plasma homocysteine levels associated with MTHFR mutation and their association with Cancer, Cardiovascular disease, neurodevelopmental disease and Type II Diabetes have been repeatedly researched, as folate, the MTHFR gene, and methylation pathways are critical to basic biological processes involving DNA and protein methylation  as well as DNA replication and mutation (Inoue-Choi et al. 2013; Jamaluddin, Young & Wang, 2007; Crider et al. 2012). Additionally, individuals with gene mutations in methylation pathways have been shown to be compromised in their ability to process environmental pollutants, with air pollution causing as much damage as that caused by cigarette smoking ( Kloog, Ridgeway, Koutrakis, Coull & Schwartz, 2013).

Despite the effect of MTHFR mutations on the most fundamental biological processes and the broader implications of these effects, many recent studies have found inconclusive evidence for high plasma homocysteine levels and resulting disease states  (Marti-Carvajal et al. 2009;  Greenland et al. 2010). With conflicting results and uncertainty as to clinical implications, most worldwide health authorities recommend against testing for MTHFR polymorphisms  (Levin & Varga, 2016). Further, high plasma homocysteine and low folate levels can be routinely and inexpensively treated via dietary changes or supplementation with folate, B₁₂ and B₆ (Prachi et al. 2010) although the form of folate supplementation (Folic acid vs. Folinic acid) is still hotly debated (Hyland et al. 2010; Diekman et al. 2014). According to the Academy of Nutrition and Dietetics:

"There is insufficient evidence regarding C677T polymorphism in the MTHFR gene to modify current folate recommendations from those provided in the Dietary Reference Intakes ." (Camp & Trujillo, 2014).

Despite this statement, pilot studies have been undertaken to treat C677T polymorphisms via dietary intervention, with results suggesting that personalized dietary recommendations based on individual genetic makeup and nutritional status are not only effective, but may reduce further somatic complications and the social costs of these diseases (Di Renzo et al. 2014 ).

ETHICS

With over 10% of the Australian population homozygous or compound heterozygous for these polymorphisms, it is perhaps not surprising that referrals for MTHFR polymorphism testing and counselling are on the increase (Long & Goldblatt, 2016), despite no clinically significant interventions that can reasonably be offered to carrier of the polymorphism (MTHFR Support Australia). Companies like 23andMe and Navigenics offer genetic testing for as little as US $99 to absolutely anyone with internet access, although as they are both American companies, GINA (the Genetic Information Nondiscrimination Act) does not apply to Australian consumers of their services. The Australian Law Reform Commission outlines that although insurance companies, for example, cannot ask an individual to undergo genetic testing, they have every right to pursue whatever genetic information may be available for underwriting purposes (ALRC, 2016). It could be argued that the ethics of genetic testing is at least as complex as the genome itself. While genetic testing enables the detection of new diseases and leads to improved clinical interventions, there remains a high level of concern regarding its social implications (Alper et al. 2002).

Knowing about the intricacies of one’s genome affects how people see themselves, their social identity, and even leads to new kinds of individual risk behaviours ( Arribas-Ayllon, Sarangi & Clark, 2011). The argument quickly boils down to the ‘the right to know’ vs ‘the right not to know’ and must focus on both individual autonomy and societal mores simultaneously (Hunt, Castaneda & Voog, 2006; Gross & Shwval, 2008). The increased anxiety, social stigma and potential discrimination resulting from poorly interpreted or incomplete genetic testing may actually end up opposing one of the oldest medical principles of all: Primum non nocere (Domaradzki, 2015). A psychiatrist friend of mine suggested that I start this paper with “It was a dark and stormy night on Wisteria Lane…” 

and although he was being as facetious as is expected of a long-term friend and academic, his suggested literary trope for this topic (‘mystery’) was not entirely misplaced. The palpable public fear and mistrust of scientific method and genetic manipulation, whether actual or simply the fear of one portion of humanity holding greater power over the individual through advanced knowledge in genetics, cannot be dismissed lightly. With every advance in epigenetics and nutrigenomics comes a responsibility for balanced and ethical stewardship of information accessibility and dissemination  (Pinigree, 2008).

REFERENCES

Allen, L. (2016). Prevention is better. New Scientist, 231(3086). 18-19 

Almon, R.R., DuBois, D.C., Sukumaran, S., Wang, X., Xue, B., Nie, J., Jusko, W. (2012). Effects of High Fat Feeding on Liver Gene Epxression in Diabetic Goto-Kakizaki Rats. Gene Regulation and Systems Biology, 6. 151-165’

Alper, J.S., Ard, C., Ash, A., Beckwith, J. et al. (2002). The double-edged helix. Social implications of genetics in a diverse society. Baltimore, Johns Hopkins University Press, 2002.

