The Overlooked Importance of Vitamin D Receptors

Life Extension Magazine August 2013 The Overlooked Importance of Vitamin D ReceptorsBy Logan Bronwell Just a few years ago, vitamin D was simply known as the “bone vitamin.” Thanks to the hard work of many scientists, especially Michael Holick, MD, a pioneer in vitamin D research, the data show that nearly every tissue and cell type in the body has receptors for vitamin D. 1 As a result of this discovery, much higher doses are required for optimal functioning. This discovery has radically changed how we understand the role of vitamin D in the body. Unless your body is at optimal levels, you are opening the door to a host of disorders, ranging from heart disease and Alzheimer’s to weak bones and diabetes.2,3 In fact, even if you have normal blood sugar today, a vitamin D deficiency makes you 91%more likely to progress to insulin resistance, or “pre-diabetes,” and it more than doubles your risk for progressing to active, type II diabetes.4 Unfortunately, vitamin D deficiency is a global epidemic. An estimated 1 billion people do not have adequate vitamin D levels.5 And 64% of Americans don’t have enough vitamin D to keep all of their tissues operating at peak capacity.6 The results of this deficiency are catastrophic. Studies have now shown that vitamin D deficiency is associated with increased risk of a long list of diseases that span all systems in the body. In fact, low levels of vitamin D increase the risk of non-Alzheimer’s dementia almost 20 times! 7 While checking for vitamin D levels is still not standard of care for many physicians, you will realize from reading this article that assessing vitamin D status is one of the most important health-protecting steps you can take. Fortunately, achieving optimal levels of vitamin D is easy, inexpensive, and highly protective against a range of lethal diseases. Why Vitamin D is so Vital While humans can make some vitamin D in their bodies, most of us require additional amounts from our diet, the sun, or from supplements in order to maintain adequate levels. Once vitamin D has been ingested in the diet or produced in the skin, the liver and kidneys convert it to its active form, called 1,25-dihydroxyvitamin D, or vitamin D3.8,9 Virtually every tissue type in your body has receptors for vitamin D, meaning that they all require vitamin D for adequate functioning.8,9 The very presence of specific receptors define vitamin D as a hormone, rather than a vitamin.8 It interacts with receptors throughout the body and has a number of different effects. It’s becoming evident that higher doses of vitamin D are required to support its other activities in tissues such as heart muscle, brain cells, and fat tissue, to name just a few. Additionally, vitamin D regulates genes that control cell growth and development, immune function, and metabolic control. 5,8 Studies have now shown that vitamin D deficiency is associated with increased risk of numerous chronic disorders, including type II diabetes, cancer, infections, and cardiovascular, autoimmune, and neurological diseases (See the table on page 2 for greater detail).8,9 The Global Vitamin D Deficiency The problem is that most of us are simply not getting enough vitamin D to allow our bodies to work optimally at all of the functions that vitamin D supports. An estimated 1 billion people(that’s about a seventh of the global population) have inadequate vitamin D supplies in their bodies.5 According to mainstream medical standards, there are three levels of vitamin D status: sufficient, insufficient, and deficient. People who are considered vitamin D “sufficient” have blood levels of at least 30 ng/mL. However, optimal vitamin D status is achieved with a minimum of 50 ng/mL.Those considered “insufficient” (meaning their bodies aren’t at optimal vitamin D capacity) have levels between 21 and 29 ng/mL.And those who are “deficient” are defined as having levels at or below 20 ng/mL.8By those criteria, 25% of Americans areinsufficient, and 39% are outright deficient.6 In other words, fully 64% of Americans don’t have enough vitamin D to keep all of their tissues operating at peak capacity. It’s hardly any wonder we are plagued with so many chronic diseases. Vitamin D Supports Cardiovascular HealthVitamin D deficiency is common in people with cardiovascular disease; almost all people with heart failure have reduced levels.10 It is now recognized as an independent predictor for diseases of the heart and blood vessels, including heart attacks and strokes.11 One study published this year found that women with vitamin D levels in the top one-third of the population had 68% lower risk of heart attacks compared with those in