Controversy in Vitamin Research

Why so much controversy about vitamin supplements lately? Do vitamins help make you healthy or not? More and more Health Professions are raising doubts according to new results from research, especially longer term studies. 

Perhaps to better understand this issue, some background information should help. Let's break up vitamin research over the years into three waves.

The first Vitamin research wave started after vitamins were discovered. Scientists analzyed food to discover vitamin content. Then scientists conpared the diets between healthy and sick people to see if the vitamin loads were different. Sick people had lower levels of many vitamins. The natural assumption from this data lead to the theory that higher vitamin containing foods in the diet prevented diseases. But, would the same results also occur with vitamin supplements?

Then came the second wave. After isolated vitamins were created in the lab, Scientists set up studies to test the new vitamins with groups of people taking different amounts of vitamins compared against people not taking any vitamins. The results were not as positive as the studies of vitamins in food. Some study results were positive, some were neutral, and some starteds to show negative results. Thus, the controversy.

One such study called the SELECT study is typical. The SELECT study looked at the possiblity of synthetic vitamin E (dl'alpha tocopherol) and Selenium to prevent prostate cancer. Some food study rssults showed this could be the case. But at the mid-point evaluation of the SELECT study, the vitamin E only group exhibited a slightly elevated cancer rate while the selenium only group had an tiny elevated risk of diabetes. The study was stopped.

CAUTION: Science can be Manipulated. article  Results of studies can be influenced by select criteria chosen by Scientists as well as the population tested. This manipulation can occur in both directions. A popular vitamin E analysis study at Johns Hopkins Medical in 2004 arrived at a result that Vitamin E over 400 IUs increases mortality risk. Almost every Newspaper headline in the World reported this finding. What was not mentioned was the follow up work by other Scientific groups that exposed this work as having numerous flaws. One might imagine that the Johns Hopkins study would mention the cause of death in the Vitamin E group used to determine findings. But, no causes listed. Someone who dies in an auto accident counts the same weight as one who falls and breaks a hip and later dies, regardless of whether or not a relationship to vitamin E is a factor.  article 

Now, over the last 15 years, a new third wave of vitamin research has quietly entered the scene. While a few are larger long term studies, many are smaller and less well published than earlier large study results. This smaller scientific research lacks grant money and the Scientific method dictates more and larger works are needed to verify the smaller studies. Plus, so far, these new vitamin results are not even getting acknowledged. Media outlets usually go for dramatic negative results rather than smaller positive ones. This could also be due to the fact that many of these new study results are challenging traditional and long held nutritional theories.

Examples from the large SELECT Study on Prostate Cancer

Using the SELECT study from above, new wave research findings splashed across Media headlines that vitamin supplements don't reduce prostate cancer. But it's the WHY part from the SELECT study that the media missed from many smaller studies explaining the slightly negative results.

First, what the Government allows to be called vitamin E represents only one out of 8 related "vitamin E" family factors in nature. It turns out that just before the SELECT study began, another smaller prostate study found that the prostate needs to be protected against both oxygen as well as nitrogen radicals. The form of vitamin E used in the SELECT study only handles oxygen radicals. It is action from the other seven of Nature's "vitamin E" family members that stop nitrogen radicals (largely d'gamma tocopherol).

For the Selenium effects, it turns out this issue is exactly opposite of the actions of vitamin E above. The body generates a radical to help with the uptake of insulin and glucose into cells. This helps to control against diabetes. One of the function of the mineral Selenium is to build a radical fighter (GPx). Too much of this Selenium produced radical fighter would destroy the radicals before they could perform their necessary work for the body of moving insulin and glucose into cells. This action reveals that there is a delicate balance needed in the body between oxidation and reduction, a redox balance. If the body is already sufficient in Selenium, supplemental Selenium could tip over this balance.

There are numerous examples of this new wave of vitamin studies upsetting nutritional establishment apple carts. While the background and behind the scenes smaller studies are painting a slightly different picture for many traditional vitamins, the real work is pointing out lesser known vitamins impact on major vitamin functions. Below presents a fundamental vitamin D body process with many related parts and vitamins worlking discovered from this new wave of research.

Of Interest: To discover many of the new third wave type vitamin research, it was necessary to look near the end of Google search listings. Some topics have over 200 pages of listings. Evidently, not many Professionals look that deep since this information is lacking in most health discussions and not yet reflected in most vitamin products. Today (Jan 2024), Google only lists about 7 to 8 pages of websites from a search. Not enough! Good luck finding real truthful vitamin studies..

Vitamin D more than just for Bones

In order for vitamin D bone building functions to occur, vitamin D first has to change into a 1000 times stronger acting form. This requires the mineral magnesium and some Kidney enzymes. Then this form picks up and reacts and combines with these elements as it enters into cells: DBP (vitamin D binding protein in blood), VDR (Vitamin D Receptors), RXR (special vitamin A form 9-cis retinic acid and its 9-cis receptor), and last with VDRE (Vitamin D Reactive Elements). This complex then stimulates genes in the cells to build proteins. One of these proteins, Osteocalcin, a hormone, then initiates a process to combine with calcium and other minerals to form mineral crystals which enter into and become new bone. Osteocalcin is first produced by vitamin D in a non-acting form. Vitamin K2 is necessary to change this osteocalcin form into an action form.

