Micronutrient Status Optimization Provides Tremendous Benefit and Should be a Premier Prevention Tool for Personalized, Smart Healthcare in the 21st Century
A Baze Whitepaper
Part 1: Micronutrients are Essential for Our Health, Yet We’re Not Getting Enough
Micronutrients are the vitamins and minerals that are essential for our bodies to both survive and thrive. These nutrients form the foundation for a wide array of metabolic processes necessary for survival: growth and development1, energy production2, blood clotting3, immunity4, and cognitive function5 to name a few.
The importance of micronutrients cannot be overstated6. However, even citizens of developed nations are not getting enough of these nutrients according to the dietary reference intakes (DRIs) for healthy individuals, set forth by the Food and Nutrition Board7.
Over 90% of Americans fail to meet the Estimated Average Requirement (EAR) or the Adequate Intake (AI) for at least one vitamin or mineral8–15, with specific populations being especially at risk16.
The true reality of insufficient micronutrient intake may be even higher than these estimates for two reasons.
- EARs are established for healthy populations only, which leaves out the estimated 60% of American adults managing chronic diseases17.
- EAR values are “set at a level assumed to ensure nutritional adequacy”7 for short term impact, like avoiding scurvy and other diseases of nutrient deficiency, not optimal health for long term well-being. This means the healthy population utilized to determine EAR values may just be apparently healthy as explained by The Triage Theory.
According to the Triage Theory posited by biochemist, nutrition scientist, and National Medal of Science winner Bruce Ames, the body has a built-in rationing system for micronutrients, wherein the body prioritizes survival over longevity when nutrient intake is deficient. He states, the “official EAR values might actually have been set too low, because they did not take long-term triage effects into account, and thus more people would be erroneously considered ‘adequate’”18.
“The triage theory posits that the spectrum of functions for a particular vitamin or mineral (V/M) are managed by the organism such that, when micronutrient availability is limited, functions required for short-term survival take precedence over functions whose loss can be better tolerated (e.g. by selection for micronutrient binding constants or targeted tissue distribution). Ames proposed that a consequence of this evolutionary adaptation is an increase in the risk of chronic diseases of aging when V/M availability is limited.”The “triage theory”: micronutrient deficiencies cause insidious damage that accelerates age-associated chronic disease
Insufficient micronutrient consumption is multifactorial
Evolving factors over time contribute to why we aren’t getting enough micronutrients in our everyday life.
- Consuming processed foods has increased, which takes up a larger percentage of calories in the average diet, leaving less room for nutrient-dense alternatives20.
- Decreased nutrient density in soil decreases the nutrient value of both conventional and organic foods21.
- Increased popularity of fad diets promoting calorie restriction and restrictive diets for medical purposes makes it more difficult to meet nutrient demand22.
- Rising rates of obesity have increased nutrient demand for many larger bodies. This is not taken into account with the DRIs set for healthy populations23.
- Increased medication, antibiotic use, and environmental toxin exposures have increased the physiological demand for metabolism and detoxification-related nutrients24–26.
- Psychological stressors are on the rise, which has been found to be a driver of micronutrient depletion27.
The contributors mentioned above shed light on why the typical argument of “just eat a balanced diet” does not bode well for the majority of Americans. Especially given that even individuals who meet the EAR for essential nutrients still carry a 16% risk for having at least one nutrient deficiency16.
With these factors working against us on a daily basis, the reason behind why insufficiency numbers are so high in our overfed nation becomes clear. It’s not surprising that the term hidden hunger, a form of malnourishment originally coined to describe populations in developing countries, is now being used to describe specific populations in the US as well.
“Hidden hunger is commonly used to describe individuals who may have adequate energy consumption, but suboptimal micronutrient intakes, placing them at risk for nutrition-related diseases. When prolonged, inadequate dietary intake of micronutrients (vitamins and minerals) and macronutrients (fat, protein, and carbohydrates) can have adverse effects on health outcomes that may result in a cycle of sub-optimal health…As hidden hunger may often not show physical symptoms, the condition can be easily overlooked by clinicians and is not always well diagnosed or documented.”From: Hidden Hunger: Solutions for America’s Aging Populations
Suboptimal nutrient status leads to suboptimal health
Poor diet (low intake of fruits, whole grains, nuts and seeds and high intake of sodium for example) accounts for 1 in 5 deaths worldwide, the majority from cardiovascular disease with smaller amounts from cancer and type 2 diabetes29. Perhaps unsurprisingly then, a systematic analysis for the Global Burden of Disease Study 2017 revealed that poor diet is the number one mortality driver; responsible for more deaths than any other risk factor studied29. The State of US Health, 1990-2016 study similarly showed dietary risks to be the leading risk factor for death in the US30.