the lowest third; men in the top third had a 44% lower risk.12 Conversely, if your vitamin D level is in that lower range, you have a 42% increased risk of dying of cardiovascular disease and a 49 to 64% increased risk of a stroke.13,14 The risk of having clogged coronary arteries (the precursor of a heart attack) is more than doubled for people with vitamin D deficiency (less than 20 ng/mL).15 Why does vitamin D deficiency lead to such a dramatic increase in the risk for having America’s #1 killer disease? It’s because the heart muscle, blood vessels, and other circulatory system components are rich in vitamin D receptors, which means they depend heavily on vitamin D for optimum function.16 Animals bred to have no vitamin D receptors have cardiovascular disease at an early age and end up with enlarged, dysfunctional hearts.10,17,18 These effects are likely due to vitamin D’s role in increasing protective signaling pathways in those tissues, while preventing harmful ones.19 In addition, vitamin D is required to prevent the excessive buildup of collagen and other fibrotic proteins that stiffen heart muscle and artery walls, reducing blood flow and raising blood pressure.11 Human Studies Verify D’s Heart BenefitsThere’s no shortage of compelling human studies of vitamin D and cardiovascular risk. One study found that a daily supplement of 3,320 IU reduced triglycerides by 13.5% (vs. a 3% increase with a standard weight-loss program) and also reduced tumor necrosis factor-alpha, a major marker of inflammation that contributes to atherosclerosis.20Supplementation has also been shown to relax blood vessels, helping to reduce blood pressure and improve blood flow.19 In a study of African-American teens (a group at very high risk for hypertension and cardiovascular disease), vitamin D supplements of2,000 IU/day boosted blood levels into the sufficient range. The supplemented group also saw a significant and beneficial decrease in aortic stiffness, a measure of cardiovascular risk.21 In another study of African-American adults (also at high risk for cardiovascular disease), 60,000 IU/month for 4 months (about 2,000 IU/day) improved endothelial function, an essential property of blood vessels that allows them to provide adequate blood flow at safe pressures.22 Similar effects have been shown in stroke survivors, who really need to optimize their endothelial function.23 In a study of vitamin D supplementation in obese and overweight women (with an average age of 38 years), supplementing with 1,000 IU/day significantly raised protective HDL-cholesterol levels and significantly lowered body fat mass after 12 weeks.24 Vitamin D deficiency is also implicated in peripheral arterial disease, in which hardened, narrowed arteries fail to provide enough blood to the extremities, especially the legs.25 People with lower vitamin D levels are more likely to develop peripheral artery disease, in direct proportion to how low their levels are. And in fact, amputation, the worst consequence of this condition, is much more likely among those with the lowest levels.25 It’s clearer than ever that you need vitamin D to maintain your cardiovascular health—but it’s important to make sure you’re taking the proper dose. Studies of cardiovascular patients who use only 400 to 600 IU/day in general show no benefits, whereas those using 2,000 IU or more do.20,21,26 One study demonstrated that 2,000 IU/day is the minimum needed to ensure that people reach the minimum target of 30 ng/mL of vitamin D in their blood.27 WHAT YOU NEED TO KNOW Vitamin D: Essential HormoneMost people think of vitamin D as the “bone vitamin,” but recent discoveries show that vitamin D is essential for a tremendous number of normal body processes.Virtually every tissue type in the body possesses receptors for the activated vitamin D molecule, defining it as a true hormone.Low vitamin D levels are associated with increased risks of cardiovascular and neurological disease, cancer, diabetes, and autoimmune disorders.The majority of Americans have vitamin D levels below the minimum recommended concentration of 50 ng/mL, explaining in part the high prevalence of these diseases.Fortunately, supplementation with vitamin D3 has been shown to be protective for all of these conditions, when taken at the dose of at least 2,000 IU/day. (Most people need 5,000 to 7,000 IU/day of vitamin D3 to achieve optimal blood levels.) Vitamin D Lowers Diabetes RiskVitamin D can also play a critical role in diabetes. People with diabetes (both types I and II) have even lower levels of vitamin D than the general population.28,29 A vitamin D deficiency makes you 91% more likely to progress to insulin resistance, or “pre-diabetes” (even