Vitamin D: a dynamic molecule. How relevant might the dynamism for a vitamin be?
Nephrology Dialysis Transplantation Volume 31, Issue 1Pp. 23-30.
Sandro Mazzaferro1, sandro.mazzaferro@uniroma1.it and Marzia Pasquali1
1Department of Cardiovascular Respiratory Nephrologic Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
2Nephrology and Dialysis Unit, Policlinico Umberto I Hospital, Rome, Italy
Received June 22, 2015. Accepted August 22, 2015.
Vitamin D has been aound for a lot longer than bones
Perhaps the early role of vitamin D was immune response
Download the PDF from VitaminDWiki
Cholecalciferol, the precursor of Vitamin D3, is a very old, highly conserved, molecule. Its presence is evident in non-mineralized 750 million-year-old living species, such as plankton. The more active metabolites, a receptor and a D binding protein, appear later, along with the increasing complexity of animal species living in the sea. In the sea, however, the biological function of vitamin D is unlikely to be linked with mineral metabolism, and we can hypothesize a relationship with an immune response. It is in terrestrial animals exhibiting cellular bone that the complexity of vitamin D increases. At this stage of evolution, we see the appearance of bone cells that are capable of producing hormones that regulate and are regulated by vitamin D. This interaction starts a sophisticated metabolic system that modulates both mineral and energy metabolism for the requirements of the musculoskeletal system. Among the so-called pleiotropic effects of vitamin D, those resulting from the inhibitory effect on the renin-angiotensin system are of particular interest for nephrologists. Intriguingly, however, more than for anti-hypertensive effects, this interaction could be relevant for anti-inflammatory actions, possibly representative of a residual ancestral role of vitamin D. In addition, this evolutionary dynamism of the vitamin D system should not be separated from the chemical dynamism that characterizes the ligand molecule and its specific receptor. Both are capable of significant tridimensional modifications that contribute to an increase in the variability and the partial predictability of their final biological effect. A dynamic overview of this system that takes into account its evolutionary and adaptive aspects may be helpful to understand its biological complexity and to envisage why using vitamin D metabolites for therapeutic purposes is still a matter of debate.
CONCLUSIONS
Vitamin D should be regarded as a very conserved molecule that probably started as a component of the plasma membrane of simple organisms, with protective or defensive roles. Its function has changed to become a necessary regulatory element of the metabolic and energetic requirements of life on Earth. The dynamism of the molecule and its receptor certainly represents an element of the plasticity that allowed the acquisition of such highly specialized properties within the musculoskeletal system. It is impressive that during evolution the appearance of cellular bone increases the complexity of the system, with the production of bone proteins that counter-regulate the effects of vitamin D on bone and muscles. Significantly, the VDR, possibly because of its ancestral biological roles, is present in numerous tissues not necessarily involved with the musculoskeletal system. Among the claimed pleiotropic properties, the systemic but generic anti-inflammatory effects could be related to the RAS-inhibitory properties. Given this complex biology, it seems rather simplistic to try to deduce its function through the assay of one or two blood circulating metabolites. A dynamic view of the interaction with its receptor is certainly helpful to try to understand why we cannot exactly predict the biological effects of the natural compounds. In fact, the recommended doses of this ‘vitamin’ either for healthy people or for patients are still a matter of debate. A dynamic view also helps to understand why synthetic analogues can have very specific biologic effects and can be considered for very different clinical purposes (from cancer to infection) through activation of the same receptor. Vitamin D and its receptor should be regarded as a rather sophisticated molecular machine that we are still discovering. Much more remains to be discovered, but a general overview that takes into account the evolutionary aspects of this system seems useful to try to understand the multifaceted biology of this ‘vital amine’.