In addition to mortality, research consistently demonstrates concrete examples of how micronutrient deficits are associated with negative health outcomes.
- Poor vitamin D status (blood levels either too low or too high) is associated with an increased risk of headaches31, liver disease32, diabetes33, multiple sclerosis34, cognitive decline35,36, rheumatoid arthritis37, cancer38–46, hypertension47, heart disease48,49, bone fracture50,51, and death from all causes51.
- Low serum magnesium is linked to an increased risk of coronary heart disease, heart failure, and sudden cardiac death52,53. Low magnesium intake is associated with an increased risk for type 2 diabetes, colorectal and other cancers, hypertension, osteoporosis, and metabolic syndrome54,55.
- Low blood levels of omega-3 fatty acids are associated with higher rates of cardiovascular disease, cognitive decline, melanoma and other cancers, and other non-communicable diseases56–58.
- Low levels of vitamin A increase susceptibility of various infectious diseases59.
- Folate deficiency is associated with various cancers60,61.
- Low levels of vitamin B12 are associated with an increased risk of coronary heart disease62,63, multiple sclerosis64, cognitive decline, and Alzheimer’s disease65.
- Low vitamin E intake is associated with a higher risk of cataracts66.
Adding to these examples, it’s important to keep two additional considerations in mind.
- Blood nutrient level deficiency data is scarce at the population level. Historically researchers and government agencies have relied on surveys and intake assessments to extrapolate status as blood testing has come with headaches at scale (expensive, inconvenient, and time-intensive). This means there could be negative health consequences not yet attributed to blood nutrient levels because we simply don’t test nutrient levels frequently enough at population levels to show any sort of significance.
- Milder forms of one or many nutrient deficits are harder to recognize and attribute symptoms to until a person has gone through advanced stages of biochemical and physiological consequences. These “subclinical deficiencies” may take years to develop into outward symptoms despite causing damage at the molecular level67.
Part 2: How Do We Fix This?
We have demonstrated that optimal nutrient status is one important aspect of survival and longevity; a key factor in which a large majority of Americans are not reaping the benefit. Just as the cause of suboptimal nutrient intake and status is multifactorial, so too is the solution. It cannot be overstated—simply eating a balanced diet is not the ultimate solution, but it is one important piece of the puzzle.
Solutions to this expansive issue can be grouped into two areas: building a diet foundation and optimizing nutrient status.
Building the Foundation:
- Increased diet quality and consumption of nutrient-dense foods68
- Increased biodiversity of the soil69
- Nutritional screenings, particularly in at-risk populations70
- Increased diet education, particularly in at-risk populations71
Optimizing Nutrient Status:
- Targeted nutrients and dietary supplements
- Greater testing and awareness of individual nutrient status
While public health policy drives dietary foundations, the remainder of this paper will focus on how innovatively targeting nutrients through testing and personalized solutions can help close the suboptimal gap.
The supplement paradox
Dietary supplements are one inexpensive and effective solution to optimizing nutrient status when utilized appropriately. Americans seem to agree—77% reported taking dietary supplements according to a 2019 report72, but how effective is this strategy?
While blindly supplementing micronutrients has proven to be somewhat effective in decreasing the percentage of the population who do not meet the EAR intake recommendations10, study after study shows these supplements don’t actualize the hypothesized real health impact. Longitudinal studies executed in both healthy and chronic disease populations found little to no benefit from supplementation in the areas of cognitive function, cancer, cardiovascular disease, prostate cancer, ischemic strokes, and all-cause mortality73–80. Additionally, some found some risk for toxicity or harm with excessive supplemental nutrients over time81,82.
Why aren’t they working as expected?
The problem is simple: the process of how we take supplements is broken. Specifically, it does not take into account the individual micronutrient status and deficiencies when deciding on what and how much to supplement.
The underlying logic to this approach is seen on the molecular level. Many micronutrients actually follow a U-shaped association for optimal status relative to disease risk, with low and high levels both resulting in compromised physiological functioning83. Blind, generic supplementation rarely achieves this often-narrow optimal zone for each nutrient. To understand and then aim for optimal status, status must be accurately measured, not assumed.