for those with normal blood sugar). Additionally, a vitamin D deficiency more than doubles your risk for progressing to full-blown type II diabetes.4 This close connection between vitamin D and diabetes is due to vitamin D receptors, which are found in the pancreas’s insulin-producing cells and in liver, fat, and muscle tissue, all of which influence the fate of glucose in your blood.28 For example, white blood cells called macrophages have vitamin D receptors. When macrophages are taken from diabetics, they display a high level of fat content, which contributes to diabetics’ increased cardiovascular risk. However, when those cells are treated in the lab with vitamin D, they stop their pathological fat uptake—ultimately helping reduce cardiovascular risk.30 Similarly, compared to healthy controls, diabetic lab animals have decreased numbers of insulin and vitamin D receptors in their brains; they have more body fat and higher levels of inflammation and DNA damage; and they perform poorly on tests of memory and cognition (remember that Alzheimer’s disease has been called “diabetes of the brain”).31,32 But vitamin D supplementation restored all of those functions to near-normal levels—including improved cognitive performance.31,33 This is an especially important finding, since it shows the potential of vitamin D to help reverse the process of diabetes. The inflammatory changes in diabetic animals, as in humans, lead to increased fat in the liver, a condition known as non-alcoholic fatty liver disease (NAFLD). This condition further degenerates due to a vitamin D deficiency.34 But when human diabetics with similar elevated inflammatory markers are supplemented with 1,000 IU/day of vitamin D, the inflammation is substantially reduced.35 Perhaps the most remarkable news about vitamin D in this context, however, is that it slows the progression from pre-diabetes to diabetes. When obese, non-diabetic adults supplemented with 2,000 IU/day of vitamin D or placebo for 16 weeks, the vitamin D group had significantly improved glucose clearance from their blood, improved insulin secretion from the pancreas, and a trend to lower levels of hemoglobin A1c (the marker of long-term glucose exposure). Control subjects instead saw a worsening of all those parameters.36 Vitamin D supplementation also benefits those who already have diabetes. Diabetics receiving 1,000 IU/day of vitamin D in yogurt saw significant decreases in fasting blood sugar, hemoglobin A1c, insulin resistance, waist circumference, and body mass index, compared with controls receiving no vitamin D.37 Studies show that supplementation with vitamin D3 can reduce blood pressure, total cholesterol, and LDL-cholesterol—all risk factors for the heart and kidney diseases for which diabetics are at increased risk.38 Treatment with active vitamin D3 also significantly reduces protein levels in urine, a marker of kidney disease.39 With few exceptions, doses of vitamin D of less than 1,200 IU/day have not been shown to be as effective as doses of 2,000 IU/day at lowering blood sugar, hemoglobin A1c, lipid levels, and other disease markers in diabetic patients.40,41 Vitamin D Protects Brain Cells Vitamin D is especially powerful against neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Long-term studies show that low vitamin D levels increase the risk of cognitive decline of any kind by 41 to 60%; increase the risk of Alzheimer’s dementia by 77%; and increase the risk of non-Alzheimer’s dementia bynearly 20-fold.7,42,43 And higher vitamin D concentrations are correlated with lower severity in Parkinson’s disease.44 Even though existing treatments for neurodegenerative diseases can only treat symptoms and temporarily slow their progression,45 vitamin D has been found to reverse neurodegenerative decline. A recent study showed that adding vitamin D to a standard memory drug, meantime, for 6 months in newly diagnosed Alzheimer’s patients produced significant gains in cognition, suggesting a synergism between vitamin D and the drug.46 Supplementation with vitamin D has such potent benefits for the brain because the brain relies on vitamin D receptors for protection against a variety of destructive processes.47 Vitamin D has been shown to have a critical role in nerve cell growth and differentiation, nerve transmission, and the “plasticity” of connections that’s so essential for normal learning and memory.48 Without adequate vitamin D, all of those functions suffer, and some fail. In Alzheimer’s disease, that failure is manifested as increased amounts of the abnormal, inflammatory protein called amyloid beta (or Abeta). Studies show that when vitamin D is added to cultures of cells from Alzheimer’s