- Open Access
Food Synergy: The Key to Balancing the Nutrition Research Effort
Public Health Reviewsvolume 33, pages507–529 (2011)
Mediterranean-type diet patterns are consistently associated with reduced risk for cardiovascular disease, diabetes, and cancer in the general population. In contrast, several randomized controlled trials (RCTs) focusing on nutrient supplements have shown no or adverse long-term effects on long-term chronic disease. Food in its natural form is a nonrandom mixture of numerous molecules, orchestrated evolutionarily to maintain the life of the organism being eaten. Food synergy assumes that the biologically determined combination of nutrients and other bioactive substances found in food plays a concerted role in influencing health. Coupled with reduced risk in the Mediterranean-type diet pattern, food synergy implies that the concerted action of nutrients and other bioactive substances in fruit, vegetables, whole grain cereals, nuts, and legumes is beneficial for health. The assumption that single molecules work in isolation as they work in food violates the food synergy concept of concerted action and often leads to a partial picture. Public health nutrition strategies that focus on single nutrients have led to a flourishing diet supplement industry and advice to the public to eat low-fat diets. The latter is questionable in two respects: not all fats are equal, and industry efforts to comply spun-off products high in refined carbohydrates. It is time to rethink the research paradigm concerning diet and health. Reductionist research, though valuable, focuses on partial pathways, rather than the whole system integrating a lifetime of food intake with the long-term health of intact humans. Epidemiology provides this information, but is subject to residual confounding. RCTs are useful, but RCTs of food differ fundamentally from RCTs of drugs; for example, in terms of blinding, long-term adherence, and specificity of the reference treatment. All research inferences are most secure when based on convergent evidence from multiple research approaches. A balanced approach is therefore needed in nutrition research.
Jacobs DR, Murtaugh MA. It’s more than an apple a day: an appropriately processed plant-centered dietary pattern may be good for your health. Am J Clin Nutr. 2000;72:899–900.
Messina M, Lampe JW, Birt DF, Appel LJ, Pivonka E, Berry B, et al. Reductionism and the narrowing nutrition perspective: time for reevaluation and emphasis on food synergy. J Am Diet Assoc. 2001;101:1416–9.
Jacobs DR, Steffen LM. Nutrients, foods, and dietary patterns as exposures in research: a framework for food synergy. Am J Clin Nutr. 2003;78:508S–13S.
Jacobs DR Jr, Tapsell LC. Food, not nutrients, is the fundamental unit in nutrition. Nutr Rev. 2007;65:439–50.
Jacobs DR Jr, Gross MD, Tapsell LC. Food synergy: an operational concept for understanding nutrition. Am J Clin Nutr. 2009;89:1543S–8S.
Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006;98:451–9.
Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR. Dietary supplements and mortality in older women: the Iowa Women’s Health Study. Arch Int Med 2011;171:1625–33.
Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, et al. for the DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344:3–10.
He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens. 2009;23:363–84.
Cook NR, Cutler JA, Obarzanek E, Buring JE, Rexrode KM, Kumanyika SK, et al. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP). BMJ. 2007;334:885–8.
World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: AICR; 2007.
Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006;354:1601–13.
Mozaffarian D, Aro A, Willett WC. Health effects of trans-fatty acids: experimental and observational evidence. Eur J Clin Nutr. 2009;63:S5–S21.
Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J, Murray CJ, et al. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med. 2009;6:e1000058.
Rimm E, Temple NJ. What are the health implications of alcohol consumption? In: Temple N, Wilson T, Jacobs DR, editors. Nutritional health: strategies for disease prevention. Totowa, New Jersey: Humana Press; 2006. p.211–21.
Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009;169:659–69.
McCullough ML, Feskanich D, Stampfer MJ, Giovannucci EL, Rimm EB, Hu FB, et al. Diet quality and major chronic disease risk in men and women: moving toward improved dietary guidance. Am J Clin Nutr. 2002;76:1261–71.
van Dam RM, Li T, Spiegelman D, Franco OH, Hu FB Combined impact of lifestyle factors on mortality: prospective cohort study in US women. BMJ. 2008;337:a1440.
