By Ian Spohn, ND
If you're looking for a quality D3 supplement, then you're probably already aware of the numerous benefits of vitamin D. You understand its role in providing immune support, and are familiar with the contemporary challenge of obtaining enough from sunlight alone. If you pay attention to alternative health sources, you may also aware of the numerous benefits of vitamin K2, which unlike K1 cannot be obtained from unfermented plant foods, but whose synergistic role in calcium metabolism is critical to obtaining the full benefits of vitamin D3. For this reason, many supplement brands now offer D3 and K2 together, but the missing piece you're unlikely to find in these other brands is vitamin A, whose synergistic action with vitamin D3 has long been ignored and forgotten, especially when it comes to immune support. In fact, without vitamin A to assist its action, vitamin D3 may be wholly ineffective.
Among the most primitive immune support supplements is cod liver oil, renowned for its rich content of both vitamins A and D, and the combination of these two vitamins to fortify milk was among the earliest and relatively successful public health measures. Around this time, vitamin D earned its fame for supporting calcium absorption, in fact being essential to the process. It was later discovered in this context to act synergistically with vitamin K2: D3 gets calcium from food into the bloodstream, K2 moves calcium from the bloodstream into bones. Hence, many D3 supplements now include vitamin K2, but here is where these supplements fall short: vitamin D3 is crucial to so much more than simply calcium absorption, In fact, vitamin D3 plays a direct role in activating over 1000 different genes[i], modifying their expression to optimize nearly every aspect of physiological function, even those which don't depend on calcium levels, like immune system function. Through the Vitamin D receptor, D3 can bind to and activate the very machinery responsible for reading genetic blueprints, influencing gene expression in almost every cell throughout the body. This explains the numerous and diverse benefits associated with a healthy vitamin D level, which extend far beyond the bones to include immune, metabolic, cardiovascular, and even mood health. While K2 is important to realize its bone support benefits, and should therefore be supplemented concurrently, there is actually a far more important synergist that traditional supplements like cod liver oil included, but which most modern D3 supplements overlook: vitamin A.
Unlike many vitamins, which act as catalysts for biochemical reactions, vitamins A and D are actually more similar to hormones in their action. Like estrogen and testosterone, vitamin D3 is a steroid molecule which acts directly at the level of DNA, switching genes on and off through activation of the vitamin D receptor, but this is actually only half the story. The body's vitamin D receptor, through which all of vitamin D's beneficial effects are mediated, must first form a complex (called a heterodimer) with a nearby activated vitamin A receptor, before any of its effects can be mediated. Essentially, the benefits of vitamin D3 are achieved by opening a lock which requires two keys, vitamins D and A. Without vitamin A to work alongside it, vitamin D3 is powerless to act, and no degree of vitamin D supplementation will overcome this. The synergistic requirement for these two vitamins might actually explain why some vitamin D studies have frustratingly failed to show positive results, such as a study by the US Preventative Services Task Force which concluded that D3 and calcium supplementation had no benefit in reducing bone fractures in the elderly[ii]. These negative studies, which contradict the wisdom, experience, and common sense of so many people, are all too common and among these studies' many flaws (the fracture study only used 400 IUs of vitamin D, probably not enough to correct a deficiency), their failure to concurrently address vitamin A levels is likely contributing to their underwhelming results.
While suboptimal D3 levels are now being recognized as a widespread problem, suboptimal vitamin A status is only beginning to be acknowledged. There are several reasons for this, and one of them has to do with vitamin A's somewhat nebulous role in the body. Unlike some nutrients, which have very clear-cut deficiency syndromes, the only symptom conventionally associated with vitamin A deficiency is night blindness – certainly an inconvenience, but in terms of severity this greatly belies the utter importance of vitamin A. In its active form of retinol, the role of vitamin A is so widespread and complex that it becomes difficult to actually recognize its deficiency, apart from a general state of sub-optimal bodily function. To fully understand the importance of vitamin A, it's necessary to explore what it actually does.
To put it simply, vitamin A is a necessary growth factor that regulates cell replication, and therefore is necessary to all tissues with actively dividing cells. It is crucial to the developing fetus during pregnancy, which is why vitamin A antagonists like Accutane are so strongly contraindicated during pregnancy. Accutane works to control acne by blocking vitamin A's action in the skin, reducing the overproduction of sebum and skin cells to keep them from blocking pores. The reason vitamin A deficiency leads to night blindness, and eventually total blindness, is because the photoreceptors in the eye constantly "burn out," and need to be replaced by newly dividing cells. You can think of the retina as a giant panel of lightbulbs that get turned on by certain wavelengths of light, but constantly burn out due to the radiation involved. Like regular light bulbs, they constantly need to be replaced, a process which requires constant supplies of vitamin A. What most people don’t understand, however, is that vitamin A is selectively stored in the retina for this purpose, and by the time the supplies of the retina have run short, vitamin A will have already been depleted in other actively dividing tissues. These include the skin, which becomes thin and dry without new cells to replenish it, the intestinal lining, which is constantly regenerating to help absorb nutrients, and white blood cells, which have a limited lifespan and need to be constantly replaced from bone marrow stem cells, just to name a few.
This last function involving the growth of white blood cells is the key to vitamin A's role in immunity, and the reason why vitamin A deficiency is among the leading causes of death in impoverished children, rendering them susceptible to otherwise preventable infectious diseases. Worldwide, it has been estimated that two million deaths in children under the age of five could be prevented every year with adequate vitamin A supplementation[iii]. And not only does vitamin A directly support the replenishing of immune cells, as explained early it also works in conjunction to unlock all of vitamin D's beneficial effects. It would not be an overstatement to claim vitamin A is an essential part of any immune support regimen, and yet it is a part that gets completely overlooked in the majority of immune support supplements, including those which combine D3 and K2. As a naturopathic medical student working with Naturopaths Without Borders, I witnessed firsthand the immune benefits of vitamin A supplementation. As a naturopathic doctor, I insist on the inclusion of vitamin A in its active form of retinol with as part of any immune support protocol, which is why I personally recommend Bold Botanica's D3-K2-A to support seasonal wellness. Cleanest ingredients, active form of each vitamin, and includes vitamin A.
Ian Spohn, ND, is a staff naturopathic doctor on the Bold Botanica Team who enjoys challenging the dogmas of both conventional and alternative medicine. He is a passionate supporter of the paleo diet and classical homeopathy.
This blog is intended for educational purposes only. This information has not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.
[i] Carlberg C. Vitamin D: A Micronutrient Regulating Genes. Curr Pharm Des. 2019;25(15):1740-1746. doi: 10.2174/1381612825666190705193227. PMID: 31298160.
[ii] US Preventive Services Task Force. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(15):1592–1599. doi:10.1001/jama.2018.3185
[iii] Humphrey JH, West KP Jr, Sommer A. Vitamin A deficiency and attributable mortality among under-5-year-olds. Bull World Health Organ. 1992;70(2):225-32. PMID: 1600583; PMCID: PMC2393289.