Personalized Nutraceuticals: Common Ingredients
Much of my free time is spent designing and compounding personalized nutraceuticals for individuals. For example, I recently combined 3,750 mcg of cholecalciferol, 450 mg of zinc picolinate, 3,000 mg of thiamin HCl, 450 mg of riboflavin, 3,300 mg of niacinamide, 6,000 mg of pyridoxal HCl, 20,000 mcg of folate, 30,000 mcg of methylcobalamin, 12,000 mcg of biotin, 3,000 mg of pantothenic acid, and 3,000 mg of magnesium citrate into 30 capsules for a close friend of mine. This individual was originally taking upwards of 5 capsules per day to meet these same dosages, none of which had NSF, USP, NPA GMP, or ConsumerLab certifications. Because OTC supplements (also coined “nutraceuticals”) are unregulated by the FDA, consumers must decipher if a brand is reputable, safe, high-quality, and/or third-party-tested. Therefore, I offered to safely source and combine these OTC ingredients for her, as well as customize the dosages and add other nutraceutical compounds based on her physiological requirements and desires. Although serum micronutrient testing prior and post-supplementation is preferred when using a precision-medicine approach (to ensure appropriate and adequate dosing, as well as bioavailability / absorption), there are several micronutrients and vitamins that the majority of Americans are deficient in, such as vitamin D, magnesium, and omega-3 fatty acids (just to name a few).¹ Despite these being essential to normal physiological functioning, inadequacy is prevalent in our over-sanitized, nutrient-scarce society, coinciding with the rise of chronic, inflammatory diseases. Below resides a discussion on why magnesium, vitamin D3, and omega-3 fatty acids are so important- these being just a handful of essential nutrients, but the three I find myself using in most of the supplements I compound.
Magnesium
Magnesium is a cofactor in hundreds of enzymatic reactions in the human body. Therefore, magnesium deficiency affects a high volume of metabolic, biochemical, and cellular processes. It is no surprise, then, that low levels of magnesium are strongly correlated with cardiovascular disease, diabetes, neurological disorders, cancer, and osteoporosis.²
The majority of magnesium is stored in bones, and its levels are maintained by intestinal absorption, renal absorption, and bone resorption and deposition (similar to the maintenance of plasma calcium levels, another essential divalent cation). Its absorption in the intestines may be modulated by age, intestinal inflammation / epithelial integrity, and the microbiota composition, as well as vitamin D3 levels, which is why supplementation of magnesium may be necessary even in cases where dietary amounts are adequate (ideally in the form of an organic salt, to increase bioavailability and bio-absorption).² Its interaction with calcium, PTH, and vitamin D3 account for some of its mechanisms of actions.
It plays a role in DNA repair and stability, as well as protein synthesis via both transcription and translation, thus its association with cell proliferation and cancer. It also is an active component of ATP utilization and carbohydrate metabolism, explaining low levels’ association with metabolic syndrome and related conditions (i.e. diabetes and CVD).² Magnesium may affect both acute neurological conditions, such as migraines, as well as chronic, degenerative conditions, like dementia and Alzheimer’s.² Insufficient levels of magnesium have been shown to lead to hyper-excitability of neurons and increase NMDA receptor activity. Magnesium’s metabolic actions in the mitochondria, however, may better explain its role in chronic neurological conditions. Low levels of magnesium also lead to decreased insulin sensitivity.² This is because of magnesium’s role in GLUT4 translocation, as well as its role in the suppression of gluconeogenesis in the liver.
All the conditions associated with magnesium deficiency described above share the feature of an increased inflammatory load. Increased circulating levels of pro-inflammatory cytokines are seen with low levels of magnesium, and this may factor into osteoporosis development by the induction of osteoclast differentiation and activation (leading to bone deposition of stored magnesium).
Vitamin D3
Vitamin D is an essential fat-soluble vitamin, most often touted for its ability to increase intestinal absorption of calcium to maintain strong, dense bones. Its synthesis is triggered by UVB radiation, and it requires cholesterol for its activation. Because most cells contain a vitamin D receptor (VDR), it can impact many organs and tissues throughout the body, including colon cells, osteoblasts, lymphocytes, gonads, heart, brain, and skin.³ One of its most widely studied functions is its ability to epigenetically modulate immune cells, and thus play a role in autoimmunity development and severity.⁴ Vitamin D supplementation may reduce the incidence of autoimmune diseases by inducing immune tolerance by promoting a shift from a Th1 to a Th2 immune response. It has been shown to lead to the induction of regulatory T-cells (Tregs), and reduce inflammation via an increase in IL-10 and a decrease in inflammatory cytokines (i.e. IL-6, NFK-B, COX-2, amongst others) via MAPK phosphorylation.⁴
A large percentage of Americans do not have adequate levels of serum vitamin D, and this is a major cause for concern, given vitamin D deficiency’s correlations to cancer, diabetes, and autoimmunity.¹ Although supplementation may not completely alleviate these conditions, vitamin D may play a role in their prevention.
