76. Key Role of Vitamin D & Sunlight in Health | Michael Holick MD, PhD

Michael Holick, MD, PhD is an endocrinologist, Professor of Medicine, Physiology and Biophysics at Boston University Medical Centre and a world leading researcher and expert on Vitamin D, having lead the initial discovery of the active form and performed foundational research in the field.

We the evolutionary role of Vitamin D in life, sunlight & Vitamin D, link between skin cancer & Vitamin D deficiency, ideal blood levels & supplementation of Vitamin D and much, much more.

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Transcript

Speaker 1: 0:06

Welcome back to the Regenerative Health Podcast. I'm having the absolute pleasure of speaking with Professor Michael Holick, who is what I would describe as the Pope of vitamin D. So, Professor Holick, thank you for speaking with me.

Speaker 2: 0:22

It's a pleasure to be on your program, mr.

Speaker 1: 0:24

Holick, thank you for speaking with me. It's a pleasure to be on your program. Let's just jump straight in into vitamin D. Tell me, how do you think about the physiology of vitamin D? Why is vitamin D unique hormonally and in the body, for human physiology?

Speaker 2: 0:43

Well, to begin with, we all recognize vitamin D as a sunshine vitamin, and that has always intrigued me since I was a graduate student. I mean, why would mother nature focus on sunlight as producing a hormone in your skin that is critically important for the evolution not only of humans but of most vertebrates on this planet? And once you begin to think about this, I think then you get a better insight as to why vitamin D is so important for overall health and well-being. So we showed, for example I wondered when did vitamin D first make its appearance on this planet? And it turns out that phytoplankton. We actually isolated phytoplankton from the Atlantic Ocean, from the sort of gas OC that has existed in that ocean unchanged for well over a half a billion years, and we exposed to simulated sunlight and showed that they made vitamin D. It turns out they made vitamin D2 because typically plants have what's called ergosterol, which is the precursor for vitamin D2. And I speculated that it's likely that because of the absorption properties of ergosterol and vitamin D2, that vitamin D played a very critical role early in evolution, acting as a natural sunscreen and even providing information to that organism as to how much exposure it had to UV radiation, and for it to then possibly go down deeper into the ocean to minimize DNA damage, for example. But, more importantly, what's really to me intriguing is how this fundamental process that happened more than a half a billion years ago continued throughout evolution.

Speaker 2: 2:51

And the thinking is that as vertebrates left the ocean, because the ocean has high calcium content, so the vertebrates in the ocean could simply, like whales, for example, or porpoises, could simply suck the calcium out of the ocean and put it into their skeleton. But once they left for terra firma, they were confronted with a problem, which was that there's very little calcium available, and the only calcium that's available is through their diet available, and the only calcium that's available is through their diet. And therefore a system had to be developed to be able to increase the efficiency of the intestine to absorb dietary calcium. And we believe that early vertebrates, as they left the ocean exposed to sunlight, making vitamin D, somehow vitamin D became critically important for that process. I joke about this, but in fact it's possible that it did play a role, that when that asteroid hit the Earth 93 million years ago and most vertebrates disappeared and most vertebrates disappeared right it would have meant that they could not make any vitamin D, and vitamin D is critically important for absorbing calcium from the diet, which is critically important for depositing calcium into eggs of the dinosaurs, right, and could have definitely played a role independent of it being cold and no food, etc. But what's really amazing to me is that what survived were the rodents, and rodents did not need vitamin D to absorb calcium from their diet and, as you probably are aware that we basically evolved from rodents, right, those are our ancestors that survived the asteroid Holocaust.

Speaker 2: 4:52

Now let's move forward to human beings, and so a major source of vitamin D for humans continues to be sensible exposure to sunlight. And how do we know that? We did a study where we collected over 2.3 million blood samples and looked at circulating concentrations of 25-hydroxyvitamin D, which is a measure of your vitamin D status, and we looked at the southern states, middle states and then northern states in the United States and looked at the blood levels, and what we found was amazing, and that is that, on average, the blood levels were around 18 to 22 nanograms per ml at the end of the winter, and at the end of the summer they went up about 10 nanograms, up to about 29 nanograms per ml, and so it shows that just in the population in general skin type, time of day, season, latitude, all of that taken into account, still improved vitamin D status. Now, why was vitamin D so critically important as humans began to evolve and migrate north and south of the equator? And the thinking is that our early ancestors, as they moved further north, say, into Europe, right, we know from studies that we've done that they could not make any vitamin D in their skin for about six months of the year. So, time of day, season, latitude, we had worked out all those issues, and it's been speculated that the Neanderthals right. We've always been taught that these are these dark, hairy creatures right, living in caves. I mean, that never made any sense to me because they couldn't make any vitamin D, couldn't make any vitamin D B.

Speaker 2: 7:12

Vitamin D is critically important for the whole process of birthing and development of the skeleton in utero and in fact DNA has shown that they in fact were Celtic in their skin color, that they basically had no skin pigment at all. Why is that important? Because we know that if the, especially for females, if they are vitamin D deficient during pregnancy, during their in utero growth and after, and they have rickets, they have a poor, deformed pelvis it's flat, with a small pelvic outlet would have made it very difficult for them to have natural child birthing without having major complications. So we think that evolution, that pigmentation, devolved as people moved north and south through the equator in order to promote adequate vitamin D. So now thinking about vitamin D for your skeleton, so everybody thinks that vitamin D is critically important for your bone health, which is true. And the reason it's true is because vitamin D and just for your listeners is that vitamin D by itself, made in your skin or coming from your diet, is biologically inactive.

Speaker 2: 8:34

And I happen to be in the right place at the right time. So my master's degree was I identified the major circulating form of vitamin D, 25-hydroxyvitamin D, that's made in your liver but that's also inactive, and then it goes to the kidneys and gets activated. And that was my PhD thesis. I identified the active form of vitamin D. And so we know that once you've ingested vitamin D, or make it in your skin, it goes to your liver, in your kidney, activated, and it's the active form of vitamin D that goes to your intestine to increase intestinal calcium absorption and phosphate absorption. So now, as the body is laying down its collagen matrix, the scaffolding of your skeleton. You have an adequate calcium and phosphate in the bloodstream similar to making concrete with cement and sand and water so that the calcium and phosphate crystallize in your collagen to start to lay down, basically the concrete in your skeleton and to give it structural strength.

Speaker 2: 9:48

Vitamin D deficiency you need to make sure that your blood calcium is normal because your body cares about your blood calcium more than anything else, and so when you're vitamin D deficient you increase the production of parathyroid hormone in your parathyroid glands, which then goes to the skeleton, releases and tells cells, osteoclasts, to release hydrochloric acid and enzymes to destroy the matrix and to release the calcium into the circulation. So when you're vitamin D deficient it will precipitate and exacerbate bone loss, leading to osteopenia and osteoporosis. But there's another consequence of being vitamin D deficient, because when your parathyroid hormone is going up, you wind up. Your parathyroid hormone goes to your kidneys and tells the kidneys to reabsorb as much calcium as it can, but at the same time it loses phosphate. And remember I said, you need an adequate amount of calcium, an adequate amount of phosphate to mineralize the skeleton. So if you don't have enough phosphate now, when you're vitamin d deficient, you have an inadequate calcium phosphate product, you can't mineralize any newly laid down collagen matrix. That leads to rickets in children and the painful bone disease, osteomalacia, in adults. So vitamin D deficiency for the skeleton has two major consequences.

Speaker 2: 11:21

But what's also interesting about vitamin D? Deficiency for the skeleton has two major consequences. But what's also interesting about vitamin D? The function of vitamin D ultimately is to maintain your calcium and phosphate levels. That's what the body cares about the most, and so if you are vitamin D deficient, the small amount of vitamin D that you have available still gets activated. But now that activated form actually goes to the bone, stimulates osteoclast formation and, like parathyroid hormone, steals calcium out of your skeleton. Story short is, vitamin D does not have any active role in bone mineralization. It's purely passive by maintaining adequate calcium and vitamin D in your circulation.