FACTS OF INTEREST (This is huge)

Most if not all bone studies are designed to fail if all the nutrients that participate in forming active vitamin D actions are not acknowledged. Vitamin K2 and 9-cis retinoic acid status are rqrely considered. THE BONE BUILDING PROCESS MIGHT BE LIMITED WITHOUT ENOUGH VITAMIN K2. Doctors have for a very long time measured the blood levels of the vitamin K2 activated form of osteocalcin. This information served as a marker for the level of activity for the bone building process. But, never was the story told that this osteocalcin form was linked to and a measure for vitamin K2 activity. Why?

Vitamin D actions have now expanded to include many immune system functions, especially on certain cancers, and blood sugar control or insulin resistance, a marker for diabetes. This new wave of studies also discovered this tidbit of information about the two forms of osteocalcin.

In a test tube study, the actions of the two different forms of osteocalcin on porstate cancer cells were measured. The non-active form stopped cancer cell growth while the active form of osteocalcin promoted cancer growth. Other studies found that each form also had a different direct action on blood sugar control. There must be a critical and optimal relationship between the active and non-active forms of osteocalin that should be respected. That balance point is not known yet. The body needs some of each form.

These smaller new wave studies may have critical implications and immediately need further testing, especially in controlled human work. Sometimes test tube actions are not duplicated the same in humans. Plus, certain facts have to be considered. Cancer cells produce an enzyme that destroys vitamin D. Scientists comparing vitamin D levels between cancer victims and healthy controls obviously found lower vitamin D levels in cancer patients. This prompted the assumption that increasing vitamin D levels in healthy people would stop cancer. This new knowledge that cancer cells lower vitamin D levels modifies that assumption somewhat.

These and other new wave vitamin work should at the very least bring about a precautionary aproach to supplement protocols. Bone formulas need vitamin K2 unless vitamin K levels are known. Vitamin K2 supplement amounts need some precautions unless osteocalcin form levels are measured. (Vitamin K2 also has another vital function that limits the calcification of artery walls).

Nature has a few different forms of vitamin A or Beta Carotene. One important form, 9-cis, is only in a few supplements. Since vitamin D processes rely on this 9-cis form, this could be another limiting factor. While it is possible the body can make some 9-cis form from the all-trans form, the exact conversion process and amounts are not known yet. But the known facts discovered about this conversion reveal that it is more likely than the 9-cis form will convert to the all-trans form than the all-trans form will build the 9-cis form, at least as determined by analyzing blood levels of each after consuming each separately. 

 A Grain of Salt 

The controversy continues in the two articles below. Other articles on this website reveal some very interesting shortcomings concerning the information as well. Here is one with research analysis with a new perspective on flawed study methods.

Interesting that within the same web page on Medscape.com, these two articles appeared. You be the Judge!

Article 1:    "Trash the Vitamins: Convince Your Patients

A Best Evidence Review

Charles P. Vega, MD; Veena Kulchaiyawat, DO

Authors and Disclosures         Posted: 01/05/2012

Best Evidence Review of Dietary Supplements and Mortality Rates in Older Women

Mursu J, Robien K, Harnack LJ, Park K, Jacobs Jr DR. Dietary supplements and mortality rate in older women. Arch Intern Med. 2011;171:1625-1633.

Dietary supplements are widely used by older adults, even though the effectiveness of these supplements in preventing illness is questionable. But can dietary supplements actually promote a higher risk for death? A new study suggests that the answer is yes for some of the most common supplements. This Best Evidence Review describes the findings of this study and puts these results in context.

Background

Vitamins and dietary supplements play an important role in the health and health care of many adults, and the business of supplements constitutes a multibillion-dollar industry worldwide. Based on the Third National Health and Nutrition Examination Survey, 40% of men and 50% of women older than 60 years of age consume at least 1 vitamin or mineral supplement.[1] A national survey by the US Food and Drug Administration found that 73% of US adults were found to use dietary supplements in 2002, providing annual sale costs in 2005 of over $20 billion.[2,3]

The widespread use of dietary supplements is not supported by practice guidelines. The US Preventive Services Task Force (USPSTF) states that there is insufficient evidence to recommend for or against the use of vitamins A, C, E, or multivitamins with folic acid or antioxidants.[4] Specifically, the USPSTF cites concerns regarding the balance of benefits vs harms of these supplements. The American Medical Association recommends supplements specifically for seniors who have generalized decreased food intake, while the American Dietetic Association advises low-dose multivitamin and mineral supplements depending on individualized dietary assessment.[5] The American Heart Association emphasizes healthy eating patterns rather than supplementation with specific nutrients.[6]

These recommendations against the routine use of supplements are grounded in good evidence. A Cochrane intervention review of 77 randomized controlled trials with 232,550 participants found no evidence to recommend antioxidant supplementation for primary or secondary prevention of mortality.[7] Moreover, there is the possibility of harm related to the use of some supplements. For example, the Alpha-Tocopherol Beta-Carotene Cancer Prevention Trial demonstrated that beta-carotene supplements increased the risk for lung cancer among male smokers.[8]"   -end of article

 **** Now compare this result to another article before you make any rash decisions that appeared recently on the same website page in Medscape.com:

Article 2:    Vitamin E May Affect the Life Expectancy of Men, Depending on Dietary Vitamin C Intake and Smoking

Harri Hemilä; Jaakko Kaprio

Authors and Disclosures

Posted: 02/23/2011; Age and Ageing. 2011;40(2):215-220. © 2011 Oxford University Press

Abstract and Introduction

Background: antioxidants might protect against oxidative stress, which has been suggested as a cause of aging.
Methods: the Alpha-Tocopherol-Beta-Carotene (ATBC) Study recruited males aged 50–69 years who smoked at least five cigarettes per day at the baseline. The current study was restricted to participants who were followed up past the age of 65. Deaths were identified in the National Death Registry (1,445 deaths). We constructed Kaplan–Meier survival curves for all participants, and for four subgroups defined by dietary vitamin C intake and level of smoking. We also constructed Cox regression models allowing a different vitamin E effect for low and high age ranges.
 Results: among all 10,837 participants, vitamin E had no effect on those who were 65–70 years old, but reduced mortality by 24% when participants were 71 or older. Among 2,284 men with dietary vitamin C intakes above the median who smoked less than a pack of cigarettes per day, vitamin E extended lifespan by 2 years at the upper limit of the follow-up age span. In this subgroup, the survival curves of vitamin E and no-vitamin E participants diverged at 71 years. In the other three subgroups covering 80% of the participants, vitamin E did not affect mortality.
Conclusions: this is the first study to strongly indicate that protection against oxidative stress can increase the life expectancy of some initially healthy population groups. Nevertheless, the lack of effect in 80% of this male cohort shows that vitamin E is no panacea for extending life expectancy. (especially if vitamin E contains only one of the E family)   -end of article

Analysis:  The first article ends by referencing the Finnish smokers study that found an increased mortality rate for smoker's taking vitamin E and or beta carotene.  While in the second study, vitamin E reduced mortality in older smokers by 24%. And if vitamin C levels were over median, extended lifespan of less than a pack a day smokers by 2 years. Is it any wonder that Doctors are giving up and creating headlines like the first article.

Follow this logic. A vitamin E heart attack study (CHAOS) found a 71% reduction of second survivable heart attacks in the vitamin E group during the study period. But there also was an unexplained dozen more deaths in the vitamin E groups when followed after the study that also needs an explanation. Check out this reference that adds some clarity to how vitamin E protects arteries.  ref 

There are better answers when the true facts are known. Sometimes the issue is the use of synthetic vitamin E versus natural from vitamin E, other times it is dosages out of balance, or even working with faulty theories, such as the antioxidant free radical theory without considering the antioxidant load balance factor. Science has lost touch with the original definitive meaning of the scientific method with it's very precise reporting or interpretation for results of nutritional studies. If synthetic vitamin E is used, the term synthetic has to be included when mentioning results. article YES, in the case of vitamin E, the synthetic is quite different from the natural form. Science knew about this difference from day one in the 1940's. This website tells more of the correct story than you will find on any other vitamin website. And gives a better explanation to understand the preceding study results that is logical and science supported.

NOTE: A couple of years ago this headline appeared: Are your vitamins killing you?  ref When you read the article, it sounds very logical, BUT, it is only part of the story and knowing the complete story again leaves you with a different view. You will have to search some to find this info, it is on this website in numerous articles.

IOWA WOMEN'S HEALTH STUDY

Another detrimental research against the use of vitamins comes from the Iowa Women's Study. The results need some explanation to understand exactly what and how these negative results and one positive result were uncovered.

ANALYSIS: The results are logical and supported by this website's new vitamin standards, like NO iron except for those who are anemic and iron should always be taken separate from other vitamins. The other nutrients showing a pronounced association, folic acid, copper, vitamin B6 are mentioned on this website with necessary precautions. Magnesium and zinc reveal the least negative association while Calcium was associated with a slight positive reduced mortality. Calcium actually participates in the natural death process for some types of cancer cells and this may prolong life. ref

The most significant fact not mentioned in this study is the cause of death. Maybe those who became ill during the 16 years started taking more vitamins after that discovery. Vitamin use was self reported at years one, ten, and 16. Deaths were recorded up to year 20. No mention of vitamins A, E, D, C, and the other B vitamins.  

In Search of a Carotenoid Complex

First, all things beta carotene and family of carotenoids have known impact. Important reference >ref

Does your Multiple Vitamin provide both vital beta carotene forms or just one? This is a controversial topic> ref

The simple pieces:

• The Carotenoid complex includes many different members. Chief among them include: Alpha Carotene, Beta Carotene, beta-crytoxanthin, lycopene, lutein, astaxanthin, and zeaxanthin
• Beta carotene comes in a few different forms. 
• The chief two are all-trans beta carotene and 9-cis beta carotene. 
• Both of these forms can split to become vitamin A. The ratio used to be thought as 6 to 1, but now is up to 28 parts beta carotene making one vitamin A. Each vitamin A form takes the same formulation of beta carotene it came from as retinoid or retinoic acid, all-trans or 9-cis retinoic acid. 
• There are receptors for each of these two retinoic acids in cells, RAR for all-trans and RXR for 9-cis.
• Both of these two receptors are needed for many vital body functions. ref <This reference talks about brain health.
• The body uses all-trans to be the dominate form and it remains measurable longer, but without just the right amount of 9-cis present, some body functions could be compromised. ref <9-cis on atherosclerosis
• Since Mother Nature knows diets vary, body adaptations developed to counter those times when one or another of these nutrients might be deficient. The different forms of beta carotene can be converted into other forms. The question is at what amounts?
• Studies show 9-cis is more likely to convert to all-trans then the other way around.
• And yes, the 9-cis form is cleared from blood serum faster. This could represent a move into tissues where it is needed to combine with vitamin D and perform vital connections.
• One study showed 9-cis had higher protective factors to limit peroxidation than all-trans beta carotene, and this could be one of the reasons it disappears faster. ref
• Foods exist that supply many of the different carotenoid forms found in human blood plasma that have health benefits. Future research may find more.
• The majority (over 97%) of multivitamins only contain one form, the synthetic all trans-beta carotene. When Beta Carotene is listed in Vitamin label box as Beta Carotene without any source mentioned, it is usually synthetic.* ref 
• The issue is not that the synthetic form of all-trans beta carotene does not work, it is the absence of the other forms that represents possible issues. 
• For active Vitamin D actions, it has to first combine with VDR, plus RAR, and RARE (elements inside cells) before vitamin D functions occur. Part of this combination needs to combine with RXR to stimulate genes to build proteins such as osteocalcin that accomplish functions attributed to vitamin D. Osteocalcin is responsible for blood sugar maintenance, cancer prevention, plus after activated by vitamin K2, bone building mineralization.
• Beta Carotene and it's pathway formed elements, like all-trans and 9-cis, have cholesterol related functions of improving HDL cell cholesterol attachments to speed elimination of cholesterol. 9-cis BC predominates here over all-trans BC. ref
• This beneficial influence of 9-cis Beta Carotene on cholesterol removal by HDL appears to inhibit atherosclerosis by limiting plaque growth.
• It appears that while all-trans is the dominate lignand for RAR with many vital functions, some RXR from 9-cis is needed to play a balancing role on and with RAR receptors, plus it also has a few vital functions by itself.
• 13-cis retinoic acid is also present in natural sources. It has some vital roles as well, it was approved in 1982 by FDA for use to reduce acne, but is best in secondary roles to not upset balance points with the other retinoids. 
• BOTTOMLINE:  Science needs more research to settle the issues raised by this article. Until then, the precautionary approach takes center stage. Find multiples with a natural source beta carotene like D. Salina algae to get the different carotenoid forms and let the body decide how to allocate and use them. This is especially true for those who do not consume enough vegetables and furits.

HEALTH FACT: Carotenoids in food are more effective than beta carotene supplements. ref The goal then is to find a carotenoid supplement that closely mimics the ratios and synergism between the different carotenoids found in food. Since food can vary in the amount of carotenoids present by many times, there is a narrow window of dosages for supplements that will fit with the related and beneficial elements in food to enhance the carotenoid benefits without upsetting natural body processes. EAT MORE VEGETABLES AND FRUITS, and take low dosages of natural source carotenoid complex supplements.

The body can convert Beta Carotene into vitamin A as needed. article article Today, Beta Carotene is found in most Multiple Vitamins. Vitamin A used to be in all multiple vitamins until toxic actions were discovered such as increasing bone fractures. Natural Beta carotene does not exhibit this effect. BUT, over 95% of multiples contain the synthetic form of only all-trans-beta carotene. In nature, there are 4 different forms of beta carotene, 2 major, all trans- and 9-cis, and 2 minor 11-cis and 13-cis.***  Plus the carotenoid family includes many other members such as alpha carotene, beta-crytoxanthin, lycopene, lutein, astaxanthin, and zeaxanthin. You will not find many Multiple vitamins that include any of these other Carotenoid family members similar to their distribution in many vegetables and fruits. Check out this study. Doesn't this information provide ammo to consume the whole carotenoid complex either in food or from wise vitamin supplements that include many of the natural family factors together such as alpha carotene rather than just Beta Carotene, especially if it is only in the all-trans synthetic form?

THE BENEFITS FROM CONSUMING BOTH BETA CAROTENE FORMS?

Read about the effects of different forms of carotenoids on breast cancer here. (A risk number, OR, under 1 is good and indicates protection with lower risk while over 1 means greater cancer risk. ·0.49 (95 % CI 0·34, 0·71) for lutein/zeaxanthin >represents a low risk) ref

This nutraceutical company website simply describes what is Dunaliella Salina algae, a natural source for Beta Carotene that includes many forms of the other carotinoid complex family members. 

This short reference article (corrupted link removed) clearly explains the differences between natural beta carotene and synthetic beta carotene. Science did not initially spot natural differences until synthetics have been in use for some time, as is the case with synthetic beta carotene.

This scientific article reviews the history of Beta carotene and cancer research. In its own words, a real Dr. Jekyll and Mr. Hyde roller coaster ride.

*SMOKERS taking (synthetic) BETA CAROTENE are in jeopardy

Smokers taking synthetic beta carotene developed more lung cancers than non-smokers in a couple of studies. There is now a better understanding of what might be happening. ref ref  Beta carotene might turn from an anti-oxidant into a pro-oxidant, but that didn't happen in this smoke test tube study on live cells. Beta carotene is highly sensitive to oxygen levels and could change to a pro-oxidant reaction at higher oxygen concentrations, such as in the lungs.  ref  (this reference cuts to the very core of the damaging free radical cause for cancer) From a ferret study, another possibility was found.  

