Vitamin D is much in the news nowadays.  Over the last 10 years it has become increasingly clear that vitamin D plays several important roles beyond those involved in bone health.  Vitamin D presence or absence is implicated in several disease processes including tuberculosis and cancer and an adequate level of vitamin D is required for immune system responsiveness.  A just-published research study reveals a critical way in which vitamin D is involved in the immune response.  This blog entry reviews a little background on vitamin D3, what is known about the vitamin D receptor (VDR) protein, the new research, and implications for health and longevity.

Vitamin D and the VDR

Vitamin D is mentioned several times in my treatise and is a central pillar of the combined anti-aging firewalls Supplement Regimen.    I have also discussed or mentioned it in many` blog posts.  The post Vitamin D – don’t fall for it  describes research on how vitamin D administration in nursing communities significantly reduces the number of falls and consequent hip fractures and other orthopedic injuries.  The blog post Klotho anti-aging gene in the news describes how “Klotho expression is also important for averting premature aging due to overexpression of Vitamin D,” citing a number of papers relevant to that topic.  And the post Hypervitaminosis D and premature aging indicates, among other topics, how mice with their VDR gene knocked out age prematurely.  “The publication Premature aging in vitamin D receptor mutant mice  (vitamin D receptor (VDR) knockout mice)  states “Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts.”  “Since the phenotype of aged VDR knockout mice is similar to mouse models with hypervitaminosis D(3), our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D(3) homeostasis regulates physiological aging.”

Vitamin D3 (1alpha,25-dihydroxyvitamin D) is the active form of vitamin D taken in supplements and is of concern in this post.  It functions as a hormone.  D3 is also known as calcitriol.  A growing body of research publications point to the health importance of D3 in numerous biological pathways that go beyond bone health.  I cite only two as examples.  According to the 2008 publication The noncalciotropic actions of vitamin D: recent clinical developments, “RECENT FINDINGS: 1,25-Dihydroxyvitamin D stimulates the innate immune system, facilitating the clearance of infections such as tuberculosis. Hypovitaminosis D has been associated with several autoimmune disorders, various malignancies, and cardiovascular risk factors in a number of recent epidemiologic reports. Based on these observational reports, vitamin D and its analogues are being evaluated for the prevention and treatment of a variety of conditions, with early findings showing mixed results. SUMMARY: The broad tissue distribution of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme and the vitamin D receptor establish a role for 1,25-dihydroxyvitamin D in the pathophysiology of various disease states and provide new therapeutic targets for vitamin D and its analogues.”

A 2007 publication Expanding role for vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1alpha-hydroxylase in the classical and nonclassical actions of 1alpha,25-dihydroxy vitamin D(3) reports “Recent advances in the understanding of vitamin D have revolutionized our view of this old nutritional factor and suggested that it has much wider effects on the body than ever believed before. In addition to its well-known effects on calcium/phosphate homeostasis, vitamin D, through its hormonal form, 1alpha,25-dihydroxyvitamin D(3) or calcitriol, is a cell differentiating factor and anti-proliferative agent with actions on a variety of tissues around the body (e.g., skin, muscle, immune system). By influencing gene expression in multiple tissues, calcitriol influences many physiological processes besides calcium/phosphate homeostasis including muscle and keratinocyte differentiation, insulin secretion, blood pressure regulation, and the immune response. The incidence of various diseases including epithelial cancers, multiple sclerosis, muscle weakness as well as bone-related disorders has been correlated with vitamin D deficiency/insufficiency and has led to a re-evaluation of recommended daily intakes both in the normal subject and CKD patient.”

Even back in the early 2000s it was clear that D3 was important for the functioning of the immune system, but how and why was unclear.  The 2004 publication Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system  reported “The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to inhibit the development of autoimmune diseases, including inflammatory bowel disease (IBD). Paradoxically, other immune system-mediated diseases (experimental asthma) and immunity to infectious organisms were unaffected by 1,25(OH)2D3 treatment. There are similar paradoxical effects of vitamin D deficiency on various immune system functions. Vitamin D and vitamin D receptor (VDR) deficiency resulted in accelerated IBD.

”The vitamin D3 receptor (VDR) gene generates a protein which is a transcription factor that is activated by the presence of D3. “The calcitriol receptor, also known as the vitamin D receptor (VDR) and also known as NR1I1 (nuclear receptor subfamily 1, group I, member 1), is a member of the nuclear receptor family of transcription factors.^[1] Upon activation by vitamin D, the VDR forms a heterodimer with the retinoid-X receptor and binds to hormone response elements on DNA resulting in expression or transrepression of specific geneproducts. In humans, the vitamin D receptor is encoded by the VDR gene.^[2]”  Exploration of the activities of VDR has been key to discovering the various roles of vitamin D3 in maintaining health.

Vitamin D3 in the immune response

The new 7 March 2010 publication Vitamin D controls T cell antigen receptor signaling and activation of human T cells reports an important finding – Presence of vitamin D3 in the bloodstream is required for T cells being activated and mounting an effective immune response.  As reported yesterday in Science Daily: “For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells must first be ‘triggered’ into action and ‘transform’ from inactive and harmless immune cells into killer cells that are primed to seek out and destroy all traces of a foreign pathogen. — The researchers found that the T cells rely on vitamin D in order to activate and they would remain dormant, ‘naïve’ to the possibility of threat if vitamin D is lacking in the blood.”  The sequence of events is “First when the naive T cell recognizes foreign invaders like bacteria or viruses with T cell receptor (TCR), it sends activating signals – to the vitamin D receptor gene. The VDR gene then starts producing DVR protein, which binds vitamin D in the T cell – and becomes activated. Then the vitamin D bound and activated DVR gets into the cell nucleus and activates the gene for PLC-gamma1 (5), which in turn produces PLC-gamma1 protein – and “the T cells can get started(ref).””

““Professor Carsten Geisler from the Department of International Health, Immunology and Microbiology explains that “when a T cell is exposed to a foreign pathogen, it extends a signaling device or ‘antenna’ known as a vitamin D receptor, with which it searches for vitamin D. This means that the T cell must have vitamin D or activation of the cell will cease. If the T cells cannot find enough vitamin D in the blood, they won’t even begin to mobilize. ” — T cells that are successfully activated transform into one of two types of immune cell. They either become killer cells that will attack and destroy all cells carrying traces of a foreign pathogen or they become helper cells that assist the immune system in acquiring “memory”. The helper cells send messages to the immune system, passing on knowledge about the pathogen so that the immune system can recognize and remember it at their next encounter. T cells form part of the adaptive immune system, which means that they function by teaching the immune system to recognize and adapt to constantly changing threats(ref).”

Implications

The new finding can explain a lot of the protective effects of D3,  ranging from reducing susceptibility to colds and flu(ref) to the role of D3 in chronic kidney disease(ref), reducing risk of asthma and respiratory infections(ref), its role in Graves’ hyperthyroidism(ref), how it fights placental infection(ref), bacterial vaginosis(ref) and pediatric infections(ref), and its protective effects against many other infections too numerous to catalog here.  And of course, vitamin D is essential for prevention and control of cardiovascular diseases(ref).  Unless someone is out in the sunlight for sustained periods every day, vitamin D3 supplementation is an absolute health necessity.

Please note the medical disclaimer for this blog.