Speaker 2: 12:15

Now, from my perspective because there's been a lot of argument and now the new recent guidelines by the Endocrine Society and now the new recent guidelines by the Endocrine Society argue that you only need a very tiny amount of vitamin D and that your blood level doesn't need to be much higher than 20 nanograms per ml, which was based on the Institute of Medicine's recommendation. From my perspective, and from all the literature that I've read, is that vitamin D, I think, has a hierarchy in activity, which is its number one responsibility is to maintain your blood calcium and phosphate. Number two is to mineralize any newly laid down collagen matrix. Three, to help in the bone remodeling process. Once you've satisfied that and I believe that you can do that, when your 25-hydroxyvitamin D is at around 30 nanograms per ml now the body takes advantage of other biologic actions of vitamin D that have absolutely nothing to do with your bones or calcium metabolism. But before I begin explaining a little bit about that, let me explain to you why.

Speaker 2: 13:39

I chaired the 2011 Endocrine Society Practice Guidelines Committee and all the members were experts in the field of vitamin D, and we carefully reviewed the literature back then, and one of the pieces of literature that really impressed us regarding what your blood level should be relative to your bone health is a study that was done by Dr Primmel. It's a German group, and what they did was that they and he's a pathologist and he collected 675 adults who had died in an accident and they were from age of 20 up to over 90 years of age, and he got a bone biopsy and he got their blood level of 25 hydroxy vitamin d and he looked histologically for the presence of osteomalacia, and he concluded that you see no osteomalacia if the blood level is at 30 nanograms per ml, and so that was one of the fundamental reasons why the Endocrine Society in 2011, our committee, made that recommendation. We also know that if you look at the blood levels between 21 and 29 nanograms per ml, about 24% of those adults had evidence of osteomalacia, and that's why we introduced the concept of vitamin D insufficiency of between 20 and 30 nanograms per ml. There's a lot of other data to also support, in my opinion, data to also support, in my opinion, minimum 30 nanograms per ml, including looking at parathyroid hormone levels as a function of 25-hydroxyvitamin D, and you will see that it begins to plateau at around 30 to 40 nanograms per ml. Now, with all that said, there was a lot of literature for the past 40 years that have made observations association observations to suggest that higher concentrations of 25-hydroxyvitamin D are important for your health. Very much impressed me was a study from the National Health Survey where they looked at the incidence of peripheral vascular disease and related it to 25-hydroxyvitamin D levels and showed that there was about more than an 80% reduced risk of developing peripheral vascular disease if your blood level was at least 30 nanograms per ml.

Speaker 2: 16:28

Framingham Heart Study showed that if your blood level is deficient at around 15 nanograms per ml, that you had a marked increased risk of developing a heart attack, and if you really were vitamin D deficient at that time, that you were more likely to perish from that heart attack. A study out of Finland showed that infants during their first year of life back in the 1960s, receiving 2,000 units of vitamin D a day during their first year of life, followed for the next 31 years, reduced their risk of getting type 1 diabetes by 88 percent. So this is an autoimmune disorder, and I'll talk a little bit more about immune function in a minute. There are also studies to show that if you live above Atlanta, georgia, for the first 10 years of your life, you have 100 percent increased risk of developing multiple sclerosis for the rest of your life, no matter where you live on this planet. And there are data from the Nurses' Health Study to show that nurses having the highest intake of vitamin D reduce their risk of developing multiple sclerosis. Vitamin D reduce their risk of developing multiple sclerosis.

Speaker 2: 17:46

So there's a lot of evidence now that macrophages, these immune cells that gobble up infectious like bacteria and viruses, immediately begin to metabolize 25-hydroxyvitamin D to 125-dihydroxyvitamin D, which then induces the production of a defense protein called cathalicidin, which helps to these infectious agents. But also, what it does is it releases 125D locally and it has a direct effect on both your T lymphocytes and B lymphocytes. On the T lymphocytes that are inactive, they develop a receptor for 125D and once that happens, 125d interacts and then alters cytokine production in a way to promote cytokines that are helpful in fighting the infection and minimizing cytokines that are detrimental to you. In terms of B cells, which make antibodies, we now recognize that active vitamin D, an activated B cell, again has no receptor. You activate the B cell and it does. And what does it do? 125d? It actually decreases immunocollabial synthesis. So initially people thought, oh my heavens, that means that it could increase risk for infection. No, what it's really doing is it's modulating immunocorbulant synthesis and we believe that that process is actually to inhibit the production of autoantibodies and that that is the likely reason for the vital study observation that when they gave healthy adults 2,000 units a day, followed them for five years, reduced risk of all autoimmune disorders by 22% and that included rheumatoid arthritis and psoriasis, for example. We also know that your beta islet cells, which make insulin, have a vitamin D receptor and there are studies to show that active vitamin D can regulate insulin production. And there's a very good study, again from the National Health Survey by PITAS many years ago, showing that those that had the highest intake of vitamin D and an adequate amount of calcium intake reduced risk of developing type 2 diabetes. Relative risk reduction 33%.

Speaker 2: 20:31

Infectious diseases, since we're talking about the immune system and COVID. So when COVID hit, and because of my relationship with Quest Diagnostics and because of my relationship with Quest Diagnostics, I was asked to help them in looking at all of their data and relating blood levels of 25-hydroxyvitamin D with acquiring COVID, and the data were remarkable. And we're not talking about a few hundred or a few thousand, we're talking about over 191,000 blood samples from individuals that were sent in that were either COVID positive or COVID negative and we reported that if your blood level is vitamin D deficient, you have a very high risk of acquiring this infection and that infection rate continued to decline and around 34 nanograms per ml reduced your risk of developing COVID by 54% A study out of San Francisco had confirmed another study that we did, showing that if you are vitamin D sufficient and have COVID and go into the hospital, that you are more likely to survive that infection and walk out of that hospital, because we believe that vitamin D is playing a critical role in modulating cytokines that were inducing the cytokine storm. There's also a lot of data out there for neurocognitive dysfunction. A study done out of Australia, showing again severe vitamin D deficiency at around less than 15 nanograms per ml marked increased risk for neurocognitive dysfunction. Alzheimer's disease and depression have been related to vitamin D deficiency. People feel better when they're taking vitamin D and there is evidence, at least in animal studies, that if you're vitamin D deficient in a rodent, that they have much lower serotonin levels and then if you give vitamin D correct their vitamin D deficiency, their serotonin levels increase. So, very much like how you know, antidepressant medications work by maintaining your serotonin levels. So too can vitamin D levels. So too can vitamin D Cancer.

Speaker 2: 23:11

So again, another study that was done for the Nurses' Health Study, asking women how much vitamin D do you take, and then relate it to their incidence of breast cancer, and showed that those women that had a blood level of around 40 nanograms per ml, reduced risk by more than 40%. There, of course, was the VITAL study, and the VITAL study said that when they gave 2,000 units a day they didn't see any decreased risk of cancer. But when they looked at mortality rate for colorectal cancer, they said 25% reduced risk. Now you would think any medication that would reduce your risk of dying of cancer colon cancer right would really get headlines, but instead the headline for that study was that it had no benefit. Study was that it had no benefit.

Speaker 2: 24:13

We're also pretty much aware of a recent study which I had the opportunity to write an editorial about. There was a study done by a Japanese group back in 2019 and published in JAMA right, a very well-respected journal, and what they did was that they took their patients that had a cancer of their entire part of their digestive system, from the esophagus all the way down to the colon, and asked the question if you give them 2 000 units of vitamin D a day, can you improve their survival? And the answer was, in 2019, no, and that that was the headline. Vitamin D has no benefit in reducing morbidity and mortality from a digestive type of cancer like colorectal cancer. But if you look at their data carefully and they began to do so those that were vitamin D deficient and received 2,000 units a day looked like there was actually a benefit. So they went ahead and did an additional study and just kind of as an introduction for those that may not be familiar with p53.