"Extensive conversion of β-carotene to oxidation products was observed in subcellular fractions from smoke-exposed ferrets. β-Carotene also enhanced smoke-induced epithelial cell proliferation and squamous metaplasia. Moreover, carotenoid supplementation also enhanced smoke repression of RARβ expression and enhanced induction of c-Fos and c-Jun. These observations suggest that β-carotene oxidation products may exert effects on retinoid signaling and affect the status of other nuclear transcription factors as well."  

OK, this is just a fancy way of saying that beta carotene might speed up the growth rate of already existing lung cancer cells. What is still open for discussion, would the carotenoid complex achieve a balance over just taking beta carotene as all trans by itself? Is 9-cis needed to balance the all-trans beta carotene form found in 95% of multiple vitamins? Yes, both 9-cis and all-trans retinoic forms are needed for proper function of retinoid signaling, with the 9-cis retinoic form having 9 times greater activity over the all-trans retinoic acid to prevent cancer cell formation. And maybe it is more active since Mother Nature knew she needed more all trans form for so many other vital functions. ref ref

Beta Carotene Factors Revealed

Here are the activation factors at the heart of the beta carotene form controversy. The all-trans form reacts only with the RAR receptor, while the 9-cis form acts with both the RAR and the RXR receptors. Why is this important? RXR is needed to combine with the vitamin D activated VDR to form VDR/RXR to complete vitamin D functions. To support RAR actions, it must first combine with RXR forming the RAR/RXR receptor. The synthetic form of beta carotene containing only the all-trans form is incomplete and that represents a very high probability for why studies are showing adverse or nil effects. Far too many multiple-vitamins only contain the synthetic form of beta carotene.

A study quite some time ago, 2001, found that beta-crytoxanthin levels were the only individual carotenoid family member related to a significant reduced risk of lung cancers in smokers. Higher total carotenoids exhibited a 37% reduction in lung cancer risks for smokers versus those with lower than normal total carotenoid amounts. This study came out of Shanghai, China: PMID: 11440962. ref  For food sources and mechanism of action, go here.    Study Ref

A BALANCED APPROACH 

First, eating vegetables and fruits is the best way to get the many carotenoid family elements. Over 600 forms exist. For those who consume limited vegetables and fruits, it would be prudent to supplement the whole mixed carotenoid complex that appears to have a synergistic ability to limit or avoid this smoke induced reaction found when only taking the synthetic beta carotene form. Dr Weil chimes in here.

This reference article pretty much sums Beta Carotene up. A matter of beginning levels, helpful if low and may not be if already high amounts present. Here are some positive studies on the value of some of the other carotenoids: For Eye health  ref   For Cancer and CVD, ref   For CVD health with alpha ref

Note that Lycopene, a carotenoid from tomatoes, was found significant for influencing cognitive actions.

NOTE: Breast cancer connection may be related to dosage levels of beta carotene. ref and this one. Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer - PubMed

And this later follow up study finding alpha carotene had the most impact. ref

 NOTE 2: See** below. Leukemia studies show vitamin D needs 9-cis retinoic acid acting together to prevent. ref

WRAP UP

The take away: Don't take synthetic beta carotene period! ref Take only multiple vitamins containing the whole natural source carotenoid complex such as from Dunaliella Salina algae. This quickly eliminates over 95% of multiple supplements in the marketplace today. How can you tell if beta carotene is from a natural source? The source is listed in the box on the side panel (i.e., D. Salina, or Spirulina). If not listed, it is 99% probably synthetic. Even many whole food type vitamins are mainly just beta carotene with only a small amount of the other carotenoids. Some multiples do list some of the other carotenoid members separately.

Regarding the two different types of beta carotene, all-trans and 9-CIS.  All-trans is considered the more active form and this is why when Scientists created the synthetic form, only all-trans was thought to be needed. BUT, as often happens in nature, the 9-CIS beta carotene excells in some functions. ref  Both forms develop metabolites in the body and turn into all-trans retinoic acid or 9-cis-retinoic acids. In these forms, 9-cis is 10 times more active in preventing neoplastic cell growth, or tumor formation. ref ref But, both retinoic acid forms can also turn into 13-cis and 13-trans.  During pregnancy, these 13- forms may have sinister effects on brain development. It is interesting to note that all-trans retinoic acid turns into 13-cis (ref) more than the 9-cis retinoic acid form. ref 

**IMPORTANT INSIGHT: The hormone or active form of vitamin D attaches to about 30 cell types that have a Vitamin D receptor, VDR, to active genes within the cells to build vital protein structures the body needs for regulation, especially for immunity and to control calcium. At the cell wall, VDR activated by vitamin D, bonds with RXR, from the 9-cis beta carotene now in it's retinoic acid form. It is this combination, VDR-RXR, that influences the genes through DNA to begin the bone building process as well as many other vital body functions. ref

Thus, vitamin D needs magnesium in an enzyme for activation and also vitamin K2, then the hormone form of active vitamin D stimulates VDR that next combines with the 9-cis retinoic acid (from 9-cis beta carotene) activated RXR to complete it's functions in the cell. SYNERGISM! The synthetic beta carotene form, containing only the all-trans form, completely misses out on participating in this RXR pathway with vitamin D activated VDR. Yes, nature often uses back up plans to allow conversion from the all-trans form into the 9-cis form. But it may not be wise to rely on this always happening, especially when the all-trans form has other functions to perform. Consuming vegetables adds to all natural beta carotene forms, but for those that do not like vegetables, be sure to get a multiple vitamin with the natural source D. Salina to get a fuller compliment of carotenoids. 