Part 3: A Paradigm Shift is Required: Personalized Nutrients Enable People to Feel the Benefits of Optimal Nutrient Status
The work of Baze Scientific Advisory Board member, Dr. Eran Segal, highlights that each individual has specific needs that can only be understood by measuring what’s going on inside their body84,85.
So, given its central importance: how do we best assess nutrient status? Status has conventionally been measured by intake, ascertained through questionnaires and food diaries.
While measuring intake through recalls is more accessible, the reality remains that:
- Nutrient density of food, even the same types of food, is variable86,87.
- Memory-Based Dietary Assessment Methods carry many accuracy and validity issues: failed memory, inaccurate portion estimations, recall bias, etc.88,89.
- Nutrient absorption varies among individuals for a wide range of reasons (genetics, chronic disease, age, etc.)90,91, which diet recalls don’t account for.
Simply put, measuring intake produces unreliable data and unclear expectations around actual nutrient status. Thus, to understand nutrient status, we should not measure intake but instead focus on actual blood nutrient levels. This is one of the key elements that make personalization scientifically sound.
Blood-based biomarkers offer a clear and dynamic window into nutrient status
Blood testing offers superior accuracy compared to other non-analytical approaches. In many cases, the specific blood nutrient level reflects its true stores in the body. Only with blood testing can you determine where an individual falls on the U-curve for optimal status relative to disease risk.
Additionally, while overt deficiencies provide clear symptoms, allowing for prompt intervention, more often, subclinical deficiencies aren’t spotted right away unless you dig deeper. In the case of vitamin B12, for instance, mild deficiency can cause tiredness92. This is a very generic symptom that isn’t very informative on its own but can easily be explained by a blood test.
With today’s state of the art analytical tools, it’s possible to safely and accurately measure micronutrients at the nanomolar level and to follow these levels over time. By doing so, a dynamic plan arises to allow an individual to take action towards optimal status. It is at this optimal status where the maximum impact is achieved, seen, and felt within the body.
Studies show being in optimal nutrient ranges provide countless positive health impacts
A growing body of research on the impact that optimal nutrient levels can have on the quality and longevity of life has been conducted over the past few years. One prominent example is Vitamin D, where a Cochrane review of 56 trials with a combined total of 95,286 participants found that simply intake, i.e. untargeted supplementation of Vitamin D was associated with a 2% lower risk of mortality93. In contrast, Zitterman et al. conducted a meta-study on all the research that looked at optimizing Vitamin D blood nutrient status94. The results showed a staggering 31% decrease in all-cause mortality, demonstrating the efficacy of measuring and dosing for nutrient status as well as the U-shape idea of optimization. Similar impact has been demonstrated for other nutrients. For example, supplementing to the optimal range in vitamin A lowers all-cause mortality by 18%95. Omega-3 fatty acids lower all-cause mortality by 42%96. Zinc shows a similar lowering of mortality by 31% when supplementing to the optimal range97.
Part 4: Baze Case Study: We’re Making It as Easy as Possible to Access and Optimize Nutrient Status in Order to Feel the Most Benefit
Baze gives people the opportunity to measure, optimize, and re-measure the blood status of key, health-driving nutrients and to experience the tangible health impacts. It begins with the “Baze Zone.” This is an individual’s optimal blood level for each essential nutrient—the level at which research has shown real benefits like improved immunity, energy, and longevity. We establish and update Baze Zones for key nutrients as the research evolves. These targets are unique to Baze and form the basis of our entire solution: evidence-driven results.
The process: accessible and actionable
The outcome: personalized and preventative healthcare for all
For the first time ever, we are giving customers the opportunity to truly optimize their nutrient status—because the data is clear on the importance of doing so. And our 2019 internal impact data is impressive. 73% of nutrient deficiencies were resolved after the first 3 months of personalized supplementation. It’s measurable, molecular change that can’t be argued.
Only Baze provides the unique targets, gets smarter and more accurate with re-testing, and can really show how the actions customers take overtime actually change their biometrics. This 360-degree approach is revolutionary while also being really simple, and it’s never been accessible in the way it is today.
We’re excited to continue to grow and expand both the data inputs (additional biomarkers and health and lifestyle data that helps better adjust the individual nutrient dosage) and the recommendation outputs (adding in food, beverage, and lifestyle options to help close nutrient gaps).