Speaker 2: 25:31

So p53 is a protein that's critically important for regulating cellular growth and preventing cells from becoming malignant. Cancers are very clever, and so when a cell becomes malignant, one of the goals of the cancer is for the cell to continue to proliferate and to grow. But the cell is trying to fight it by making p53. So what the cancer cell has done is it would mutate somatic mutation of the p53 gene. And what it does which is really to me shocking but very clever of the cancer is that that mutant protein helps that cell to continue to proliferate and it also binds the vitamin D receptor to inhibit the anti-proliferative activity of 125-dihydroxyvitamin D the anti-proliferative activity of 125-dihydroxyvitamin D. So with that information, this group went back and looked at their data and they had blood and they asked the question what if the patient had developed antibodies against the mutant p53 protein? Would that have been beneficial for survival? And they demonstrated that those that had antibody to p53, thus they're fighting the mutant p53 protein that there was 150% increased benefit of surviving that cancer. I mean, to me that's incredibly remarkable. That in and of itself, you would think, would be one reason why people would begin to think that maybe I should be increasing my vitamin D intake.

Speaker 2: 27:46

So how much vitamin D do you need and how do you get there? So first let's talk a little bit about the sun. Right, as I kind of introduced in the beginning, that time of day, season, latitude, degree and skin pigmentation. I was curious about all those questions and answered them, and to give you some examples so, for example, in the summertime in Boston, at noontime, you're definitely going to make a lot of vitamin D, but at eight o'clock in the morning, when the sun is shining bright and it's warm outside, you make no vitamin D. And we demonstrated that. Whether you live in Panama, india, europe, doesn't matter At eight o'clock in the morning bright sunlight you're not going to make any vitamin D. And the reason is that the zenith angle is too oblique and it has to go through more ozone and the vitamin D producing rays are being absorbed by the ozone layer. Also, the same is true at the end of the day. So you know it's often we're told to go out 5 o'clock in the afternoon, go jogging and make your vitamin D less damaging to your skin. No, no, no, make no vitamin D. It's very clear. It's from about 10 am until 2 pm is the major times when you're making vitamin D. It basically ends at around 3, 4 o'clock and doesn't begin until around 9 o'clock in the morning, and that doesn't matter where you go on this planet. Season right Again, season alters your zenith angle of the sun, xenothangula sun, and we showed in Boston. You basically make no vitamin D in your skin from about October until next April. If you live further north, like in Edmonton, canada, six months of the year they can make essentially no vitamin D from sun exposure. And the same, of course, is true in Europe, because Edmonton, canada, is very similar to the latitude in Europe.

Speaker 2: 29:47

Skin pigmentation If you are African American, for example, that melanin is very efficient in absorbing ultraviolet B radiation. That makes vitamin D and reduces the capacity of that skin to make vitamin D by about sometimes a tenfold less than it would be compared to a Caucasian Sunscreen use SPF of 30, by definition, if properly applied is absorbing 97.5% of UVB radiation and therefore it reduces your ability to make vitamin D in your skin by 97.5%. There's a myth out there, by the way. If you go on the internet and they say when you're exposed to sunlight, like at noontime, and you're sweating, you should never bathe, because if you did, you'd be washing off the vitamin D that's preciously made on your skin, not true, and the reason is that we showed many years ago that when you're exposed to sunlight, it's the living cells in your skin that make vitamin D and that's what's released then into your blood circulation. So I always joke about this. To my audience, I said please bathe after you've been outside and sweating profusely. It will not have any influence on washing off your vitamin D.

Speaker 2: 31:23

Now, since time of day, season, latitude, degree of skin pigmentation all influence your ability to make vitamin D, how does a person know when and what time to go out and how long to stay out? And so I worked with Ontometrics and developed an app, because I had been sending samples. I had developed a model system with ampules that contained a precursor of vitamin D and I sent them to laboratories down in Terra de Huelfago in South America, to India, to Asia and to Europe and Canada, and with all that information and with the ability to track how much UVB is coming in from the satellites, an app was developed called dminderinfo D-M-I-N-D-E-R dot I-N-F-O, and it will tell you anywhere on this planet when you can make vitamin D, how much vitamin D you make, and it warns you to get out of the sun so you don't get a sunburn. Realistically, in my opinion, we cannot get enough vitamin D from sun exposure because we're not hunter-gatherers, and so supplementation, in my opinion, is really important, which is why the Endocrine Society in 2011 said that for infants, they need 400 to 1,000 units a day and, by the way your listeners may or may not be aware, human breast milk essentially contains no vitamin D, so if you give your infant human breast milk as a sole source of nutrition, that infant will be vitamin D deficient for that period of time.

Speaker 2: 33:11

Children one year of age and above recommendation 600 to 1,000 units a day. I think teenagers should be treated like adults, which is 1,500 to 2,000 units a day, and if you're obese, you need two to three times more, because the body dilutes the vitamin D in your body fat and it's not as bioavailable. We know from studies that I did with Bob Heaney and other studies that we've done, for every 100 units of vitamin D that you ingest, when your blood levels are around 15 nanograms per ml, you will raise your blood level by about 0.6 to 1 nanogram per ml. And so, as I had said early on in the wintertime, as I had said early on in the wintertime, at the end of the winter people are usually around 18, maybe, if you're lucky, 20, 22. If you take 1,000 units a day, you would only raise your blood level to 28 to maybe, if you're lucky, 30 nanograms per ml.

Speaker 2: 34:18

And so that's the reason why, when I give my presentations, I make it simple for the audience, and that is I think children should be on 1,000 units a day. It's simple. There's no evidence that it causes toxicity. Adults minimum 2,000 units a day. Preferably, many of my patients were taking 5,000 units a day. I personally take 8,000 units every day. My blood level is 72 nanograms per ml. The Endocrine Society states that 30 should be your minimum for maximum bone health, but 40 to 60 is a good preferred range and up to 100 nanograms per ml is perfectly safe.

Speaker 1: 35:04

Very, very interesting. Thanks for that overview. There's a lot we could specifically talk about, but I really want to hone in on cancer and particularly skin cancer. 125-dihydroxyvitamin D has these anti-proliferative effects, basically meaning that it reduces or dampens down replication of cells. And there's some fascinating literature that I've come across that culturing of malignant melanoma cell lines, so the most feared and dangerous skin cancer. If you culture those cell lines with both 25-hydroxy and 125-dihydroxy vitamin D, you actually see proliferation of those cells decrease. So, given that sun avoidance narratives surrounding the risk of skin cancer are the biggest reason why more people don't get healthy, deliberate sun exposure, what are your perspectives on skin cancer and this mechanism that to me looks quite obviously like the more UVB you get and the more consistent UVB you get to generate a consistently high level of serum vitamin D, the lower the risk of malignant melanoma. And just a quick aside is that we have observational data showing that both melanoma and non-melanoma skin cancer incidents and severity is associated with vitamin D deficiency.

Speaker 2: 36:44

So all very good points. So for your audience that may not be totally familiar with this area non-melanoma skin cancer, which is basal cell and squamous cell carcinoma they're mainly found on sun-exposed areas that have had excessive exposure, and it's usually the face, top of your hands, maybe on your ears, but not usually other places. And this is one of the reasons why I'll often advise people that if they want to go out into the sun, is that you could expose your arms and your legs and your back, and because they haven't been exposed constantly to UV radiation and they're not likely to significantly increase your risk for non-melanoma skin cancer, but you will get the benefit of making vitamin D Melanoma, as you're well aware. What are the risk factors? Right, and the risk factors are that sunburning experiences, especially as a teenager and young adult, having Celtic skin, being redheaded, having a family history, so bad genetics, are all risk factors for melanoma. What's also interesting to me, of course, is that most melanomas occur on the least sun-exposed areas, and so therefore, this concept that sun exposure is directly associated with increased risk of malignant melanoma, I think is not well justified. You're correct, david Feldman, many years ago out at Stanford, and even we had played around with melanoma cells. So melanocytes have a vitamin D receptor, melanoma cells have a vitamin D receptor and, yes, if they have a vitamin D receptor, you incubate them with active vitamin D it will inhibit their growth. And you're correct.

Speaker 2: 38:51

There are data out there to suggest that if you're vitamin D sufficient and you have melanoma, that it's less aggressive, and that there may be some good evidence that occupational sun exposure decreases your risk for melanoma.