Notes on evolutionary history of Vitamin D after reading the PDF
550 million years ago Vitamin D involved in mineralization of snails etc,
450 million years ago Vitamin D Receptor and Vitamin D Binding Protein
Has a nice chart of Vitamin D-related features vs 100's millions of years
Vast majority of the article deals with the structure of Vitamin D and that of the VDR
See also VitaminDWiki
- History of Vitamin D from 500 million years ago to orthopaedic practice today – 2019
- Vitamin D history back to Egyptians and fortification - Aug 2011
- More sunshine: more teeth (1862), fewer cavities (1934) – Oct 2011
- Sunshine is a cure for “weak and soft muscles” – 425 BC
- SOLAR ultraviolet radiation and vitamin D: a historical perspective – Aug 2007
- The Healing Sun –1999 book highlights at VitaminDWiki
- Teeth getting worse due to lower level of vitamin D during the past 5,000 years
History of Vitamin by Lorenz Borsche - written to a friend - March 2022
A brief history of 750 million years of vitamin D
A brief history of 750 million years of vitamin D
750-500 million years ago the "Vitamin D" system evolved in organisms. Vitamin D3 in fact is not a vitamin, but a secosteroid, built from steroids. Steroids are lipids and their names stem from the first of all steroids: cholesterol. Well known ones are estrogen, testosteron and cortison, to name a few. With the help of D3, calcium could be utilized and thus stiff skeletons were feasable in the making for the first time. Since then virtually all animals use D3. Deep sea fish get it from their food, but ultimately it comes from the algae that krill feed on. Later, some fish, that swam nearer to the water surface, developped the conversion of 7-dehydrocholesterol into Cholecalciferol (D3) with the help of high-energy UV(B) light, which is how it came down on us when these creatures became land-dwelling. From Cholecalciferol our liver sythesizes Calcefediol or Calcidiol: 25(OH)D3, which is, what the doctor measures in your blood. And from that, the kidneys and many body cells turn it into the active form, Calcitriol, shortlived and important in the biochemical function of all cells with a VDR, a Vitamin D receptor - which the majority of our cells do contain. All of the different forms are generally known as D3, but when speaking of blood levels, it's always Calcefediol, 25(OH)D3.
A big jump in time now to our genetically closest cousins: the chimpanzees. They have fair skin under their fur, which you can discover in the zoo. Mankind had that too, the fur as well as the fair skin, when the rainforest became a savannah by a climate change many millions of years ago, and these hominidae had to climb down from the retracting trees. In the savannah, the upright gait was helpful as it allows you to spy over the high grasses. Also running down gazelles, an animal with escape response like the horse, that needs to digest constantly and therefore collapses after 2-3 hours of "escaping" from the hunter constantly trotting behind it. Upright gait there was much more effective then being a four feeter, as two-feet running is by far the most efficient way of locomotion - it keeps the center of mass almost unchanged in height and that saves energy. That's how mankind became the best endurance runners under the sun - men these days can even triumph over horses over a distance of a hundred kilometers.
But when running, you have to be able to cool down your body by sweat much more then usual, and then, isolating fur is a big hindrance. So our kind needed to lose the fur. But the fair skin in the blazing equatorial sun and unshielded was rather unfavorable: sunburn and especially skin cancer threatened. Thus the skin became dark by Melanin - most probably simultaneously with the loss of fur: less fur, more melanin etc. until there was essentially no more fur, but lots of perspiration glands and - jet-black skin.
Melanin blocks UV(A) radiation quite reliably to save the species from skin cancer, but still enough UV(B) passes through to produce a D3 level of about 46-50 ng/ml D3 (here: calcefediol - 25(OH)D3) in the blood, if you live at the equator and mostly outside - apparently considered sufficient by nature in a highly infectuous environment, as that's the level to be found by traditional living hunters and gatherers (Hadza) in North Tanzania, the craddle of mankind, as well as in our cousins from the rainforest, who have, despite leaf canopy and fur, good 48 ng/ml, because of the white skin under the fur. And they are known to bask in the sun, lying on their back and presenting their less hairy belly and insides of the upper legs to the sunlight.