We are building the world’s most powerful personalized nutrition platform, based on cutting edge science, and we hope to bring this solution to as many people as possible as we transform population health into personalized health.
1. Fall CHD, Yajnik CS, Rao S, Davies AA, Brown N, Farrant HJW. Micronutrients and Fetal Growth. J Nutr. 2003;133(5):1747S-1756S. doi:10.1093/jn/133.5.1747s
2. Huskisson E, Maggini S, Ruf M. The role of vitamins and minerals in energy metabolism and well-being. J Int Med Res. 2007;35(3):277-289. doi:10.1177/147323000703500301
3. Vitamin K | Linus Pauling Institute | Oregon State University. https://lpi.oregonstate.edu/mic/vitamins/vitamin-K. Accessed December 3, 2019.
4. Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab. 2007;51(4):301-323. doi:10.1159/000107673
5. Huskisson E, Maggini S, Ruf M. The influence of micronutrients on cognitive function and performance. J Int Med Res. 2007;35(1):1-19. doi:10.1177/147323000703500101
6. Kraemer K, Semba RD, Eggersdorfer M, Schaumberg DA. Introduction: The diverse and essential biological functions of vitamins. Ann Nutr Metab. 2012;61(3):185-191. doi:10.1159/000343103
7. National Institutes of Health Office of Dietary Supplements. Nutrient Recommendations : Dietary Reference Intakes (DRI). https://ods.od.nih.gov/Health_Information/Dietary_Reference_Intakes.aspx. Accessed September 10, 2019.
8. Bailey RL, Fulgoni VL, Keast DR, Dwyer JT. Examination of Vitamin Intakes among US Adults by Dietary Supplement Use. J Acad Nutr Diet. 2012;112(5). doi:10.1016/j.jand.2012.01.026
9. Fulgoni VL, Keast DR, Bailey RL, Dwyer J. Foods, Fortificants, and Supplements: Where Do Americans Get Their Nutrients? J Nutr. 2011;141(10):1847-1854. doi:10.3945/jn.111.142257
10. Wallace TC, McBurney M, Fulgoni VL. Multivitamin/Mineral Supplement Contribution to Micronutrient Intakes in the United States, 2007–2010. J Am Coll Nutr. 2014;33(2):94-102. doi:10.1080/07315724.2013.846806
11. Bailey RL, Fulgoni VL, Keast DR, Dwyer JT. Dietary supplement use is associated with higher intakes of minerals from food sources. Am J Clin Nutr. 2011;94(5):1376-1381. doi:10.3945/ajcn.111.020289
12. Agarwal S, Reider C, Brooks JR, Fulgoni VL. Comparison of Prevalence of Inadequate Nutrient Intake Based on Body Weight Status of Adults in the United States: An Analysis of NHANES 2001–2008. J Am Coll Nutr. 2015;34(2):126-134. doi:10.1080/07315724.2014.901196
13. Micronutrient Inadequacies in the US Population: an Overview | Linus Pauling Institute | Oregon State University. https://lpi.oregonstate.edu/mic/micronutrient-inadequacies/overview. Accessed December 3, 2019.
14. Blumberg JB, Frei B, Fulgoni VL, Weaver CM, Zeisel SH. Vitamin and Mineral Intake Is Inadequate for Most Americans: What Should We Advise Patients About Supplements? J Fam Pract. 2016;65(9 Suppl):S1-S8. http://www.ncbi.nlm.nih.gov/pubmed/27672694. Accessed December 3, 2019.
15. Klevay LM. Is the Western diet adequate in copper? J Trace Elem Med Biol. 2011;25(4):204-212. doi:10.1016/J.JTEMB.2011.08.146
16. Bird JK, Murphy RA, Ciappio ED, McBurney MI. Risk of deficiency in multiple concurrent micronutrients in children and adults in the United States. Nutrients. 2017;9(7). doi:10.3390/nu9070655
17. Chronic Diseases in America | CDC. https://www.cdc.gov/chronicdisease/resources/infographic/chronic-diseases.htm. Accessed December 3, 2019.