This is one reason OVER 95% OF MULTIPLE vitamin mineral SUPPLEMENTS available in the marketplace today are NOT ACCEPTABLE according to the NEW VITAMIN CRITERIA?

They only contain synthetic all-trans beta carotene and miss out on all the benefits of 9-cis beta carotene plus the synergistic actions with all carotenoid members. Of course the all-trans form is important too, but many beta carotene functions require both forms to act together. Eating vegetables and fruits, priority one. AVOID THE SYNTHETIC FORM OF BETA CAROTENE.

SIDEBAR: A valid point needs to be highlighted by the issues presented here. When Scientists attempt to study just one or two nutrients, they can miss synergism with other nutrients that may influence the results. As an example, Vitamins C and E levels with their anti-oxidant activity could have possibly mitigated beta carotene results. Plus, cancer cells reacting in a test tube or small animal for the nutrient in question often are not always the same as how cancer cells react in the human body. These concepts make research on vitamins difficult and challenging. And most likely are responsible for contradictory results for the same nutrient from study to study. When questions arise, Scientists should look at how Nature packages nutrients in food. And analyze why? Harmonizing with Nature is probably the better choice rather than trying to control, manipulate, or dominate.

During a virus generated common cold, Nature uses sneezing, coughing, fever, and free radical generation as healing mechanisms to help rid the virus from the body. Are Cold medicines drug and vitamin companies develop working with Nature or against? Is it wise to always work against or might it be more appropriate to first attempt to harmonize with and support natural body immune forces, as long as conditions safe for the body. Many Vitamin issues fall into this situation. Science in the past has decided to work against with limited positive outcomes. And the few apparent short term successes are now showing long term failures, like just calcium for bone fractures.  In this website, you will begin to discover how and why.

*** Clarification for the different forms of Beta Carotene

This is a little confusing, but vital points about the different forms of Beta Carotene and their respective retinoic acid forms increase understanding for supplement choices. All-trans and 9-cis are the two dominate forms in fruits and vegetables. These two forms have the ability to turn into vitamin A as retinoic acid when needed. 9-cis beta carotene not only turns into 9-cis retinoic acid, but can also turn into all-trans and 13-cis retinoic acids. Both all-trans and 13-cis beta carotene turn into mostly only all-trans retinoic acid. Studies have also revealed that the all-trans retinoic acid can turn into 9-cis retinoic acid, but the level of conversion may be compromised under certain conditions and only limited amounts are found in tissues when tested after all-trans ingestion. ref   

SIDEBAR: When Scientists analyze blood levels for the different forms of beta carotenes, they mostly find all-trans. This prompted them to only include the all-trans form thinking that the 9-cis form must be quicly oxidized. Later they discovered that the 9-cis form was found in greater amounts in some organs and tissues, similar to what happens with the other famuly members of vitamin E. 

The 11-cis retinoic acid form gets very little play. It is mostly produced from all-trans retinoic acid and is involved in vision and eye retina light functions. ref 13-cis is very similar in actions to all-trans beta carotene.

Actions of the two dominate retinoic forms are carried out in two ways, either directly, or after they activate nuclear receptors on certain cell walls, including cancer cells. The all-trans retinoic acid only activates the RAR receptor while 9-cis retinoic acid activates both the RAR and RXR receptors. This is a very crucial point. These receptors than combine with another receptor, retinoic acid receptor elements, (RARE) to complete their functions. RAR combines with RXR to form RAR/RXR. RXR can combine with another RXR (RXR/RXR) or a vitamin D receptor, VDR as VDR/RXR, and even a thyroid hormone receptor. Without first combining with RXR, the Vitamin D Receptor, VDR, does not perform its functions. Thus, the importance of the 9-cis form is magnified since it combines with many receptors, as well as RAR. It appears to not be wise to hope enough of the all-trans form will convert into the 9-cis form in adequate amounts since in some studies, it was not present when tested. Of course, both all-trans and 9-cis beta carotene are vital to health. Immune functions, vision, bones, skin, cardiovascular, etc.

TAKE AWAY

It is not necessary to understand all these different forms and actions. The important take away is that nature is a team player. Many nutrients have synergistic actions to balance functions. When Scientist test only one form, sooner or later, adverse conditions can erupt. Like for Vitamin E, and here with beta carotene. A drug form of All-trans retinoic acid, a vitamin A form, at very high dosages has been used to arrest leukemia for over 20 years. BUT, after awhile it stops working and blood levels fall allowing the disease to relapse. The 9-cis form did not develop this resistance. One theory is that without 9-cis present to totally activate the all-trans nuclear receptors, this resistance developed.