Speaker 2: 39:11

Right Now there's a study done many years ago by Dr Kennedy in Journal of Investigative Dermatology. He said, yes, non-melanoma skin cancer definitely due to chronic excessive exposure to sunlight, but melanoma occupational sun exposure decreases risk. And so you're right. I think that making vitamin D in your skin we believe your skin can activate vitamin D is playing a critical role in helping to control cellular growth, and it does it in a multitude of ways. Right, if the cell starts to go crazy and become malignant, 125d can induce its destruction by causing apoptosis. It can generate proteins to help and regulate the cell, to help control it from becoming malignant. And for tissues, including melanoma cells, because they're so metabolically active they need nutrition is that 125D will decrease angiogenesis and decrease blood flow to these tumors, and so there's a variety of mechanisms that can help explain why vitamin D sufficiency may be able to actually help improve risk for melanoma and reduce the aggressiveness of that tumor.

Speaker 1: 40:40

Yeah, and I think another very valuable data point in this story is the findings of Peli Lindquist in his Melanoma in Southern Sweden cohort, and what he found is that of the patients who developed melanoma and skin cancer, those who had the highest self-reported sun exposures had the lowest mortality, and it was something like an eightfold relative risk reduction in those with the highest versus the lowest sun exposures, implying that the more sun someone got, the more likely they were to survive from skin cancer. And Richard Weller, who is a dermatologist and did a similar analysis of the UK Biobank, also found that the greater UV exposure in terms of further southern latitude and greater sun-seeking behavior was also associated with lower skin cancer mortality. So I think these are critical points to make because, again, people seem to be deathly scared of getting sun and getting UV light on unexposed skin without sunscreens on. Yet the data is really pointing towards there not being a risk. In fact, there is a benefit, especially in skin cancer mortality, for getting more, not less, uv light. Agree.

Speaker 2: 42:05

And, like I said and that's why I've been promoting for now almost 50 years sensible sun exposure. Never want to get a sunburn. Go out there for a period of time that you know from your own experience will not cause a sunburn, followed by good sun protection.

Speaker 1: 42:23

And a little bit about the physiology of what is actually happening on a cellular level. And you mentioned p53. And the process of the physiological response to ultraviolet radiation is an upregulation of p53 and then the transcription and translation of beropio melanocortin, which then gets cleaved into alpha-MSH and that alpha-MSH induces melanin production in melanocytes. The point I think that again not many people realize is that beta-endorphin is another cleavage product of that polypeptide. So what are your perspectives on this? Because to me that looks like this is such a critical reaction. The foundational reaction of photobiology is the generation of vitamin E or the use of UV light that the body is actually rewarding us with an endogenous opioid peptide.

Speaker 2: 43:23

So I've written a review on this because I've been very interested not only in UVB producing vitamin D in your skin, but what really impresses me is and we don't really appreciate it is that you know, you of energy and that your body evolved in sunlight and it took advantage of these different packets of energy. And you're correct. Is that? There is really good evidence. I mean, we did just one of the studies, as did Dr Parrish at Mass General Hospital, to show that UVB stimulates the production of beta-endorphin and that may help explain why people feel well when they're outside.

Speaker 2: 44:19

Uvb and UVA will cause the release of nitric oxide right, which causes vasodilation. It induces the gene to produce the enzyme to make more nitric oxide. So when you're out in the sun you feel more relaxed. Your blood pressure decreases in part because of this. What's also interesting is and people, when they hear the term carbon monoxide, which is incredibly deadly, I don't know if you're aware that when you're exposed to sunlight, that hemoglobin, if it absorbs sunlight, will release carbon monoxide. And it turns out that carbon monoxide acts as a neurotransmitter and also causes vasodilation and, just like you said, that what's called the POMC gene that has this chock full of information making all types of peptides that have all kinds of biologic functions right, including ACTH right, which stimulates your adrenal glands to make cortisol.

Speaker 2: 45:23

And there is evidence right that when you're exposed to sunlight that it causes your immune system to be altered, and I think, for the most part in a positive way.

Speaker 2: 45:38

And so there and then we know that red light right lasers are now being used and blue light lasers for surgery, enhancing wound healing. The FDA permits, right in the United States, the promotion of red light laser for helping stimulate hair growth. They wouldn't permit that if there wasn't any evidence for it right and or for on the lips, to kind of improve the collagen underneath. Red light definitely enhances collagen synthesis in your skin, and all the more reason, I think, that hopefully someday, sooner than later, that industry will begin to mimic sunlight in your home or in your office and to take advantage of all of the beneficial effect that evolution had provided us, from us being exposed to sunlight for tens of thousands, of millions of years that we kind of no longer appreciate and kind of live in a cave in our offices and in our homes. So you're right, the vitamin D story for sunlight is great, but exposure to sunlight has a lot of other health benefits.

Speaker 1: 46:57

Yes, and I don't know what your encounters have been with our colleagues in the field of dermatology, but to me it seems like their attempts at primary, secondary prevention of their diseases that are their remit, namely the skin cancers that we mentioned earlier and their attempts to prevent those. And again, this linkage or this strong association of all types of skin cancer with vitamin D deficiency really calls into question the strategy of blocking ultraviolet light to achieve that end. But this attempt, I see, is having negative collateral effects on the rest of medicine. It's actually preventing or inhibiting the cardiologists in the primary and secondary prevention of ischemic heart disease, of peripheral vascular disease, as you alluded to earlier, and the endocrinologists in the terms of osteomalacia and osteoporosis. So what do you think about this negative effect that this one specialist specialties approach is kind of having on the holistic health of the body and these other specialties, as we're trying to improve the holistic health of our patient, not just the narrow prevention of skin cancer which, as we mentioned, I don't think is necessarily an optimal strategy in the first place?

Speaker 2: 48:25

Right, the first place, right. So yeah, I think that it's important, I think, to be vitamin D sufficient, like I said, not only for your bone health but, in my opinion, has just enormous other health benefits Separately. Again, sun exposure you know, we, we were born, we evolved in sunlight and I think that we really need to fully appreciate how different wavelengths of light impact our health. And it's really a nascent science even to this day. Um, very few studies are being done, not well funded, um, because everybody just assumes that you can have a healthy body by having a healthy diet and a healthy lifestyle, but that should definitely include exposure to sunlight.

Speaker 1: 49:27

Yeah, and a moment about the specifics again of what is actually happening when UVB so between 290 and 315, 312, 315 nanometer lights is actually hitting this 7-dehydrocholesterol molecule, and part of that process is the generation of these other vitamin D analogs and metabolites, amongst them lumistrol and tacostrol. I've read papers that said that these are biologically inert, and then I believe the work of Andres Slemenski I might be mispronouncing his name has shown that those metabolites and they also get hydroxylated in all kinds of weird and wonderful ways they actually have potent anti-proliferative effects as well. So my question is to what degree are the benefits of having or being vitamin D replete? Maybe in the observational literature might be due to these metabolites that we can't get from simply taking 25-hydroxy in purified pill form?

Speaker 2: 50:34

Right. So you're absolutely correct, and I was the one actually that had introduced this concept back in the 80s, because the thinking was that melanin pigmentation evolved to prevent vitamin D intoxication. And then I went on to show that when you're exposed to simulated sunlight in a laboratory and looking at the conversion of 70-harder cholesterol, that it goes to pre-vitamin D. Pre-vitamin D will also absorb that radiation and it's converted to lumistriol and tachysterol, which are then converted to other photoproducts. Vitamin D is also UV sensitive and so you can develop. They're called toxycerols and supersterols.

Speaker 2: 51:21

You're right, dr Andrzej Sleminski that we've collaborated with. He started introducing the concept that maybe these photo products actually have biologic function and demonstrated a variety of enzymes p53 enzymes that are able and capable of metabolizing them, and he's tested them in cultured cells to show that they have anti-proliferative activity and other signal transduction mechanisms. So you're quite correct and I've always had been promoting this that independent of taking oral dose of vitamin D, which I think we should take, is that sensible sun exposure making vitamin D and these photo products may very well have significant additional health benefits, and not only for your skin but for your entire body.