18. Ames BN. Prolonging healthy aging: Longevity vitamins and proteins. Proc Natl Acad Sci U S A. 2018;115(43):10836-10844. doi:10.1073/pnas.1809045115
19. Bruce N. Ames, Ph.D. - About Dr. Ames. http://bruceames.org/. Accessed December 5, 2019.
20. Steele EM, Baraldi LG, Da Costa Louzada ML, Moubarac JC, Mozaffarian D, Monteiro CA. Ultra-processed foods and added sugars in the US diet: Evidence from a nationally representative cross-sectional study. BMJ Open. 2016;6(3). doi:10.1136/bmjopen-2015-009892
21. Amundson R, Berhe AA, Hopmans JW, Olson C, Sztein AE, Sparks DL. Soil and human security in the 21st century. Science (80- ). 2015;348(6235). doi:10.1126/science.1261071
22. Gardner CD, Kim S, Bersamin A, et al. Micronutrient quality of weight-loss diets that focus on macronutrients: Results from the A to Z study. Am J Clin Nutr. 2010;92(2):304-312. doi:10.3945/ajcn.2010.29468
23. Kaidar-Person O, Person B, Szomstein S, Rosenthal RJ. Nutritional deficiencies in morbidly obese patients: A new form of malnutrition? Part A: Vitamins. Obes Surg. 2008;18(7):870-876. doi:10.1007/s11695-007-9349-y
24. Karadima V, Kraniotou C, Bellos G, Tsangaris GT. Drug-micronutrient interactions: Food for thought and thought for action. EPMA J. 2016;7(1). doi:10.1186/s13167-016-0059-1
25. Lim H-S, Kim S-K, Hong S-J. Food Elimination Diet and Nutritional Deficiency in Patients with Inflammatory Bowel Disease. Clin Nutr Res. 2018;7(1):48. doi:10.7762/cnr.2018.7.1.48
26. Kordas K, Lönnerdal B, Stoltzfus RJ. Interactions between Nutrition and Environmental Exposures: Effects on Health Outcomes in Women and Children. J Nutr. 2007;137(12):2794-2797. doi:10.1093/jn/137.12.2794
27. Lopresti AL. The Effects of Psychological and Environmental Stress on Micronutrient Concentrations in the Body: A Review of the Evidence. Adv Nutr. August 2019. doi:10.1093/advances/nmz082
28. Eggersdorfer M, Akobundu U, Bailey RL, et al. Hidden hunger: Solutions for America’s aging populations. Nutrients. 2018;10(9). doi:10.3390/nu10091210
29. GBD 2017 Diet Collaborators A, Sur PJ, Fay KA, et al. Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet (London, England). 2019;393(10184):1958-1972. doi:10.1016/S0140-6736(19)30041-8
30. Murray CJL, Mokdad AH, Ballestros K, et al. The state of US health, 1990-2016: Burden of diseases, injuries, and risk factors among US states. JAMA - J Am Med Assoc. 2018;319(14):1444-1472. doi:10.1001/jama.2018.0158
31. Virtanen JK, Giniatullin R, Mäntyselkä P, et al. Low serum 25-hydroxyvitamin D is associated with higher risk of frequent headache in middle-aged and older men. Sci Rep. 2017;7(1):39697. doi:10.1038/srep39697
32. Eliades M, Spyrou E, Agrawal N, et al. Meta-analysis: vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2013;38(3):246-254. doi:10.1111/apt.12377
33. Gorham ED, Garland CF, Burgi AA, et al. Lower prediagnostic serum 25-hydroxyvitamin D concentration is associated with higher risk of insulin-requiring diabetes: a nested case–control study. Diabetologia. 2012;55(12):3224-3227. doi:10.1007/s00125-012-2709-8
34. Munger KL, Åivo J, Hongell K, Soilu-Hänninen M, Surcel H-M, Ascherio A. Vitamin D Status During Pregnancy and Risk of Multiple Sclerosis in Offspring of Women in the Finnish Maternity Cohort. JAMA Neurol. 2016;73(5):515-519. doi:10.1001/jamaneurol.2015.4800
35. Miller JW, Harvey DJ, Beckett LA, et al. Vitamin D Status and Rates of Cognitive Decline in a Multiethnic Cohort of Older Adults. JAMA Neurol. 2015;72(11):1295. doi:10.1001/jamaneurol.2015.2115
36. Feart C, Helmer C, Merle B, et al. Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer’s disease in older adults. Alzheimer’s Dement. 2017;13(11):1207-1216. doi:10.1016/j.jalz.2017.03.003
37. Hong Q, Xu J, Xu S, Lian L, Zhang M, Ding C. Associations between serum 25-hydroxyvitamin D and disease activity, inflammatory cytokines and bone loss in patients with rheumatoid arthritis. Rheumatology. 2014;53(11):1994-2001. doi:10.1093/rheumatology/keu173