Lockheart MS, Steffen LM, Rebnord HM, Fimreite RL, Ringstad J, Thelle DS, et al. Dietary patterns, food groups and myocardial infarction: A case-control study. Br J Nutr. 2007;98:380–7.
Nettleton JA, Schulze MB, Jiang R, Jenny NS, Burke GL, Jacobs DR. A priori-defined dietary patterns and markers of cardiovascular disease risk in the multi-ethnic study of atherosclerosis (MESA). Am J Clin Nutr. 2008;88:185–94.
Nettleton JA, Steffen LM, Ni H, Liu K, Jacobs DR Jr. Dietary patterns and risk of incident type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2008;31:1777–82.
Jacobs DR, Sluik D, Rokling-Andersen MH, Anderssen SA, Drevon CA. Association of 1-y changes in diet pattern with cardiovascular disease risk factors and adipokines: results from the 1-y randomized Oslo Diet and Exercise Study. Am J Clin Nutr. 2009;89:509–17.
Heidemann C, Schulze MB, Franco OH, van Dam RM, Mantzoros CS, Hu FB. Dietary patterns and risk of mortality from cardiovascular disease, cancer, and all causes in a prospective cohort of women. Circulation. 2008;118:230–7.
Appel LJ, Moore TJ, Obarzanek E, et al: Aclinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336:1117–1124.
Svetkey LP, Simons-Morton D, Vollmer WM, Appel LJ, Conlin PR, Ryan DH, et al. Effects of dietary patterns on blood pressure: subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial. Arch Intern Med. 1999;159:285–93.
Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Multivitamin use and the risk of mortality and cancer incidence: the multiethnic cohort study. Am J Epidemiol. 2011;173:906–14.
Hardman WE, Ion G, Akinsete JA, Witte TR. Dietary walnut suppressed mammary gland tumorigenesis in the C(3)1 TAg mouse. Nutr Cancer. 2011;63:960–70.
Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.
Willett W. Nutritional Epidemiology. New York: Oxford University Press, 1998.
Jacobs DR. Challenges in research in nutritional epidemiology. In: Temple NJ, Wilson T, Jacobs DR, editors. Nutritional health: strategies for disease prevention. 2nd ed. Totowa, NJ: Humana Press; 2006. p.25–35.
Alonso A, Nettleton JA, Ix JH, de Boer IH, Folsom AR, Bidulescu A, Kestenbaum BR, Chambless LE, Jacobs DR Jr. Dietary phosphorus, blood pressure, and incidence of hypertension in the atherosclerosis risk in communities study and the multi-ethnic study of atherosclerosis. Hypertension. 2010;55:776–84.
Jacobs DR, Pereira MA, Meyer KA, Kushi LH. Fiber from whole grains, but not refined grains, is inversely associated with all-cause mortality in older women: the Iowa women‘s health study. J Am Coll Nutr. 2000;19:326S–30S.
Kish L. Statistical Design for Research. Hoboken, NJ: (Wiley Classics Library) Wiley; 2004.
Blumenthal JA, Babyak MA, Hinderliter A, Watkins LL, Craighead L, Lin PH, et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med. 2010;170:126–35.
Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML, Wassertheil-Smoller S, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295:655–66.
Carty CL, Kooperberg C, Neuhouser ML, Tinker L, Howard B, Wactawski-Wende J, et al. Low-fat dietary pattern and change in body-composition traits in the Women’s Health Initiative Dietary Modification Trial. Am J Clin Nutr. 2011;93:516–24.
Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematicreview and meta-analysis of randomized controlled trials. PLoS Med 2010;7:e1000252.
Jakobsen MU, Dethlefsen C, Joensen AM, Stegger J, Tjønneland A, Schmidt EB, Overvad K. Intake of carbohydrates compared with intake of saturated fatty acids and risk of myocardial infarction: importance of the glycemic index. Am J Clin Nutr. 2010; 91:1764–8.
Kromhout D, Geleijnse JM, Menotti A, Jacobs DR. The confusion about dietary fatty acids recommendations for CHD prevention. Brit J Nutr. 2011;106:627–32.
Shekelle RB, Lepper M, Liu S, Maliza C, Raynor WJ Jr, Rossof AH, et al. Dietary vitamin A and risk of cancer in the Western Electric study. Lancet. 1981;2:1185–90.