Speaker 1: 52:16

Yeah, I think it's very much an interesting and active area of further research, and would there be any value in testing serum levels? I'm not sure, because the way I think also about 25-hydroxyvitamin D is it's really a proxy. It's a proxy for total sunlight exposure and you alluded to the benefits of other wavelengths and I've spoken to people like Scott Zimmerman and Bob Bosbury who are talking about near-infrared and the amazing role that's having on mitochondrial function. So I'm wondering maybe those other photo products would simply be other ways of simply assaying or estimating someone's total solar yield, so to speak.

Speaker 2: 52:59

Yep, at this time, like you said, the major one is 25-hydroxyvitamin D, but that also includes your intake from supplement and or from food, so it makes it a little bit more difficult. But, like I said, that study of 2.3 million samples, I think, clearly demonstrates what the sunlight is doing, at least for that one outcome measure least um for that one outcome measure.

Speaker 1: 53:32

yeah, I want to say thank you for um making the demod app, because I think it is an absolute amazing tool and it's one that I recommend to clients and patients to to use, because it it really integrates all that information to to really allow people to essentially um auto titrate their transcutaneous vitamin D dosing, and it's something that I think is just so valuable and important. In your experience, what are the troubleshooting things that you think about if someone is struggling to raise their 25-hydroxyvitamin D in response to, maybe, persistent sunbathing and UVB exposure?

Speaker 2: 54:12

Yeah, I get emails from individuals. A lot about this is that they are disappointed that they're not seeing better levels, and what I explain to them is what's and to me, amazing is that there was a study done a couple of years ago where they looked at Hazda and, as you know, they're now likely the only group that are hunter-gatherers. But they also looked at Maasai herders and they showed that their blood levels are in the range of about 40 to 60 nanograms per ml and it's not coming, in my opinion, from their diet, it's certainly not hasta. It could be coming from blood for the Maasai herders, but certainly not for hasta. And we've done a study in children that we're in the process of trying to publish, of African children that are outside all the time. Their blood levels are perfectly fine, but they have rickets because they're calcium deficient.

Speaker 2: 55:23

So to me, that's really giving us an insight for where our blood levels should be and that it's likely that there are other issues I think that people aren't taking into account that are limiting their sun vitamin D production, and another reason that I believe this is that I've done studies in individuals that like to go to a tanning salon, and their blood levels are usually in the range of about 30 to 60 nanograms per ml, and they actually had higher bone density.

Speaker 2: 56:03

By the way, we had published this several years ago. So your body has the ability to make enough vitamin D to satisfy that requirement. We also ask a simple question, which is if you expose your whole body to one minimal erythema dose a light pinkness to your skin 24 hours later not a sunburn and then give an oral dose to see what the equivalence is for raising the blood level, it's equivalent to making about 15,000 to 20,000 units of vitamin D in your body. So your body has a huge capacity to do this. So it's possible that when people are using topical emollients and creams to keep their skin you know nice and smooth and healthy, they probably have sunscreens in them, but for the most part, your skin has the capacity to make vitamin D. Aging decreases that capacity, but it can definitely based at least on that publication in Hasta and Messiah Herders, you can raise your blood level into that healthy range of 40 to 60 nanograms per ml free-ranging humans observe what their 25-hydroxybutylamide naturally gravitates to, and then that gives us an idea about what is appropriate.

Speaker 1: 57:38

And I think the point for the listeners is that if we are matched to our UV conditions ancestrally, then the amount of epidermal melanin is going to allow the permission of the right, exact amount of UVB light to generate the right amount of vitamin D for our skin type in that area.

Speaker 1: 57:55

So I think even maybe people in northern latitudes who are of darker origin are following advice to cover up and maybe even avoid the sun or wear sunscreen, and yet that's probably the opposite of what they need to be doing, given that they have this endowment of melanin that's going to be interfering with that conversion. So where are we in terms of public health, in terms of these vitamin D recommendations? Because to me, and reading your work on the Vitamin D Society, getting everyone's vitamin D recommendations. Because to me, and reading your work on the vitamin D society, getting everyone's vitamin D level and I prefer, I think that's best achieved through sunlight wherever possible. Like you have said, with the amount of diseases that we could prevent, from chronic to infectious to developmental, skeletal and mainly non-skeletal is so enormous that that should be almost the first priority of public health is to get people's 25-hydroxy, as a proxy of their sun exposure, up to at least those levels that you've mentioned. So where are we in terms of recognition or progress towards that goal?

Speaker 2: 59:05

Well, unfortunately, we're going in the opposite direction towards that goal. Well, unfortunately, we're going in the opposite direction. The most recent endocrine society practice guidelines that just came out and I know all the members on the committee and I respect them they decided to take randomized controlled trials as gospel to tell you how much vitamin D that you require. And in my opinion, the randomized controlled trials are poorly done and often misinterpreted. In my opinion, I mean many of the randomized controlled trials use 400 units of vitamin D a day. I mean that raises your blood level by three to four nanograms per ml. That's useless. And even studies that are 2000 units a day, like the VITAL study, I mean, what's amazing about that study is that more than 50% of the participants at the time they started the study were vitamin D sufficient at greater than 30, at 30 nanograms per ml or a little bit higher. And so how you would expect giving a vitamin D sufficient person vitamin D and expecting to see an outcome to me is difficult to understand.

Speaker 1: 1:00:28

It's seeking a null finding. Almost that's almost like an intentional study designed to seek a null finding.

Speaker 2: 1:00:34

Exactly. But yet when they do subset analysis of the data from the vital study, they show reduced risk of autoimmune disorders by 22%. I mean that by itself you would think would gain some attention. You know there's what's called the D2D study, asking the question does vitamin D reduce risk for developing type 2 diabetes if you have prediabetes? And the answer was no. But again, many were vitamin D sufficient, getting vitamin D. And then when they did a subset analysis, they showed well, wait a second, if you're vitamin D deficient and you now improve your vitamin D status, actually it reduces your risk of developing type 2 diabetes.

Speaker 2: 1:01:18

But unfortunately right now randomized controlled trials are considered to be gospel and they ignore association studies, and I think I point out that it's sometimes not wise to do that. A good example that you probably know about is Dr Semmelweis. Right Back in 1840,. Here's this very brilliant young physician, austrian physician, who goes to Budapest and realizes something and he makes an association and he publishes a paper. And he publishes a book saying that if you wash your hands with chlorine water before you deliver babies, that the mom and the baby are more likely to survive.

Speaker 2: 1:02:05

But at the time the thinking was this is bad humors in the air and nobody could possibly comprehend how washing your hands would have any impact. And so the mentors right and I think that's the same that we're dealing with today right is that they are going to quiet him in some way. Well, back then it was simple All he had to do was to declare that he was crazy. And so now they put him in a cart and they take him off to an insane asylum. But, to make the point, they had thugs beat him up on the way and this poor guy died two weeks later of an infectious disease. He's now the most revered physician in Austria, right, they have a medical school in his name, they have a gold coin in his name and stamps in his name. But the poor guy was ridiculed by making a simple observation, and, in my opinion, we're in the same boat today.

Speaker 1: 1:03:13

Yeah no I think that I agree.

Speaker 1: 1:03:16

I think that when you build up the case and I've read your review papers going back from the early 2000s and each one of them just makes so much sense, the early 2000s, and each one of them just makes so much sense yet it is baffling that we're seeing the opposite, as you mentioned, in this latest guidelines.

Speaker 1: 1:03:36

And, yeah, I think it's the perspective. I think the perspective of, as you mentioned, this over-occupation with the RCT, the randomized control trial, is one of the reasons, for sure, and I see patients in family medical clinic and to me and children's pediatric presentations with things like recurrent respiratory tract infections, otitis media, ear infections, all these types of things, but it's difficult to measure their vitamin D because you don't want to subject a four-year-old to a venous blood draw. And what are the options in terms of testing? Can we do like a dried blood spot? Is that a validated or useful test? How can we gather more data? Because to me, the easier and the cheaper it is to measure a widespread measurement, the easier. I could simply say okay, now here's D-Minder, put little Johnny out in the sun without his shirt on and let's fix this problem.