38. Gorham ED, Garland CF, Garland FC, et al. Optimal Vitamin D Status for Colorectal Cancer Prevention. Am J Prev Med. 2007;32(3):210-216. doi:10.1016/j.amepre.2006.11.004
39. Crew KD, Gammon MD, Steck SE, et al. Association between Plasma 25-Hydroxyvitamin D and Breast Cancer Risk. Cancer Prev Res. 2009;2(6):598-604. doi:10.1158/1940-6207.CAPR-08-0138
40. Garland CF, Gorham ED, Mohr SB, et al. Vitamin D and prevention of breast cancer: Pooled analysis. J Steroid Biochem Mol Biol. 2007;103(3-5):708-711. doi:10.1016/j.jsbmb.2006.12.007
41. Murphy AB, Nyame Y, Martin IK, et al. Vitamin D Deficiency Predicts Prostate Biopsy Outcomes. Clin Cancer Res. 2014;20(9):2289-2299. doi:10.1158/1078-0432.CCR-13-3085
42. Nyame YA, Murphy AB, Bowen DK, et al. Associations Between Serum Vitamin D and Adverse Pathology in Men Undergoing Radical Prostatectomy. J Clin Oncol. 2016;34(12):1345-1349. doi:10.1200/JCO.2015.65.1463
43. Kristal AR, Till C, Song X, et al. Plasma Vitamin D and Prostate Cancer Risk: Results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2014;23(8):1494-1504. doi:10.1158/1055-9965.EPI-14-0115
44. Amaral AFS, Méndez-Pertuz M, Muñoz A, et al. Plasma 25-hydroxyvitamin D(3) and bladder cancer risk according to tumor stage and FGFR3 status: a mechanism-based epidemiological study. J Natl Cancer Inst. 2012;104(24):1897-1904. doi:10.1093/jnci/djs444
45. Yao S, Kwan ML, Ergas IJ, et al. Association of Serum Level of Vitamin D at Diagnosis With Breast Cancer Survival. JAMA Oncol. 2017;3(3):351. doi:10.1001/jamaoncol.2016.4188
46. Song M, Nishihara R, Wang M, et al. Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status. Gut. 2016;65(2):296-304. doi:10.1136/gutjnl-2014-308852
47. SCRAGG R, SOWERS M, BELL C. Serum 25-hydroxyvitamin D, Ethnicity, and Blood Pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens. 2007;20(7):713-719. doi:10.1016/j.amjhyper.2007.01.017
48. Muhlestein JB, Bair TL, May HT, Le VT, Lappe DL, Anderson JL. Threshold Effect of Vitamin D Deficiency on Cardiovascular Outcomes: Below What Level of 25(OH) Vitamin D is Cardiovascular Risk Really Increased? Circulation. 2015;132. https://www.ahajournals.org/doi/abs/10.1161/circ.132.suppl_3.18102?sid=333c3e0e-9415-422e-9a31-faf768f2d01b.
49. Parker J, Hashmi O, Dutton D, et al. Levels of vitamin D and cardiometabolic disorders: Systematic review and meta-analysis. Maturitas. 2010;65(3):225-236. doi:10.1016/j.maturitas.2009.12.013
50. Busse B, Bale HA, Zimmermann EA, et al. Vitamin D Deficiency Induces Early Signs of Aging in Human Bone, Increasing the Risk of Fracture. Sci Transl Med. 2013;5(193):193ra88-193ra88. doi:10.1126/scitranslmed.3006286
51. Dobnig H, Pilz S, Scharnagl H, et al. Independent Association of Low Serum 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Levels With All-Cause and Cardiovascular Mortality. Arch Intern Med. 2008;168(12):1340. doi:10.1001/archinte.168.12.1340
52. Kieboom BCT, Niemeijer MN, Leening MJG, et al. Serum Magnesium and the Risk of Death From Coronary Heart Disease and Sudden Cardiac Death. J Am Heart Assoc. 2016;5(1). doi:10.1161/JAHA.115.002707
53. Kunutsor SK, Khan H, Laukkanen JA. Serum magnesium and risk of new onset heart failure in men: the Kuopio Ischemic Heart Disease Study. Eur J Epidemiol. 2016;31(10):1035-1043. doi:10.1007/s10654-016-0164-4
54. Dong JY, Xun P, He K, Qin LQ. Magnesium intake and risk of type 2 diabetes meta-analysis of prospective cohort studies. Diabetes Care. 2011;34(9):2116-2122. doi:10.2337/dc11-0518
55. Ames BN. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrient by triage. Proc Natl Acad Sci U S A. 2006;103(47):17589-17594. doi:10.1073/pnas.0608757103
56. Nutri-Facts. Mapping Public Health Benefits of Adequate Omega-3 Levels . https://www.nutri-facts.org/en_US/news/Mapping-Public-Health-Benefits-of-Adequate-Omega-3-Levels.html. Published 2016. Accessed December 6, 2019.