Omega-3 fatty acids
Most Americans are not meeting the recommended daily intake of omega-3 fatty acids, largely due to the Standard American Diet (SAD), which is high in omega-6 fatty acids but often lacking in omega-3 fatty acids (due to the low conversion of ALA to EPA and DHA). These two fatty acid types compete for the same enzymes in their conversions and metabolism in COX and LOX pathways, leading to either pro-inflammatory metabolites or anti-inflammation.⁵ Specifically, the ratio of omega-6 to omega-3 fatty acids is thought to play a role in inflammation, obesity, and other chronic, modern diseases. For example, a high omega-6 fatty acid concentration has been shown to lead to a different differentiation of pre-adipocytes (adipogenesis) than a high omega-3 fatty acid concentration.⁶ Whereas omega-6s stimulate white adipose tissue proliferation (preventing browning of adipose) and decrease fatty acid oxidation, omega-3s inhibit this stimulation, allowing UCP-1 and PPARy activation and fatty acid oxidation.⁶ Meta-analyses have correlated higher omega-3 fatty acid intake with lowered levels of triglycerides and reduced risk of cardiovascular disease.⁷
Omega-3 fatty acids are known for their anti-inflammatory effects. This occurs through a variety of mechanisms. One is via the competitive blocking of omega-6 fatty acid metabolites that induce pro-inflammatory cytokines.⁵ It would be overly reductionistic, however, to claim that all omega-6s lead to inflammation in the body; omega-6 fatty acids are essential, and in appropriate amounts and ratios, have been found to also lower the risk of cardiovascular disease.
The most reliable source of omega-3 fatty acids is fish oil, which contains EPA and DHA. Although ALA can be found in nuts and meats, it has a low conversion rate to EPA and DHA. Observational studies have shown an association between a high intake of omega-3 fatty acids and reduced risk of heart disease, cancer, autoimmunity, and mild cognitive impairment.⁷ Given DHA’s essential roles in brain development and functioning, it is unsurprising that studies have found fish oil to be critical for proper fetus development, with the benefits outweighing the risks of heavy metal exposure.⁷
Although additional OTC ingredients are often beneficial for individuals (based on quantitative research) (i.e. berberine for lowering blood sugar levels and improving blood lipid levels), the nutrients listed above are truly essential and foundational for a preventative, functional approach, which is at the core of precision medicine. Both allopathic and naturopathic medicine sometimes make the mistake of resorting to symptom suppression via exogenous administration of chemicals, whether they be patented pharmaceuticals or synergistic / “natural” plant products, ultimately blurring the distinction between the two complementary approaches. It is never superfluous to be reminded that both fields are striving for the progressive prevention of patient disease onset, rather than merely symptom amelioration.
References
Reider CA, Chung R-Y, Devarshi PP, Grant RW, Hazels Mitmesser S. Inadequacy of immune health nutrients: Intakes in US adults, the 2005–2016 NHANES. Nutrients [Internet]. 2020 [cited 2023 Dec 15];12(6):1735. Available from: http://dx.doi.org/10.3390/nu12061735
Fiorentini D, Cappadone C, Farruggia G, Prata C. Magnesium: Biochemistry, nutrition, detection, and social impact of diseases linked to its deficiency. Nutrients [Internet]. 2021 [cited 2023 Dec 15];13(4):1136. Available from: http://dx.doi.org/10.3390/nu13041136
Chang S-W, Lee H-C. Vitamin D and health - The missing vitamin in humans. Pediatr Neonatol [Internet]. 2019;60(3):237–44. Available from: https://www.sciencedirect.com/science/article/pii/S187595721830651X
Martens P-J, Gysemans C, Verstuyf A, Mathieu C. Vitamin D’s effect on immune function. Nutrients [Internet]. 2020 [cited 2023 Dec 15];12(5):1248. Available from: http://dx.doi.org/10.3390/nu12051248
Araujo P, Belghit I, Aarsæther N, Espe M, Lucena E, Holen E. The effect of omega-3 and omega-6 polyunsaturated fatty acids on the production of cyclooxygenase and lipoxygenase metabolites by human umbilical vein endothelial cells. Nutrients [Internet]. 2019 [cited 2023 Dec 15];11(5):966. Available from: http://dx.doi.org/10.3390/nu11050966
Simopoulos A. An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity. Nutrients [Internet]. 2016 [cited 2023 Dec 15];8(3):128. Available from: http://dx.doi.org/10.3390/nu8030128
Omega-3 fatty acids [Internet]. Nih.gov. [cited 2023 Dec 15]. Available from: https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/