Speaker 2: 1:04:39

So the blood spot actually works quite well. There are a couple of companies that are able to do that. Ie even the blood spot at the time of birth. You can determine what your infant's 25-hydroxyvitamin D level is. When I chaired that End Society Guidelines Committee back in 2011, we all agreed all the committee members you should not screen everybody. I mean somehow now they're saying you know what we had recommended. To screen everybody is really not true. What we were doing was we're selecting certain groups, malabsorption patients, for example.

Speaker 2: 1:05:19

So for me, the answer is very simple. I tell my pediatric friends and my family medicine doc friends look, if you give an infant 400 to 1,000 units a day and my preference is 1,000 units a day you don't have to worry about vitamin D deficiency. All right, unless they have a malabsorption problem or they're on anti-seizure medications or something that's altering it. Right? Children 1,000 units a day. Again, to my thinking, teenagers and adults should be on 2,000 units a day. That's what I typically recommend and if you do that, you'll be able to maintain your 20-fidoxy-D in that range of about 35 to 40 nanograms per ml. But if you want to take and improve it, 5,000 units a day is not unreasonable, and I had a lot of my patients on it and their blood levels were around 40 to 60 nanograms per ml, and so it's very cost-effective to take a supplement and almost everybody's going to be vitamin D deficient.

Speaker 2: 1:06:21

Because you're not hunter-gatherers, you're not getting your vitamin D from sun exposure and there's essentially no vitamin D in your diet right, because the argument has been well, if you have a healthy diet, you shouldn't have to worry about this nutrient. It's only condover oil, oily fish like salmon, mackerel and they have to be wild caught and mushrooms expose the sunlight. Those are your major sources. There's a tiny amount now in some fortified foods in the United States 100 units in a serving, for example but if you need 2,000 units a day, it helps a little bit, but it's not going to get you to where you need to be. So, in my opinion, the simple answer is for that four-year-old or 40-year-old is to take a vitamin D supplement. That will help to guarantee your vitamin D status and you then don't have to worry about having a venous blood draw or pay extra money to have your blood test done.

Speaker 1: 1:07:21

Yeah, okay, that is definitely one way of doing it, and one of your colleagues, dr Alexander Wunsch, in his presentations described the difference in the physiological action of ingested versus sun-derived vitamin D and he used an analogy of registered male versus just the regular post versus just the regular post, and the point he made was that the cutaneously derived vitamin D, essentially, is almost totally bound to vitamin D binding protein, whereas the orally ingested one I believe 60% is found in the lipoprotein fraction, if I'm not wrong. So can you talk a little bit about those differences and what is the significance in terms of vitamin D status into people who might have the same 25-hydroxy level but have achieved that through those different means?

Speaker 2: 1:08:20

So, dr Haddad, more than 50 years ago had asked some of these fundamental questions.

Speaker 2: 1:08:22

More than 50 years ago had done, asked some of these fundamental questions, and that is if you give it orally versus making it in your skin, is the half-life any different?

Speaker 2: 1:08:39

And the answer is yes. That just like you said that when you ingest it and it goes into your lymphatic system right, because it's fat soluble and then it gets dumped into your serpina venicaeva and then goes to your liver and, as a result of that whole process, about 40 to 50% is bound to your vitamin D binding protein and the other is bound to lipoproteins that are more rapidly degraded. As opposed to making it in your skin, it gets into your blood and it's associated with the vitamin D binding protein. So we then did a study to confirm that concept, which was that we took healthy adults, put them in our tanning bed, one minimal erythemal dose versus 15,000 units of vitamin D and looked at their blood level of vitamin D over time and, looking area under the curve, the amount of vitamin D in your circulation was two to three times more lasted two to three times longer in your body than it does when you take it orally.

Speaker 1: 1:09:43

Yeah, and I think of it almost as if you're getting a drip feed. If you've generated it cutaneously, the body's dripping it out over a longer period of time. In terms of people who are of Caucasian and Fitzpatrick 1, 2 Celtic origin, they're obviously seasonally having no UVB light, say they are living this ancestral hunter-gatherer type lifestyle. They would expect to generate massive amounts during the summer and then, for a long period in the winter, have none. So do you have any idea about what is an acceptable nadir of 25-hydroxyvitamin D over winter in, say, a population like that?

Speaker 2: 1:10:32

My thinking is but we don't really have good scientific evidence for it is that our hunter-gatherers, when they were making if the only living, say in Europe, they were making vitamin D six months of the year and they were storing it in their body fat.

Speaker 2: 1:10:52

Because what's interesting about vitamin D is that, yes, it's true that you make vitamin D in your skin and it slowly enters into your circulation, but it also gets associated with your body fat, and your body fat is not inert.

Speaker 2: 1:11:06

These are living cells, right, that are absorbing vitamin D, and my thinking is that, as our hunter-gatherers were utilizing that body fat in the wintertime as an energy source, that they were releasing vitamin D back into the circulation and helping to maintain vitamin D sufficiency. Now, whether that is going to be in the range of 30 or 40 nanograms per ml, I don't think we'll ever know, but my sense is that it certainly would be above 20 nanograms per ml to at least maximize bone health. And so you're correct is that the body evolved in an environment and it's very good at what it does. And to me, what's also very impressive is that if the body only cared about preventing skin cancer, right, then people living at the equator should have such dark skin that it would never permit a photon of UVB to ever enter, but it does, and that's why, to me, the study in Hazda and in Maasai is so impressive, because they live in a sunlight environment, they make just the right amount of vitamin D and yet it doesn't damage their skin.

Speaker 1: 1:12:31

Yeah, incredible. And I think the corollary of that hypothesis that you just made, Professor, is that it's appropriate that those people are in ketosis during the winter because that would be the way that they would be liberating those fat stores. And if, say, you're eating imported food from the equator in Scandinavia during the wintertime and you're blocking the process of ketosis, then there'd be no way of unlocking those fat-soluble vitamin D stores that are in the adipose tissue. So, yeah, that's very interesting. I hope maybe we'll get a bit more research about exactly what is going on there. We're doing that right now. Oh, fantastic.

Speaker 2: 1:13:19

Yeah, we're in the process of submitting a publication right now on trying to understand how your fat cells, adipocytes, store vitamin D.

Speaker 1: 1:13:30

And that would obviously have relevance to obesity because, as you've mentioned in several of your papers, there's almost a twofold increase requirement from a supplementation point of view to get to the same 25-hydroxy level. So what do you think about generating sufficient amounts in the obese patient?

Speaker 2: 1:13:53

So, again, we did a study in collaboration with the group up in Canada, and the data are clear, which is that they measured serum 25-hydroxyvitamin D in a large number of adults and they related it to their BMI, and what they showed was that the blood level of 25-hydroxyvitamin D, based on the intake, was much less in obese than it was in a normal weight and in middle and and those that are overweight. It was in the middle. The difference is 2.5. And so therefore, the conclusion was that obese people with a BMI of greater than 30 should have at least 2.5 times more vitamin D to satisfy that requirement.

Speaker 2: 1:14:42

And just a caveat, because you would think right now that morbid obesity and bypass surgery is becoming very popular and they lose like 50 kilograms of fat over a year, are they going to take all that vitamin D in their fat stores and release it and cause toxicity? So we did the study and we showed no change. If anything, it goes down Because when you become, when you have bypass surgery, you bypass the ability to easily absorb vitamin D, so that's very difficult sometimes to be able to correct their D deficiency. And the reason is just like you said it has nothing to do with the ketogenic diet. It has nothing to do with the way we evolved. It had to do with a massive loss of fat over a very short period of time and, as a result, the vitamin D was just rapidly destroyed.