patients, it speeds the clearance of Abeta.49 When laboratory animals bred to spontaneously develop Abeta plaques are supplemented with vitamin D, they show a decrease in brain inflammation, an increase in protective nerve growth factor, and they develop fewer Abeta plaques compared to control animals.50 Even normal elderly lab rats (those without Alzheimer’s) can experience cognitive benefits from vitamin D supplementation. Older rats have significant difficulty with cognitive testing, along with elevated levels of pro-inflammatory cytokines, decreased levels of anti-inflammatory cytokines, and higher levels of Abeta proteins in their brains.51 But supplementing with vitamin D for as little as 21 days significantly reversed the inflammatory changes and improved clearance of Abeta.51 This shows the potential of vitamin D to prevent the onset of age-related cognitive decline—even when it’s not associated with Alzheimer’s disease. Vitamin D can benefit people with Parkinson’s disease as well. In humans, it’s already known that vitamin D supplementation reduces falls and improves balance in healthy older adults—two problems often faced by patients with Parkinson’s.44 A randomized, placebo-controlled clinical trial has shown that 1,200 IU/day of vitamin D3 prevents deterioration in Parkinson’s disease patients over a 12-month period.52 Intriguingly, this effect depended on the patients’ type of vitamin D receptors in brain tissue. Vitamin D Blocks Cancer Low levels of vitamin D in the blood are strongly associated with elevated cancer risk. Compared to people with higher vitamin D levels, those with low levels have an 83 to150% increased risk of developing cancer.53-55 This strong correlation is due to vitamin D receptors, which regulate a number of signaling pathways involved in inflammation, tumor growth, and immune system surveillance for cancer—especially in the epithelial cells of the skin, breast, prostate, and colon (tissues that are prone to cancer development).56-58 The problem is that in cancer cells, the vitamin D receptor is dramatically decreased, leaving cells unregulated and prone to reproduce in an out-of-control fashion.57 Treating cancer cells in culture with vitamin D, however, produces a number of actions that help fight against cancer: it decreases tumor cell proliferation, quells inflammation, reduces invasiveness, and increases tumor cell death (apoptosis).57,59,60 The benefits of these actions are especially seen in cancers of the breast, prostate, and colon. Breast CancerIn animals with experimentally induced breast cancer, for example, these effects of vitamin D reduced the incidence, number, and size of tumors, particularly when vitamin D was combined with EPA and DHA from fish oil.59,61 In vivo studies have shown that activated vitamin D3 has some benefits specific to estrogen-dependent breast cancer. It reduces overall tumor-promoting estrogen effects by decreasing the expression of the aromataseenzyme that makes estrogen in breast tissue and by decreasing the expression of the alpha form of estrogen receptor that aggravates certain malignancies.60 Human studies are now pointing in a similar direction. In the large Women’s Health Initiative study, even a low dose of 400 IU/day of vitamin D combined with calcium was associated with an up to 20% decrease in breast cancer in women who had not taken supplements previously.62,63 Prostate CancerCancers of the prostate also respond to vitamin D supplementation, as shown by a study in which men with early prostate cancer received4,000 IU/day for a year.64 Fifty-five percent of supplemented subjects showed a decrease in tumor-positive biopsies or a decrease in the Gleason tumor score, while an additional 11% showed no change (meaning the cancer had not progressed). Since prostate cancer is often such a slow-growing malignancy, it is ideal for prevention with vitamin D.65 Colorectal CancerCancers of the colon and rectum usually start as benign polyps (or adenomas), which progress to malignancy as a result of chronic inflammation. Colorectal adenoma patients who took 800 IU/day of vitamin D3 experienced a significant 77%decrease in inflammatory markers that can promote cancer development.56 In a similar group of patients, 800 IU/day of vitamin D3 produced marked decreases in levels of the tumor promoter beta-catenin, with an increase in the tumor suppressor known as APC.66 INCREASED DISEASE RISK WITH LOW VITAMIN D LEVELS Condition Risk Increase with Low Vitamin D Levels* Autoimmune: Multiple Sclerosis78 61% Autoimmune: Psoriasis79 189% Autoimmune: Rheumatoid Arthritis80 24% (Patients taking vitamin D supplements had 24% lower risk.) Cancer, Bladder54 83% overall; 494% for