57. Denkins Y, Kempf D, Ferniz M, Nileshwar S, Marchetti D. Role of ω-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma. J Lipid Res. 2005;46(6):1278-1284. doi:10.1194/jlr.M400474-JLR200
58. McCann JC, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. Am J Clin Nutr. 2005;82(2):281-295. doi:10.1093/ajcn/82.2.281
59. Vitamin A | Linus Pauling Institute | Oregon State University. https://lpi.oregonstate.edu/mic/vitamins/vitamin-A#deficiency-related-disorders. Accessed December 6, 2019.
60. Choi S-W, Mason JB. Folate and Carcinogenesis: An Integrated Scheme. J Nutr. 2000;130(2):129-132. doi:10.1093/jn/130.2.129
61. Ames BN, Wakimoto P. Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer. 2002;2(9):694-704. doi:10.1038/nrc886
62. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: Scientific review. J Am Med Assoc. 2002;287(23):3116-3126. doi:10.1001/jama.287.23.3116
63. Pawlak R. Is vitamin B12 deficiency a risk factor for cardiovascular disease in vegetarians? Am J Prev Med. 2015;48(6):e11-e26. doi:10.1016/j.amepre.2015.02.009
64. Miller A, Korem M, Almog R, Galboiz Y. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. In: Journal of the Neurological Sciences. Vol 233. ; 2005:93-97. doi:10.1016/j.jns.2005.03.009
65. Vitamin B12 | Linus Pauling Institute | Oregon State University. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12#deficiency. Accessed December 6, 2019.
66. Vitamin E | Linus Pauling Institute | Oregon State University. https://lpi.oregonstate.edu/mic/vitamins/vitamin-E#marginal-deficiency. Accessed December 6, 2019.
67. Shenkin A. Micronutrients in health and disease. Postgrad Med J. 2006;82(971):559-567. doi:10.1136/pgmj.2006.047670
68. Nair MK, Augustine LF, Konapur A. Food-Based Interventions to Modify Diet Quality and Diversity to Address Multiple Micronutrient Deficiency. Front Public Heal. 2016;3. doi:10.3389/fpubh.2015.00277
69. Bot A, Benites J. The Importance of Soil Organic Matter. Rome; 2015. http://www.fao.org/soils-2015/news/news-detail/en/c/277682/.
70. Reber E, Gomes F, Vasiloglou MF, Schuetz P, Stanga Z. Nutritional Risk Screening and Assessment. J Clin Med. 2019;8(7):1065. doi:10.3390/jcm8071065
71. Nutrition Education in US Schools. https://www.cdc.gov/healthyschools/nutrition/school_nutrition_education.htm. Accessed December 5, 2019.
72. Council for Responsible Nutrition. Dietary Supplement Use Reaches All Time High. https://www.crnusa.org/newsroom/dietary-supplement-use-reaches-all-time-high-available-purchase-consumer-survey-reaffirms. Accessed December 5, 2019.
73. Guallar E, Stranges S, Mulrow C, Appel LJ, Miller ER. Enough is enough: Stop wasting money on vitamin and mineral supplements. Ann Intern Med. 2013;159(12):850-851. doi:10.7326/0003-4819-159-12-201312170-00011
74. Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: An updated systematic evidence review for the U.S. preventive services task force. Ann Intern Med. 2013;159(12):824-834. doi:10.7326/0003-4819-159-12-201312170-00729
76. Grodstein F, O’Brien J, Kang JH, et al. Long-term multivitamin
supplementation and cognitive function in men: A randomized trial. Ann
Intern Med. 2013;159(12):806-814.