ALRC (2016) www.alrc.gov.au/publications/26-genetic-discrimination-insurance/existing-regulatory-framework. Accessed 03/04/2017

Annema, N., Heyworth, J.S., McNaughton, S.A., Lacopetta, B., Fritschi, L. (2011). Fruit and Vegetable Consumption and the Risk of Proximal Colon, Distal Colon, and Rectal Cancers in a Case-Control Study in Western Australia. Journal of the American Dietetic Association, 111(10). 1479-1490  doi: http://dx.doi.org.ezproxy.csu.edu.au/10.1016/j.jada.2011.07.008

Arribas-Ayllon, M., Sarangi, S., Clark, A. (2011). Genetic testing: Accounts of autonomy, responsibility and blame. London, Routledge.

Australian Dietary Guidelines Introduction [online] (2013). Journal of the Home Economics Institute of Australia, 20(1). 8-17

Botto, L.D. & Yang, Q. (2000). 5,10-methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. American Journal of Epidemiology, 151(9). 862-877

Brownie, S., Muggleston, H. & Oliver, C. (2015). The 2013 Australian dietary guidelines and recommendations for older Australians. Australian Family Physician, 44(5). 311-315

Burda, P., Schäfer, A., Suormala, T. et al. (2015). Insights into severe 5.10-methylenetetrahydrofolate reductase deficiency: Molecular genetic and enzymatic characterization of 76 patients. Human Mutation, 36(6). 611-621

Clarke, R., Halsey, J., Lewington, S., Lonn, E., Armitage, J., Manson, J.E. et al. (2010). Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer and cause-specific mortality: meta-analysis of 8 randomized trials involving 37, 485 individuals. Archives of Internal Medicine, 170(18). 1622-1631

Crider, K.S., Yang, T.P., Berry, R.J. & Bailey, L.B. (2012). Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s role. Advances in Nutrition, 3(1). 21-38

Culson, N.J., Naug, H.L., Nikbakht, E., Zhang, P., McConnack, J. (2015). The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies. European Journal of Nutrition, 1-14. Advanced online publication.  Doi: 10.1007/s00394-015-1076-x.

Diekman, E.F., de Koning, T.J., Verhoeven-Duit, N.M., Rovers, M.M., van Hasselt, R.M. (2014). Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurologica, 71(2). 188-194

Di Renzo, L., Marsella, L.T., Sarlo, F., Soldati, L., Gratten, S., Abenavoli, L., De Lorenzo, A. (2014). C677T gene polymorphism of MTHFR and metabolic syndrome: response to dietary intervention. Journal of Translational Medicine, 12. P 329.  Doi: 10.1186/s12967-014-0329-4

Domaradzki, J. (2015). Patient rights, risks, and responsibilities in the genetic era –a right to know, a right not to know, or a duty to know? Annals of Agricultural and Environmental medicine, 22(1). 156-162

Dupas, J., Goanvec, C., Feay, A., Guernec, A., Guerrero, F., Mansouriti, J. (2016). 0021: Type II diabetes induced by a fructose enriched diet: benefits of exercise training. Archives of Cardiovascular Disease supplements, 8(3). P 265

Eng, C. (2011). Cancer Genetics. The Journal of the American medical Association, 305(22). P 2353

Ferguson, L.R. (2014). Nutrigenomics and nutrigenetics in functional foods and personalized nutrition. Boca Raton, Florida: CRC Press/Taylor & Francis Group.

Gross,S.E. & Shwval, J.T. (2008). On knowing and believing: prenatal genetic screening and resistance to ‘risk-medicine’. Health, Risk & Society, 10(6). 549-564  doi: 10.1080/13698570802533721

Hobbs, M., Pearson, N., Foster, P.J., Biddle, S.J.H. (2014). Sedentary behaviour and diet across the lifespan: an updated systematic review. British Journal of Sports Medicine, 49(18). http://dx.doi.org/10.1136/bjsports-2014--093754

Hosking, D. & Danthiir, V. (2013). Retrospective lifetime dietary patterns are associated with demographic and cardiovascular health variables in an older community-dwelling Australian population. British Journal of Nutrition, 110(11). 2069-2083   doi: https://doi.org.ezproxy.csu.edu.au/10.1017/500711451300144X

http://ghr.hlm.nih.gov/gene/MTHFR

Huemer, M., Mulder-Bleile, R., Burda, P. … Morris, A. et al. (2016). Clinical pattern, mutation and in vitro residual activity in 33 patients with severe 5,10 methylenetetrahydrofolate reductase (MTHFR) deficiency. Journal of Inherited Metabolic Disease, 39(1). 115-124

Hunt, L.M., Castañeda, H., de Voog, S. (2006). Do notions of risk inform patient choice? Lessons from a study of prenatal genetic counselling. Medical Anthropology, 25(3). 193-219

Hyland, K., Shoffner, J., Heales, S.J. (2010). Cerebral folate deficiency. Journal of Inherited Metabolic Disease, 33(5) 563-570

Inoue-Choi, M., Nelson, H.H., Robien, K., Arning, E., Bottiglieri, T., Koh, W., Yuan, J. (2013). Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore. BMC Cancer, 13. 389.  Doi: 10.1186/1471-2407-13-389

Jamaluddin, M.S., Yang, X. & Wang, H. (2007). Hyperhomocysteinemia, DNA methylation and vascular disease. Clinical Chemistry and Laboratory Medicine, 45(12). 1660-1666.