Kept in zoos in the western world they have only 24 ng/ml although being in the outer enclosure most of the time, it's the high geographical latitude with its lower sun angle and thus less UV(B) reaching the surface being responsible for that.
The 50 ng/ml are to be understand as a consideration optimum of the evolution, as with it approximately 95% of humans are well protected against most severe infections like flu etc. The so-called Vitamin D Low responders being genetically disfavoured (beyond and outside the two Sigma area of the Bell curve) might have the same protection at 100-120 ng/ml (D3 becomes toxic only far, far beyond), but to save 99% of the populateion, evolution would have to keep up such a high level for all - and producing vitamins and hormones is an energy expensive task.
Thus evoution would have to refrain from saving every shred of energy as fat, which it usually does, as the fat is badly needed - famines through regular annual droughts were not only the biggest killer back then, but hunger is it today still and causes much more deaths than any of the worlds diseases. Hence, our so called "love handles" are a precaution against famine. Just like D3 is a precaution against infections as well as for the down regulation of a cytokine storms, for a better regulation of blood coagulation, for the down regulation of killer cells, attacking even healthy cells, but first of all for the production of all possible components of the immune system via the activation of about 700 immune relevant genes.
Mankind has strongly interfered with both preventive measures in the past 100,000 years. Nowadays, obesity is our most massive problem despite continuing hunger, partly even so in poor societies. Evolution had unfortunately endowed us with an insatiable greed for the mixture of sugar and fat, which in this form is absolute rare and naturally exists only in mother's milk, an extremely nutritious combination and therefore today the No. 1 reason for diabetes-II with candy bars consisting mainly of sugar and fat and potatoe chips made of quick carbohydrates and again fat. The sugar quickly raises the blood sugar level, triggering a massive release of Insuline. Insuline now opens the fat cells to store the fat in blood in them. Meanwhile the energy consuming muscles live on the sugar instead of burning fat. Sugar levels in the blood then sink quickly and the result is a hungry feeling, asking for more quick sugar. That's how obesity begins.
And instead of staying at the equator and black skinned, mankind has migrated, further to the south but especially to the north, where the sun shines much less, so little that, as soon as the shadow is longer than a person high. i.e. at less than 45° angle of radiation, no UV(B) can penetrate the atmosphere at all and, despite white skin, from the end of September to the end of March UV(B) can no longer synthesize D3, although we can still tan a little, as the longwave UV(A), which causes the tanning by producing Melanin, still passes through the athmosphere. All of that is a bit different in great heights above 1.500 m, as the way through the athmospere is shorter and less "thick" than living on sea level. You may remember that in former times they send Tuberculosis patients to Davos and treated them with long sun baths during the winter - now you know the reason.
Mother Nature of course knew such times of sun shortage, but at the equator it was only through the clouds efficiently blocking UV(B) in the rainy seasons. For this she has provided us with a storage: Fat binds cholecalciferol, the precursor, and also calcefediol, the 25(OH)D3, which is measured in the blood. But this storage is not designed for 6 months of UV(B)-shortage, even if it would be filled up to the max. And the storage won't be full even in summer in the higher latitudes. Young people, who sunbathe undressed for half an hour every day at noon in Berlin, Paris or London might reach some 40 ng/ml by the end of August, but at the age of 70 you have only 1/3 - 1/4 of the synthesis capacity of a 25 year old - the thinning subcutaneous fat layer made of cholesterol is partly responsible for this among other ageing processes. But one can get white skin cancer with such a heavy portion of unfiltered UV(A) light, because this form of cancer is almost always UV(A)-induced - not to mention the wrinkles in the face. Being over 60, I know this as I had both, the just wimpy 32 ng/ml after three months of excessive 2-3 hours sunbathing in the hot and cloudless summer of 2016 - and later the Basalioma on my forehead.
So here is a real dilemma. But today it can be solved very easily, for which the scientific research of the last 100 years is responsible: a sunscreen factor 50, when we go out, and daily 5,000-10,000 IU vitamin D3 supply, that costs almost nothing and with both we are shielded against skin cancer and immunologically just as well equipped as were our jet-black ancestors at the equator with their 50 ng/ml.