75. Jenkins DJA, Spence JD, Giovannucci EL, et al. Supplemental Vitamins and Minerals for CVD Prevention and Treatment. J Am Coll Cardiol. 2018;71(22):2570-2584. doi:10.1016/j.jacc.2018.04.020
77. Lamas GA, Boineau R, Goertz C, et al. Oral high-dose multivitamins and minerals or post myocardial infarction pateitns in TACT. Ann Intern Med. 2013;159(12):797-804. doi:10.1016/j.biotechadv.2011.08.021.Secreted
78. Rayman MP, Winther KH, Pastor-Barriuso R, et al. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial. Free Radic Biol Med. 2018;127:46-54. doi:10.1016/j.freeradbiomed.2018.02.015
79. Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk of prostate cancer: The selenium and vitamin E cancer prevention trial (SELECT). JAMA - J Am Med Assoc. 2011;306(14):1549-1556. doi:10.1001/jama.2011.1437
80. De Abajo FJ, Rodríguez-Martín S, Rodríguez-Miguel A, Gil MJ. Risk of ischemic stroke associated with calcium supplements with or without vitamin D: A nested case-control study. J Am Heart Assoc. 2017;6(5). doi:10.1161/JAHA.117.005795
81. Bjelakovic G, Nikolova D, Gluud C. Antioxidant supplements to prevent mortality. JAMA - J Am Med Assoc. 2013;310(11):1178-1179. doi:10.1001/jama.2013.277028
82. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1). doi:10.7326/0003-4819-142-1-200501040-00110
83. Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA - J Am Med Assoc. 2011;305(13):1348-1349. doi:10.1001/jama.2011.383
84. Zeevi D, Korem T, Zmora N, et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell. 2015;163(5):1079-1094. doi:10.1016/j.cell.2015.11.001
85. Segal E. What Is the Best Diet for Humans? TEDxRuppin; 2016. https://www.youtube.com/watch?v=0z03xkwFbw4. Accessed December 5, 2019.
86. Leonhardt M, Wenk C. Variability of Selected Vitamins and Trace Elements of Different Meat Cuts. J Food Compos Anal. 1997;10(3):218-224. doi:10.1006/jfca.1997.0536
87. Singh J, Upadhyay AK, Prasad K, Bahadur A, Rai M. Variability of carotenes, vitamin C, E and phenolics in Brassica vegetables. J Food Compos Anal. 2007;20(2):106-112. doi:10.1016/j.jfca.2006.08.002
88. Archer E, Pavela G, Lavie CJ. The Inadmissibility of What We Eat in America and NHANES Dietary Data in Nutrition and Obesity Research and the Scientific Formulation of National Dietary Guidelines. Mayo Clin Proc. 2015;90(7):911-926. doi:10.1016/j.mayocp.2015.04.009
89. Archer E, Pavela G, Lavie CJ. A Discussion of the Refutation of Memory-Based Dietary Assessment Methods (M-BMs): The Rhetorical Defense of Pseudoscientific and Inadmissible Evidence. Mayo Clin Proc. 2015;90(12):1736-1739. doi:10.1016/j.mayocp.2015.10.003
90. Russell RM. Factors in Aging that Effect the Bioavailability of Nutrients. J Nutr. 2001;131(4):1359S-1361S. doi:10.1093/jn/131.4.1359s
91. Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK. Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract. 2012;27(2):201-214. doi:10.1177/0884533611436116
92. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014;349:g5226. doi:10.1136/BMJ.G5226
93. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane database Syst Rev. 2011;(7):CD007470. doi:10.1002/14651858.CD007470.pub2
94. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: A meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012;95(1):91-100. doi:10.3945/ajcn.111.014779
95. Goyal A, Terry MB, Siegel AB. Serum antioxidant nutrients, vitamin A, and mortality in U.S. adults. Cancer Epidemiol Biomarkers Prev. 2013;22(12):2202-2211. doi:10.1158/1055-9965.EPI-13-0381
96. Harris WS, Tintle NL, Etherton MR, Vasan RS. Erythrocyte long-chain omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: The Framingham Heart Study. J Clin Lipidol. 2018;12(3):718-727.e6. doi:10.1016/j.jacl.2018.02.010
97. Wu T, Sempos CT, Freudenheim JL, Muti P, Smit E. Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann Epidemiol. 2004;14(3):195-201. doi:10.1016/S1047-2797(03)00119-4