Kasapoglu, B., Turkay, C., Yakin, K.S., Kosov, A., Bozkurt, A. (2015).MTHFR 677C/T and 1298 A/C mutations and non-alcoholic fatty liver disease. Clinical Medicine, 15(3). 248-251

Kloog, I., Ridgway. B., Koutrakis, P., Coull, B.A., Schwartz, J.D. (2013). Long- and short-term exposure to PM2.5 and mortality: using novel exposure models. Epidemiology, 24(4). 555-561

Levin, D.L. & Varga, E.J. (2010). MTHFR. Addressing Genetic Counselling Dilemmas Using Evidence-Based Literature. Journal of Genetic Counselling, 25. P 901. Doi: 10.1007/s10897-016-9956-7

Lang, S. & Goldblatt, J. (2016). MTHFR genetic testing: Controversy and clinical implications. Australian Family Physician, 45(4). 237-240

Lynch, B. (2016). MTHFR.Net: your expert resource on MTHFR Gene Mutations. Retrieved from http:///www.mthfr.net

Marti-Carvajal, A.J., Sola, I., Lathyris, D., Salanti, G. (2009). Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database System Reviews, 4: CD006612. Doi: 10.1002/12651858.CD006612.pub.2

McBride, C.M. & Koehly, L.M. (2017). Imagining roles for epigenetics in health promotion research. Journal of Behavioural Medicine, 40(2). 229-238

McMahon, S. & Amaya, G. (2013). Obesity Prevention in Urban Settings: Creating Healthy Environments. American Journal of Health Sciences, 4(1). 45-50

Nankervis, A. (2015). Genetics in Diabetes: Type 2 Diabetes and Related Traits. Australian Family Physician, 44(5). P.333

Paulidis, C., Patrinos, G.P., Katsila, T. (2015). Nutrigenomics: A controversy. Applied and Translational Genomics, 4. 50-53

Pinigree, R.J. (2008). Is there truth out there? Neutral reporting and epistemic political efficacy. (Order No. 3327808), Available from ProQuest Dissertations and Theses Global. (304457675). Retrieved from https://search-proquest-com.ezproxy.csu.edu.au/docview/304457675?accountid=10344

Prachi, K., Dattaray, B., Lubree, H., Otivi, S., Jushi, S. et al. (2010). Vitamin B12 and folic acid supplementation and plasma total homocysteine concentrations in pregnant Indian women with low B12 and high folate status. Clinical Nutrition, 19(3). 335-343

Printz, C. (2013). Researchers continue to explore links between diet and cancer. Cancer, 119. 1447-1448

Rodriguez, N.R. & Millder, S.L. (2015). Effective translation of current dietary guidelines: understanding and communicating the concepts of minimal and optimal levels of dietary protein. American Journal of Clinical Nutrition, 101(6). 1353-1358

Shanmugam, V., Wati, A., Al-Taweel, N., Busselberg, D. (2013). Disruption of circadian rhythm increases the risk of cancer, metabolic syndrome and cardiovascular disease. Journal of Local and Global Health Science, 3. Doi: 10.5339/jlghs.2013.3

Shiao, S.P.K. & Yu, C.H. (2016). Meta-prediction of MTHFR Gene Polymorphism Mutations and Associated Risk for Colorectal Cancer. Biological Research for Nursing, 18(4). Doi: 10.1177/1099800415628054

Skeptical Raptor’s Blog (7^th May 2015). MTHFR gene mutations are the root of all health problems. Skeptical Raptor’s Blog: GENETICS, Nutrition, Vaccines. Retrieved from: http://www.skepticalraptor.com/skeptical/raptorblog.php/mthfr-gene-mutations-are-the-root-of-all-health-problems/.

Wade, C.H., McBride, C.M., Kardia, S.L., Brody, L.C. (2010). Considerations for designing a prototype genetic test for use in translational research. Public Health Genomics, 13(3). 155-165

WHO (2003). Diet, Nutrition and the prevention of diseases. Wolrd Health Organization, 20 Avenue Appia. Geneva Ch-1211. Switzerland.

Worldwide death rates from cancer. (2014, April 19). Retrieved from World Health Organisation: http://www.who.int/mediacentre/factsheets/fs297/en

Worldwide deaths from cardiovascular disease. (2014, April 19). Retrieved from World Health Organisation: http://www.who.int/mediacentre/factsheets/fs317/en

Worldwide death rates from diabetes (2014, April 19). Retrieved from World Health Organisation: http://www.who.int/mediacentre/factsheets/fs312/en/.

Yu, E., Rimm, E., Qi, L., Rexrode, K., Albert, C.M. et al. (2016). Diet, Lifestyle, Biomarkers, Genetic Factors, and Risk of Cardiovascular Disease in the Nurse’s Health Studies. American Journal of Public Health, 106(9). 1618-1623

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