Our skin probably became white only 5-10,000 years ago, "Ötzi", the 5,300-year-old glacier mummy would be perceived today as a person of colour. How then could we survive with dark skin in the northern hemisphere? At the coasts: eat a lot of (cold water) fish, that's why the indigenous people of the north (Inuit/Yuppik) get along practically without UV(B). Inland? Meat also has certain amounts of vitamin D, especially the liver and also nutritious fat as a D3 storage. Today of course we try to avoid fatty meat, seldomly are eating beef liver and cattle are kept indoors and fed on corn instead of grass! And thus are supplemented with D3 up to a level of 70 ng/ml not to loose the offspring. And the calves, without sunlight and fed on pasteurized milk do not have more than 15 ng/ml, which is, why they are also supplemented by the farmers. Does your familiy doctor also supplement you with D3? The difference may be: the farmer looses money, if he does not keep his stock as healthy as can be.
BTW: Grazing cattle are said to have no D3 deficiency problem, there's D not only through the sund, but also contained in different grasses and plants on the meadow, but in corn it is nearly not existent - just like in our food, if there is not a big portion of cold water fish on your menu every day. Is there?
With the shift in nutrition to arable farming, mankind lost this D3 source, which was, after all, population density dependent, todays population couldn't be fed on freerunning Mammoth or Bison herds, so we had to develop fair skin when grain became the main food source. Natural selection....
And so we bob around in Europe with a yearly average of 20 ng/ml D3, in the infection-rich winter it is often only 12 ng/ml, which the flu viruses find enchanting, while they hold back in summer, when the average level raises to 23 ng/ml. This seasonal effect is the same world-wide, i.e. inexistent at the equator - the flu infections there show only a rainy season peak effect - but in the southern hemisphere the waves are exactly reverse to ours and half way to the equator, e.g. in North Africa, only half as strong as in England. Not to forget the care homes of the seniors, where D3 levels of well below 10 ng/ml are unfortunately not the exception but the rule in winter. From which everyone may draw his own conclusions to death counts during the Covid-19 pandemia especially in winter and especially between seniors.
Of course the same goes for the flu and when the flu vaccines were targetting the wrong virus sidelines in the winter 2017/18, we had about 1/3 as many deaths due to the flu in Germany as we had from corona in the first Covid-19 winter (25.000 vs. 80.000). Which could have been only a few thousand in both cases, if everyone, especially the elderly, had been kept on a 50 ng/ml D3 level instead of the meager level of 20 ng/ml, which your doctor thinks is enough. The farmer knows that this is by far not enough for his cattle to stay healthy.
This natural level of 50 ng/ml also would save us - in combination of modern medicine as well as co-factors like Vitamin K2, Vitamin C, Zink, Selen, Magnesium and Iodine (which also should be supplemented) - from 50% to over 80% of many, many other diseases plagueing mankind, most of them called "autoimmune" diseases, which all arise from a consistent and long lasting elevated and so called "silent" inflammation level, measured by an increased level of inflammation markers (e.g. CRP), as there is Diabetes I (and II), Rheumatic Arthritis, Multiple Sklerosis, Psioriasis, Alzheimer and Parkinson and all kinds of cancers like colon, prostrate and breast cancer, also Lupus erythematodes, allergies, Migraine and Cluster Hheadaches as well as Atherosclerosis leading to Cardiovascular Diseases (CVD).
But, as said, it also can save us from the severe courses and fatalities of a Corona infection. If you don't believe it, see for example these studies:
COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3
in VitaminDWiki COVID-19 mortality extrapolates to zero at 50 ng of vitamin D – 18th Meta-analysis Sept 2021
(Nutrients 2021, 13(10), 3596; https://doi.org/10.3390/nu13103596)
Lorenz Borsche, March 2022