DO NOT take large dosages of vitamin A or beta carotene on your own. At certain levels, retinoic acid can generate cellular mutations and increase cell growth. This is one reason why vitamin A is limited to lower dosages. Beta carotene so far has not exhibited these tendencies, but probably best to limit to mainly food sources, eat salads, veggies, and fruits. And for multiples, stay at the lower range of only natural source beta carotene, as D. salina algae, or maybe spirulina. Remember, many multiple-vitamins contain just the synthetic form of beta carotene with only all-trans beta carotene. This form should not be consumed, especially since the Finnish study on Smokers should an increased lung cancer risk.

 PRECAUTION:  Even beneficial nutrients can be overdone. In people who drink a lot of carrot juice, their skin and even the whites of their eyes often turn yellow. This indicates that the liver is not able to process the amount of color carotenoids coming in and places the overflow into out of the way areas until the liver can catch up. This not a desirable action. Another situation where too much carotenoids can also gather, the yellow color elements show up as a ring around the back of the eye. There are definite benefits from a certain intake of carotenoids in protecting the eyes from blue light damage. But, can this too become overdone? More on this soon.

NEW RESEARCH: Obesity linked to low retinoic acid levels. Return soon!

Light-hearted Vitamins (first laugh, then cry)

If vitamin issues to health were not so critical, they could be a lot of fun. Here is an article "Sure fire tricks to get the most out of your vitamin supplements" ref that actually has some truths, tongue-in-cheek style. But, what about the cases when certain nutrients are found to prevent dementia, or slow down heart disease, etc. without the many side effects of drugs.

While Scientists like to paint in black and whites, and their studies reflect this aberration, real life exists mostly in gray tones. Vitamins are not either all good or all bad, they can be one or the other as well as 50 shades of gray in-between. Again, individual biological differences account for many of these variations. Often these are expressed as gene mutants. Nature gone wrong. There are many wayward mutant genes that exist to change the way vitamin D is processed. If one does not factor in these, study results can widely vary, as they do.

The same can be said for soy reactions since the number of people with the ability to convert Daidzein, an isoflavone phytoestrogen found in soy, to equol shows great variation. ref    Equol is proving to be the beneficial element. It needs a certain bacteria in the intestinal tract for this conversion and only 35% have this bacteria in the USA while in Asia as high as 50% have it.

Vitamin A

Vitamin A as retinol from animal sources is vital to health. NIH Information listed here: ref

NOTE: Vitamin A and beta carotenes mentioned in the above reference studies often just use synthetic forms. The natural forms might overcome some of the negative toxic reactions linked to synthetic vitamin A supplements compared to the results from food source studies since they contain the same forms found in food while the synthetic form is missing critical elements. Read on.

Some studies have found that higher vitamin A levels interfere in bone health increasing fractures and also exhibit potential liver damage. ref Other research does not show this toxic effect from higher vitamin A, so there might be related nutrient levels that influence direction of action, or it could simply be a synthetic form that is at the heart of the toxicity. ref ref Since retinoic acid is involved in cell health, differentiation, metabolism, and cell death, it is important to get the proper amount for these activities but not tip into potential toxic reactions. Luckily, retinoic acid is effective against cancer at both low and high amounts, thus the potential for high amounts to turn toxic drives the necessity of lower dosages for prevention. ref 

NOTE: Vitamin A is from animal sources. The past low fat diets for cholesterol control and heart health were a disaster on the intake of vitamin A foods like cream, butter, and organ meats. Fish did get a boost. Plus, the changes to animal production, namely grain feedlots, also lowered the vitamin A content. Grass fed meats and organic dairy products will help increase natural vitamin A. 

Plants with carotenoids supply a preform of vitamin A. It takes six units of plant previtamin A to convert into one unit of animal source vitamin A. Beta carotene from plants can be split by the body into vitamin A as retinoic acid when needed. While animal source vitamin A as retinol can be converted into the retinoic acid, there might not be enough due to the diets that limit fat.

There are two receptors for retinoic acid, one derived from all-trans beta carotene and one from 9-cis beta carotene which divide into All-trans and 9-cis retinoic acids. While both can bind to and influence the retinoic acid receptors (RAR), it is only the 9-cis form that can bind with Retinoic X Receptors (RXR). The 9-cis RXR action is 10 times more effective than RAR action to prevent mutations of cells that can turn into cancers. Both all-trans and 9-cis must be present for these actions.

VITAL: Copied here is one of the retinol functions of RXR combining with hormone vitamin D receptor to influence organs. "1,25(OH)2D3 acts mainly through binding to its nuclear receptor, the VDR. The VDR interacts with the retinoid X receptor (RXR), forming a VDR-RXR hetero-complex, by which VDR acts as transcription factor able to bind to vitamin D-responsive elements (VDREs) in the promoter region of target genes (13)."  The synthetic beta carotene form of all-trans would not directly participate in this action.** Simply, vitamin D attaches to Vitamin D receptor which then combines with 9-cis RA receptor RXR and together they work with DNA to build vital proteins for the positive bone actions attributed to vitamin D, and other areas as well. see copy below too ref