Speaker 1: 1:15:35

Yeah, wow, that's interesting for sure. The other kind of point that I was kind of curious about and it ties back into OMC pro-opioid melanocortin physiology is that the role of alpha-MSH that we talked about, in terms of when it binds to the melanocyte, it induces melanin synthesis in response to UV exposure. The role of alpha-MSH in the brain is a profound one of reducing hunger and satiety at the hypothalamic level. So it makes sense to me that anyone with obesity by definition has an ultraviolet B deficiency, and especially someone who's eating too much. So the fact that someone like that might be applying sunscreens that block UVB and therefore that have this effect is kind of the opposite thing of what they need to be doing. And the more obese, the more metabolically sick, the more insulin resistant, the more sunlight and UV light that person needs. Do you have any particular thoughts on that?

Speaker 2: 1:16:52

I mean. So we looked at it from a different perspective, which was if you take a normal weight and an obese person and give them an oral dose of vitamin D or expose them to tanning bed to simulate sunlight, is that we showed that it didn't make any difference, that you had about only a 45% rise in the vitamin D levels not 25 hydroxy D, but vitamin D levels either when you ingested it or if you were obese compared to a normal weight individual. So it has a dramatic effect and if you think about it right, an obese person is a lot more body surface and and uh. As a result, um yeah, the vitamin d is not utilized very well at all. We think that maybe vitamin d helps in obesity.

Speaker 2: 1:17:52

Certainly, obese people are more likely to be depressed. They're not very active. Vitamin d helps muscle function, helps you feel better, become more active, helps you maybe to Helps you feel better, become more active, helps you maybe to reduce weight and improve your activity. So obese people, in my opinion, should be as concerned or more concerned about their vitamin D deficiency. And so wearing a sunscreen always before going outside and not taking advantage of the natural benefit of sensible sun exposure, I agree with you. It doesn't make any physiologic sense.

Speaker 1: 1:18:38

Yeah, and a question about the possible side effects of dosing, and particularly maybe dosing, dosing, and particularly maybe dosing, as you mentioned, 5,000, 8,000 units. And I guess my question is what is the outcome measure that we're making the conclusion that there isn't toxicity? And the way I pose that question is that is it possible that taking vitamin D in absent of the other fat-soluble vitamin cofactors that might be occurring naturally, such as K2, might that be promoting, say, increased vascular calcification? And if we're not, simply if the study hasn't been done that maybe the patient could be having maybe accelerated plaque deposition, perhaps with the supraphysiological dosing of vitamin D?

Speaker 2: 1:19:34

A couple of thoughts about this. The first is, in my opinion and I helped edit a book with Jerry Neves on nutrition and bone health and had Dr Sarah Booth, who's one of the world's experts on vitamin K I mean, I'm aware of the literature about vitamin K2 and reducing risk potentially of cardiovascular calcification, but K2, in my opinion, has no impact on vitamin D function and that there is no need to be taking vitamin K2 with vitamin D. If you wish to do it, perfectly fine with me, but I don't think it's necessary. In terms of how do we know that vitamin D at different doses has an effect and, more importantly, causes toxicity. So we did a study. What we did was we took healthy adults that were deficient or insufficient and gave them either 600, 4,000, or 10,000 units a day and we looked at their serum calcium level, their PTH level and expression analysis of almost 23,000 genes in their white blood cells at the beginning and at the end. What did we find? 600 units a day basically no impact significantly on PTH. 4,000 units a day definitely helped to decrease the PTH levels very much, like we had discussed early on that if you improve your vitamin D status, your PTH levels will come down On 10,000 units a day. The PTH levels came down as well, pretty much to the same degree. But now let's look at and the serum calcium was normal across the board.

Speaker 2: 1:21:19

But now look at gene expression. On 600 units a day it was about 150 genes were up and down, regulated, so A it tells us already from these so-called RCT studies, where these people are permitted to take up to 800 units a day, that that's having an impact independent. So it's diluting your outcome measure right. 4,000 units a day, about 300 genes. 4,000 units a day about 300 genes. But on 10,000 units a day we showed over 1,200 genes up and down, regulated.

Speaker 2: 1:21:54

Controlling apoptosis, which we talked about for cancer and autoimmune inhibition, activity on your immune system, antioxidant activity, over 80 different metabolic processes being controlled. So how much vitamin D will cause toxicity and what are you looking for? Another good example is pregnancy. Bruce Hollis and Carol Wagner showed very nicely that when they gave pregnant women 4,000 units a day throughout their entire pregnancy and looked at urinary calcium, which is the most sensitive indicator for any alteration in calcium metabolism induced by vitamin D, there was no change. And so I always typically recommend pregnant women should be on at least 4,000 units of vitamin D a day throughout their pregnancy reduces risk of preeclampsia.

Speaker 2: 1:22:48

reduces risk of preeclampsia and has a lot of other health benefits and you need to take. Literally. And if you go back in the literature again, back in the 1940s, when they began to think that vitamin D was this miracle drug, they started giving patients with rheumatoid arthritis massive doses, hundreds of thousands of units a day, and ultimately it helped. But in the end they become severely toxic. And what does that mean? A you increase urinary calcium excretion. B you increase risk for kidney stones. C you begin to calcify your kidneys nephrocalcinosis and then you begin to calcify your kidneys nephrocalcinosis and then you begin to calcify your blood vessels and other soft tissues. They showed and what scared everyone which is why even today, physicians are taught that vitamin D is one of the most toxic fats out of vitamins is that when they stopped the vitamin D, it continued to have the toxicity because there was so much vitamin D built up in their body fat that was constantly being released. The other study, by the way, that you're probably familiar with, is that even though now in Europe, for example in the UK, you can't fortify food with vitamin D, right Back in the 1930s and 40s, you know, custard, bread, milk, everything was fortified with vitamin D and then they had an outbreak of mild hypercalcemia, mild mental retardation and supravalvular aortic stenosis in a few infants and at the time, back in the early 50s, they had not a clue what that could be caused by. They bring in the experts and they said well, we don't know. But if you look at the literature, if you give pregnant rodents high doses of vitamin D, their pups have funny looking faces. And that was what was found also in these infants that they had hypercalcemia, supravalvular aerosinosis. So they concluded back in the 1950s that those outbreaks of those few infants was due to vitamin D intoxication. But turns out that they likely had Williams syndrome, which causes alphanphases, supervalvular aortic stenosis, and they have a hypersensitivity to vitamin D, causing them to be hypercalcemic. So you literally have to still take hundreds of thousands of units of vitamin D a day for a year and get blood levels above 250 to 300 nanograms per ml before you have to begin to worry about developing hypercalcemia and hyperphosphatemia and the consequences. So vitamin D intoxication is one of the rarest medical conditions and very difficult to achieve.

Speaker 2: 1:25:33

I mean we published a paper in the New England Journal of Medicine of a guy down in Florida who wanted to prevent prostate cancer. So he went online and got a product out of Canada that had a thousand units in a teaspoon. So he took two teaspoons a day for more than a year. He had called me up and I told him you know, set up the vitamin D, we'll do an analysis for you, because it doesn't make any sense. And sure enough the company didn't dilute it. He was taking over a million units a day for more than a year and became severely toxic. So I became his doc. I told him sunscreen, no vitamin D, low calcium intake. His 25-hydroxyde gradually came down, calcium quickly came down and he had no consequences.

Speaker 1: 1:26:19

Interesting. Yeah, those N equals one. Those outliers are instructive, so I guess that's quite reassuring. Every once in a while a patient will come in who's having had their vitamin D measured and in Australia we use nanomoles per liter and they might come in at 250, 300 and maybe a lot of people. They might have been told that they're, you know, stop supplementing, stop supplementing. But the patient hadn't been supplementing at all. They just simply had a, you know, a fairer skin type in Australia and it's all endogenously generated. So, and maybe share your perspective on this idea about hypervitaminosis D from the sun and the fact that it's biologically not, um, not possible correct?

Speaker 2: 1:27:10

I mean we, we asked that question back in the 1980s and we showed that when you're constantly exposed to simulated sunlight, that the body is very clever and you don't continue to make the pre-vitamin d, but that the pre-vitamin d and the vitamin d absorb that radiation to convert to the other products that we talked about lamestrol, tachysterol, et cetera. So you can't become vitamin D toxic from sun exposure. Mother Nature designed us in such a way that that, in my opinion, is not possible.