Temple NJ, Basu TK. Role of beta-carotene in the prevention of cancer — a review. Nutrition Res. 1988;8:685–701.
Block G. Vitamin C status and cancer. Epidemiologic evidence of reduced risk. Ann N Y Acad Sci. 1992;669:280–90.
Knekt P, Ritz J, Pereira MA, O’Reilly EJ, Augustsson K, Fraser GE, et al. Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts. Am J Clin Nutr. 2004;80:1508–20.
Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, et al. Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials. Int J Cancer. 2010;127:172–84.
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007;297:842–57.
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2008;CD007176.
Hollman PC, Cassidy A, Comte B, Heinonen M, Richelle M, Richling E, et al. The biological relevance of direct antioxidant effects of polyphenols for cardiovascular health in humans is not established. J Nutr. 2011;141:989S–1009S.
Srivastava S, Singh M, George J, Bhui K, Murari Saxena A, Shukla Y. Genotoxic and carcinogenic risks associated with the dietary consumption of repeatedly heated coconut oil. Br J Nutr. 2010;104:1343–52.
Natella F, Nardini M, Belelli F, Scaccini C. Coffee drinking induces incorporation of phenolic acids into LDL and increases the resistance of LDL to ex vivo oxidation in humans. Am J Clin Nutr 2007;86:604–9.
Natella F, Nardini M, Belelli F, Pignatelli P, Di Santo S, Ghiselli A, et al. Effect of coffee drinking on platelets: inhibition of aggregation and phenols incorporation. Br J Nutr. 2008;100:1276–82.
Roberts S, Temple NJ. Medical research: a bettor’s guide. Am J Prev Med. 2002;23:231–2.
Temple NJ. Medical research: a complex problem. In: Temple NJ, Burkitt DB, editors. Western diseases: their dietary prevention and reversibility. Totowa, New Jersey: Humana Press; 1994. p.419–36.
Temple NJ. Nutrition and disease: challenges of research design. Nutrition. 2002;18:343–7.
Burton GW, Ingold KU. beta-Carotene: an unusual type of lipid antioxidant. Science. 1984;224:569–73.
Schwartz J, Suda D, Light G. Beta carotene is associated with the regression of hamster buccal pouch carcinoma and the induction of tumor necrosis factor in macrophages. Biochem Biophys Res Commun. 1986;136:1130–5.
Rhodes J. Human interferon action: reciprocal regulation by retinoic acid and beta-carotene. J Natl Cancer Inst. 1983;70:833–7.
Asmis R, Llorente VC, Gey KF. Prevention of cholesteryl ester accumulation in P388D1 macrophage-like cells by increased cellular vitamin E depends on species of extracellular cholesterol. Conventional heterologous non-human cell cultures are poor models of human atherosclerotic foam cell formation. Eur J Biochem. 1995;233:171–8.
Temple NJ, Thompson A, editors. Excessive medical spending: facing the challenge. Oxford: Radcliffe Publishing; 2007.
McGuire AL, Cho MK, McGuire SE, Caulfield T. The future of personal genomics. Science. 2007;317:1687.
Seshadri N, Robinson K. Homocysteine, B vitamins, and coronary artery disease. Med Clin North Am. 2000;84:215–37.
Stubbs PJ, Al-Obaidi MK, Conroy RM, Collinson PO, Graham IM, Noble IM. Effect of plasma homocysteine concentration on early and late events in patients with acute coronary syndromes. Circulation. 2000;102:605–10.
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006;296:2720–6.
Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027–36.
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010;303:2486–94.
Wolff T, Witkop CT, Miller T, Syed SB; U.S. Preventive Services Task Force. Folic acid supplementation for the prevention of neural tube defects: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;150:632–29.
Hubner RA, Houlston RS. Folate and colorectal cancer prevention. Br J Cancer. 2009;100:233–9.
Mason JB. Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons. Nutr Rev. 2009;67:206–12.
Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009;101:432–5.
Stolzenberf-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, et al. Folate intake, alcohol use and postmenopausal breast cancer risk in the Prostate Lung Colorectal and Ovarian Screening Trial. Am J Clin Nutr. 2006;83:895–904.
Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302:2119–26.