Does it make any sense to only use synthetic all-trans beta carotene in over 90% of multiple-vitamins when the simple addition of D. Salina algae can supply BOTH all-trans and 9-cis beta carotene forms together in their NATURAL state? Since a balance of actions exists between all-trans and 9-cis, this one vitamin improvement could have a meaningful impact on health. article

**NOTE: The body recognized the importance of all-trans in many areas of actions, but for vitamin D gene influence, the 9-cis form is essential. It is interesting to note that 9-cis beta carotene will form both 9-cis retinoic acid as well as all-trans retinoic acid at about a 50-50% level. ref The all-trans beta carotene has only been found to convert 99% into all-trans retinoic and 13-cis retinoic acids. The exact mechanism is not yet understood, It is also not sure if all-trans will convert to 9-cis forms. Some does, but amounts notyet determined. The importance of a balance between all-trans and 9-cis is necessary for proper cell differentiation where dysfunction could result in as a potential cancer producer. While this study was in animals, further science shows actions similar in humans.

FYI: Of course, it is sometimes not logical to understand how or why nature works. All-trans is by far the most stable and active retinol form in the body. The 9-cis forms disappear with greater speed. But this does not mean they are not important. This is similar to the rather significant mistake scientists made with vitamin E forms when only d'alpha tocopherol was still found in blood plasma after a few days. The reason known now is that this form has a transporter protein to hold it there. The body has greater antioxidant needs where oxygen abounds at greater levels.

VITAMIN A IS NEEDED BEFORE VITAMIN D WORKS 

Copied here due to the importance of this interaction, the reference listed at end of VITAL: 

Biomed Res Int. 2018 May 22;2018:9276380. doi: 10.1155/2018/9276380. eCollection 2018.

The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health.

Khammissa RAG1, Fourie J1, Motswaledi MH2, Ballyram R1, Lemmer J1, Feller L1.    Author information 

Abstract

Vitamin D plays an important role in calcium homeostasis and bone metabolism, with the capacity to modulate innate and adaptive immune function, cardiovascular function, and proliferation and differentiation of both normal and malignant keratinocytes (SKIN CELLS). 1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR) (FROM 9-CIS BETA CAROTENE converting to 9-CIS RETINOIC ACID FORMING RXR)( <These are forms of vitamin A). In turn, VDR/RXR binds to DNA sequences termed vitamin D response elements in target genes, regulating gene transcription. In order to exert its biological effects, VDR signalling interacts with other intracellular signalling pathways. In some cases 1,25(OH)2D exerts its biological effects without regulating either gene expression or protein synthesis. Although the regulatory role of vitamin D in many biological processes is well documented, there is not enough evidence to support the therapeutic use of vitamin D supplementation in the prevention or treatment of infectious, immunoinflammatory, or hyperproliferative disorders. In this review we highlight the effects of 1,25(OH)2D on bone and calcium homeostasis, on cancer, and refer to its effects on the cardiovascular and immune systems.

PMID: 29951549   PMCID: PMC5987305   DOI: 10.1155/2018/9276380

Remember that the synthetic from of beta carotene, ALL-TRANS, only or mostly forms into the RAR receptor while the 9-cis beta carotene (after converting into vitamin A retinoi acid) forms with both RAR and RXR receptors. These receptors have polar opposite combining attractions and this is why only the RXR mainly participates and forms with the vitamin D receptor, VDR, to stimulate DNA into supplying the elements necessary for bone building, etc. 

DO NOT PICK MULTIPLE VITAMINS WITH only SYNTHETIC BETA CAROTENE. Even some whole food multiple vitamins may not have both forms. Usually there is not enough information on labels to clarify what forms are present and when present if at a significant amount. Look for Dunaliella salina algae on label. The trade names like Betatene that use natural source D. salina algae offer various percentage products, so the exact amount of active elements may be difficult to determine.

Vitamin Rationale to take or not

There are studies with results on all sides of the vitamin supplement question. Here two sides are examined to further complicate the question about taking supplements or not to take supplements and just get vitamins from food.

• STUDY 1: This study showed people who take multi-vitamin supplements have longer telomeres on DNA strand coils in cells than people who have not consumed supplements. Longer telomeres mean that the cells are younger and more responsive to challenges. Every time a cell divides, the DNA strands unwind and after duplication, they rewind forming two identical DNA strands. To prevent the strands from breaking during this process, a little bit of the telomeres at the tips of the DNA strands break off. Older cells reach a point after dividing a certain number of times when the telomeres are so short that they can no longer protect the unwinding DNA strands and they break causing the cell to die. ref  ref
• It is of interest to note that cancer cells produce an enzyme to prevent telomeres from shortening when cancer cells divide, which they do very quickly to cause the rapid growth in some tumors.
• STUDY 2: Another study on people consuming certain vitamins, B6, B12, and Folic acid, designed to show a positive affect on cardiovascular disease by reducing homocysteine levels. Even though homocysteine levels dropped, there was only a slight positive affect on CVD from higher folate and vitamin B6. The study also found a slightly negative influence of increased cancer risk. Many of the test people smoked, so the cancer that increased was lung cancer. Thus, smokers, especially males, should not consume supplements of B vitamins. But, check out the next study. ref
• STUDY 3:  This study looked at B complex vitamins on Esophageal Cancer. While vitamins B1, B3, B6, and B9, reduced EC, higher vitamin B12 increased EC rate. ref