Speaker 1: 1:27:44

Can you speak about the sulfation of vitamin D and the process of all of the sulfation that occurs from the sun versus oral supplementation? Is that something that you're aware?

Speaker 2: 1:27:59

of? Is there enzymes that remove the sulfate to release the vitamin D? Does it make the vitamin D more water soluble and more bioavailable? We don't have enough, in my opinion, enough information to say whether or not that sulfation activity is a good thing or whether the body is somehow realizing you have too much and is making it water soluble to have it get excreted into the urine.

Speaker 1: 1:28:33

Okay, and maybe a final couple of points.

Speaker 1: 1:28:36

And I'm not sure if you're familiar at all with the history of heliotherapy, but there was a Swiss physician, auguste Roliere, who actually I think you've mentioned him in some of your talks, but he obviously put patients with extra pulmonary tuberculosis in the Swiss Alps at altitude, in the snow and obviously for the purposes of massively exposing them to ultraviolet light.

Speaker 1: 1:29:04

And those techniques are specifically aiding in increasing the UV yield. So what he found was that was very effective in essentially curing extra pulmonary tuberculosis. But he made a comment in one of his papers that the general health of patients and this is a gentleman who cured over 1,500 cases seemed to be specifically a function of their pigmentation. So it actually sounded in his clinical experience that the more UV light the person got, the more melanin they essentially had cultivated, the greater not only their susceptibility to infectious disease but their overall health. So I mean I just imagine what those vitamin D levels would have been in those patients. Do you have any insight or thoughts about that? And from my point of view I think it would be ideal or appropriate if we in many ways could get back to certain techniques like that in certain situations for general and robust health. Do you have any thoughts on that?

Speaker 2: 1:30:13

So I mean it turns out that you're right. I mean they knew back then about heliotherapy right and promoting it. I mean, one of the reasons, by the way, that heliotherapy became less popular was with the introduction of pharmacology penicillin, for example, right so?

Speaker 2: 1:30:32

it turns out that if you lived at 5,000 feet or above in Switzerland that you had zero chance of getting tuberculosis. So I was just curious and I did a study with a surgeon who decided he was going to go to base camp in the Himalayas and I asked him to put out my model at various altitudes. And so we started at Agra in November zero vitamin D production, but at 5,000, I think it was kilometers 15% conversion and we could show very nicely the altitude effect that the higher your altitude, less ozone, less UVB being absorbed, more vitamin D that you're producing.

Speaker 1: 1:31:25

Yeah, so a profound effect of altitude on increasing uv yield. And if you look at the sherpa, I mean they are quite pigmented um, and they're not equatorially living, they're they're north of the equator but they're very pigmented um, so that that makes, uh, total sense to me. And maybe some final questions um, you mentioned in one of your talks about clock genes, and particularly in the skin. What are your perspectives on circadian biology and how this fits into the whole picture that you've painted for us so far?

Speaker 2: 1:32:00

Right. I mean we know that circadian rhythm is mainly controlled by blue light, right, and having an effect through your eyes into your pineal gland, right and that the intensity and duration is important in suppressing melatonin. And so if you don't get enough and you get up in the morning and you have melatonin, you feel tired and can induce seasonal affective disorder. But we did a study because I was just curious. There are these transcription factors called clock genes and period genes and we asked the question if you're exposing keratinocytes, skin cells, can you alter these circadian rhythm translational factors? And the answer is yes.

Speaker 2: 1:32:49

But to me, what's even more interesting and important and people I don't think think about this is that when you're exposed to sunlight, uvb the highest energy penetrates the least amount. Right, because it's absorbed by your DNA and protein, but there's very little in your skin that absorbs red light, but there's very little in your skin that absorbs red light. So when you're exposed to sunlight, red light and visible light penetrates into your body and these are photons. These have energy. It's likely that they're doing things in your body when you're exposed to sunlight. So you're correct is that there's a lot more to the story of sunlight in terms of its biologic actions, including regulating your internal clocks of your cells and circadian rhythm of clock, genes and period genes.

Speaker 1: 1:33:40

Yes, it's so interesting and something that again is being disrupted, and not only the blocking of UVB light through sunscreen use and sun avoidance, but also blue light exposure on the skin. We know that it's a photoaging factor, but what else is it doing? I think there's an abundant of questions. The final point I'll make and you mentioned it really briefly it actually circles back to the points that you made about skin cancer at the beginning, which is DNA is actually absorbing UVB light. And that really has got me thinking because, again, the narrative is that UVB is essentially toxin and is inherently toxic. That's a narrative that is really coming very strongly out of our dermatology colleagues.

Speaker 1: 1:34:33

But if we think about the physiological response, we know that UVB is essential for vitamin D generation, and then we know that it can damage DNA and is from the formation of these cycloperidine dimers and other DNA products, photo products. But there's DNA repair mechanisms and then there's the triggering of apoptosis. But to me it points to if the UVB is being absorbed by DNA specifically and it's generating vitamin D. It's obviously so critical and it makes better endorphin. It's obviously so critical and it makes better endorphin. It's obviously so critical for the organism and then it must just simply be that it's the dose titration, and obviously too much unrepaired will essentially contribute to malignancy, but below that threshold it's an absolutely fundamental requirement for human thriving.

Speaker 2: 1:35:25

I mean, like I said, from our studies from half a billion years ago, I think that vitamin D began to play that role and I think that today you're correct is that our body was designed to be in sunlight and, like you said, what's happening is that you induce DNA repair enzymes. Right, there was a study done right by Felton, published in British Journal of Dermatology, and what he did was he took skin type 2 and skin type 4 and exposed to tanning bed similar to sunlight for a few weeks and he looked at DNA damage in the urine and in the skin and he showed that, even though, yes, he saw the DNA damage in the beginning, there wasn't any increased DNA damage and likely if he had continued that study, it probably would have been decreased. Right, the Nobel Prize was given right for the observation of DNA repair enzymes. The body responds appropriately. Right, there's a genetic disorder that you're well aware of, right, that can't repair DNA and that those individuals can't be exposed to any because they have marked increased risk for non-melanoma and melanoma skin cancer.

Speaker 1: 1:36:39

Yeah, that's. Is it zeropigmentosum, Correct?

Speaker 1: 1:36:43

Yeah yeah, I mean, that is an elegant model for showing that the sun isn't inherently toxic. What is our physiological response to that sun? And if that molecular machinery is broken, as in the case of that genetic disorder, then that's a problem. And it also, I think, is further evidenced by an acquired form of impaired DNA repair, which is immunosuppression, an acquired form of impaired DNA repair, which is immunosuppression. And the fact that transplant recipients are at a higher risk of non-melanoma skin cancer. And again I know I'm really mindful of your time, but again I'm just really mindful of pushing back against this sun harm narrative.

Speaker 1: 1:37:25

And there was a South African study, just an observational study, by dermatology group, who took 150 or maybe it was about 230 patients with non-melanoma skin cancer. And this is a cancer that's, as you mentioned, is predominantly associated with sun-exposed areas. But those patients were vitamin D deficient and the more vitamin D deficient, the larger their basal cell tumors. So maybe sunlight exposure somewhere along the line has triggered DNA damage. But it clearly can't be the be-all and end-all because otherwise those patients would have high vitamin D levels. So it seems like the prerequisite for the development of any malignancy is actually, to some degree, in general, a low vitamin D from sunlight avoidance or indoor living.

Speaker 2: 1:38:17

Good way to end.

Speaker 1: 1:38:19

Yeah, thank you very much. I really appreciate your time, professor Holick. I think people are going to love this and very much looking forward to more research that you're putting out, because it's sorely needed. And, yeah, the semolwaste analogy is very, very appropriate. So, thank you, thank you for all you do.

Speaker 2: 1:38:38

My pleasure, and you can go to my website just drmichaelholickorg. Learn a lot more about vitamin D, and I'd be grateful if you could send me the URL for this, because I'll put it on my website as well.

Speaker 1: 1:38:51

Fantastic, definitely will do that.

Speaker 2: 1:38:53

Pleasure, take care, have a delightful day.

Speaker 1: 1:38:56

Thank you very much, thank you.