invasive tumors Cancer, Breast53 150% Cancer, Thyroid55 100% Cognitive Decline7 41 to 60% Cardiovascular: (Risk of Heart Attack)12,13,15 38 to 192% Dementia, Alzheimer’s43 77% increase for lowest vitamin D intake Dementia, Non-Alzheimer’s7 Almost 20-fold increase Infection, Respiratory81 36% Metabolic: Diabetes4,82 91% for insulin resistance, 38 to 106% for type II diabetes Metabolic: Risk of progression from normal blood glucose to diabetes83 77% Stroke13,84 22 to 64% * Defined either as serum levels less than 30 ng/mL (75 nmol/L), or as lowest percentiles vs. highest; risk expressed as percent increased for those with normal or highest levels. Vitamin D and Autoimmune DiseaseVitamin D is essential for maintaining a balanced immune system. Immune system cells are well-supplied with vitamin D receptors, which along with vitamin D itself, help the system modulate its response: from “attack mode” in the face of pressing threats to “cleanup and wind-down” mode once the threat is past and tissue damage becomes a concern.67-69 Vitamin D plays a role in the onset and progression of autoimmune diseases, including type I diabetes, lupus, rheumatoid arthritis, psoriasis, and multiple sclerosis.68,70-72 Fortunately, studies show that restoring vitamin D levels to the healthy range through supplementation can help patients with autoimmune diseases. Supplementation has been shown to increase the number of regulatory T-cells that restore immune system activity to its normal state, preventing the overactive response characteristic of autoimmune diseases.73 The increase in vitamin D levels through supplementation has a number of disease-specific benefits: It causes a decline in the disease activity in rheumatoid arthritis and lupus.71,72It reduces the risk of developing type I diabetes and preserves insulin-producing pancreatic cells once the disease has started. 74It suppresses the development of multiple sclerosis in animal models of the disease, and a large human trial has shown that supplementation was associated with a 40% reduction in the risk of developing multiple sclerosis.70,75The Vitamin D SolutionWith over 1 billion people worldwide faced with insufficient levels of vitamin D, it’s easy to see why so many of these life-threatening diseases are skyrocketing to epidemic proportions. Fortunately, the solution is straightforward. Start by taking a high quality vitamin D3 supplement of at least 2,000 IU daily (small children need at least 400 to 1,000 IU).8,9 Next, get your vitamin D level checked as soon as possible. Be sure the lab tests for “25-hydroxyvitamin D,” which is the best measure of vitamin D status.8 To get your blood concentration up to the sufficient level, you’ll need to take 100 IU of additional D3 for each 1 ng/mL you need to raise it.8 So if your level comes in at a low 20 ng/mL, you’ll need to take an additional 3,000 IU (100 IU x 30 ng/mL) to get yourself up to 50 ng/mL. Recheck the level in 2 to 3 months. Once you are in the sufficient range, you might be able to maintain that level by taking 2,000 IU daily, though most people nowadays are taking doses of 5,000 IU and higher to get their levels closer to high optimal range of 80 ng/mL. Confirm this with repeat testing at least once a year.76 Many people, especially those with pre-existing chronic illness, find they need more to boost their levels adequately.76,77 SummaryDespite reams of evidence to the contrary, mainstream medicine continues to mainly regard vitamin D as essential only for healthy bone maintenance. But the discovery that the vitamin D receptor is found in virtually all human tissues has suggested to many that the vitamin (actually a hormone) is vital for most human functions. Frighteningly, though, the majority of Americans have insufficient vitamin D levels to support good health, resulting in an increase in a host of chronic diseases. Supplementing with 2,000-8,000 IU/day of vitamin D3 is the best way to get your levels back to normal and to promote your body’s maintenance—not just of bone health, but of robust cardiovascular, metabolic, neurologic, and immune function, while also preventing cancers of the breast, prostate, and colon, and likely many others. Remember to take your vitamin D with the meal of the day that contains the most fat, as this greatly enhances vitamin D absorption. You owe it to yourself to get your vitamin D level tested now—but don’t wait for the results. Odds are that you haven’t got enough vitamin D in your body for optimal health, so you should begin a vitamin D3 supplement today. If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at1-866-864-3027. Read on the Site where the article includes a detailed list of journal references.