Skip to main content
Download PDF

Food Synergy: The Key to Balancing the Nutrition Research Effort

Public Health Reviews volume 33, pages 507–529 (2011)Cite this article

Abstract

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.

References

  1. 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.

    CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    CAS  PubMed  Google Scholar 

  4. Jacobs DR Jr, Tapsell LC. Food, not nutrients, is the fundamental unit in nutrition. Nutr Rev. 2007;65:439–50.

    PubMed  Google Scholar 

  5. Jacobs DR Jr, Gross MD, Tapsell LC. Food synergy: an operational concept for understanding nutrition. Am J Clin Nutr. 2009;89:1543S–8S.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Google Scholar 

  12. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006;354:1601–13.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  Google Scholar 

  15. 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.

    Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. 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.

    Article  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Willett W. Nutritional Epidemiology. New York: Oxford University Press, 1998.

    Book  Google Scholar 

  30. 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.

    Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Kish L. Statistical Design for Research. Hoboken, NJ: (Wiley Classics Library) Wiley; 2004.

    Google Scholar 

  34. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Temple NJ, Basu TK. Role of beta-carotene in the prevention of cancer — a review. Nutrition Res. 1988;8:685–701.

    Article  CAS  Google Scholar 

  42. Block G. Vitamin C status and cancer. Epidemiologic evidence of reduced risk. Ann N Y Acad Sci. 1992;669:280–90.

    Article  CAS  PubMed  Google Scholar 

  43. 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.

    CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. Roberts S, Temple NJ. Medical research: a bettor’s guide. Am J Prev Med. 2002;23:231–2.

    Article  PubMed  Google Scholar 

  52. 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.

    Chapter  Google Scholar 

  53. Temple NJ. Nutrition and disease: challenges of research design. Nutrition. 2002;18:343–7.

    Article  CAS  PubMed  Google Scholar 

  54. Burton GW, Ingold KU. beta-Carotene: an unusual type of lipid antioxidant. Science. 1984;224:569–73.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. Rhodes J. Human interferon action: reciprocal regulation by retinoic acid and beta-carotene. J Natl Cancer Inst. 1983;70:833–7.

    CAS  PubMed  Google Scholar 

  57. 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.

    Article  CAS  PubMed  Google Scholar 

  58. Temple NJ, Thompson A, editors. Excessive medical spending: facing the challenge. Oxford: Radcliffe Publishing; 2007.

    Google Scholar 

  59. McGuire AL, Cho MK, McGuire SE, Caulfield T. The future of personal genomics. Science. 2007;317:1687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Seshadri N, Robinson K. Homocysteine, B vitamins, and coronary artery disease. Med Clin North Am. 2000;84:215–37.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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.

    Article  Google Scholar 

  65. 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.

    Article  PubMed  Google Scholar 

  66. Hubner RA, Houlston RS. Folate and colorectal cancer prevention. Br J Cancer. 2009;100:233–9.

    Article  CAS  PubMed  Google Scholar 

  67. Mason JB. Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons. Nutr Rev. 2009;67:206–12.

    Article  PubMed  PubMed Central  Google Scholar 

  68. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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.

    Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Minnesota, School of Public Health Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 S 2nd St, Suite 300, Minneapolis, MN, 55454, USA

    David R. Jacobs Jr., PhD (Mayo Professor of Public Health)

  2. The Smart Foods Centre, University of Wollongong, Wollongong, Australia

    Linda C. Tapsell PhD

  3. Centre for Science, Athabasca University, Alberta, Canada

    Norman J. Temple PhD

Authors
  1. David R. Jacobs Jr., PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda C. Tapsell PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norman J. Temple PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David R. Jacobs Jr., PhD.

Rights and permissions

Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Cite this article

Jacobs, D.R., Tapsell, L.C. & Temple, N.J. Food Synergy: The Key to Balancing the Nutrition Research Effort. Public Health Rev 33, 507–529 (2011). https://doi.org/10.1007/BF03391648

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03391648

Key words

  • Food synergy
  • dietary patterns
  • epidemiology
  • research implications
  • reductionism

Public Health Reviews

ISSN: 2107-6952

Contact us