The Nuances of Vitamin D—and How to Get Enough of It.


We’ve been interested in the role vitamin D plays in our overall health for a while—particularly as it emerges that so many of us are quite deficient, particularly in the age of sitting inside all day and sunscreen. “Vitamin D” is sort of a misnomer because it doesn’t really behave like a vitamin; rather it functions more like a hormone. The form you typically consume (in food or supplements, or indirectly via the sun) is vitamin D3, but your body converts this into a steroid hormone, called calcitriol. Once vitamin D is turned into this active form, it travels throughout the body and plays a part in a number of diverse (and vital) functions: It builds bones and muscles; it also has anti-inflammatory effects, and helps to make enzymes and proteins that prevent diseases; it affects aging. High levels of vitamin D have been linked to stronger immune systems, while low levels are associated with cardiovascular disease, diabetes, and cancer. The full extent of vitamin’s D impact has yet to be fully understood—nearly every cell and tissue in our body has vitamin D receptors (proteins that bind to vitamin D); and in its active form, vitamin D can interact with the vast majority of the body’s cells. Below, vitamin D expert, Rhonda Patrick, Ph.D., shares the latest research on vitamin D (including some of her own)—which touches on aging, mood, autoimmunity, and autism (to name a few)—and spells out how to be sure you’re getting enough.

A Q&A with Rhonda Patrick, Ph.D

How many people globally are thought to be vitamin D deficient, and how does that compare to the U.S.?


First, we need to define “vitamin D deficiency.” The U.S. Endocrine Society, which uses a medical model that considers the broader set of vitamin D3 functions instead of just those related to bone, recommends that serum vitamin D levels above 30 ng/ml are adequate, levels between 29 ng/ml and 20 ng/ml are inadequate, and below 20 ng/ml are deficient. If we are to use this definition of adequate, much of the world falls in the category of either inadequate or deficient. According to meta-analyses of several studies that have assessed serum vitamin D3 levels worldwide, the global average vitamin D3 level is actually 20 ng/ml, which is pretty close to full-on deficient…and that’s the average. In the United States, approximately 70% of the population has vitamin D levels below 30 ng/ml.


Is our modern lifestyle (more time at the computer, less outside) and increased sunscreen use the major cause of this widespread deficiency, or do other factors play into the epidemic?


Yes, it is generally thought that the main reasons why vitamin D3 levels have decreased over the last few decades is due to more sunscreen use and spending more time indoors on computers. Since UVB radiation from sunlight is required to produce vitamin D in the skin, anything that blocks UVB rays such as sunscreen will also prevent your skin from making vitamin D3.

Another possible contributing factor to low vitamin D3 is the increased obesity epidemic. Vitamin D3 is a fat-soluble vitamin, which means it is stored in our fat. A higher body fat percentage can decrease the bioavailability of vitamin D3 by as much as 50% by soaking up the vitamin D and preventing it from making its way to our other tissues. This means that overweight and obese individuals may have less vitamin D that is available to be used by the body.

Other factors that regulate the ability of the skin to make vitamin D3 include age (a seventy-year-old makes about four times less vitamin D3 from the sun than a twenty-year old); melanin, which acts as a natural sunscreen; and latitude, which dictates whether UVB rays can reach the atmosphere.


Beyond skin coloration and latitude, what else determines how much vitamin D a particular individual needs? Are there genetic differences?


Genetics also play an important role when it comes to vitamin D. Gene polymorphisms, normal variations in the sequence of DNA of a gene that can alter its function, exist in several different genes involved in the vitamin D pathway. One gene that is subject to these sort of variations that can either affect how good we are at converting the precursors of what we normally call “vitamin D,” 25-hydroxyvitamin D, is known as CYP2R1. If we have a polymorphism that makes this gene less efficient at doing its’ job, then we’ll see less 25-hydroxyvitamin D being converted in the kidneys, and this will show up on the blood test we can get at our doctor’s office. In the future, we may see this giving us valuable insights since it may mean that certain individuals would have to take more vitamin D in order to achieve “sufficiency.”


What role does vitamin D play in aging?


Vitamin D3 is actually much more than a vitamin; it gets converted into a steroid hormone that has been shown to affect the activity (expression) of almost 1,000 different genes in the body, which is about 4.6% of the human protein-encoding genome! Let that sink in for a moment. I wouldn’t want 5% of the parts in my car engine to be working inappropriately if I wanted the car to have longevity!

But…returning to your question: Vitamin D does seem to affect the way we age. Mice that have been genetically engineered to not be able to respond to vitamin D (a vitamin D receptor “knockout”) manifest dramatic signs of aging in all the organs on a cellular level. You do not want to be these mice. There are multiple mechanisms by which vitamin D regulates the aging process, including telomeres. Every cell in your body contains DNA, which is present in your chromosomes, and the integrity of your DNA is crucial for your cells to function properly. Telomeres, which are caps at the end of chromosomes, help maintain that integrity. They protect our DNA from damage and deterioration. The length of our telomeres has been shown to correlate pretty well with our biological age. In this capacity, they serve as a marker for aging. If you have short telomeres, you’re biologically old. If you have long telomeres, you’re biologically younger. As in all things, there’s more nuance to it than that, but for our purposes, it’s useful to realize that we can be chronologically older, but have a biological age that is in line with those younger than us.

A couple of studies have shown that vitamin D can slow this telomere shortening that naturally happens with age. In one study involving 2,100 female twins, those with the lowest vitamin D levels had shorter telomeres that corresponded to five years of aging. Women that had serum levels between 40-60 ng/ml also had the longest telomeres compared to age-matched controls with lower vitamin D levels. Telomere shortening is accelerated by inflammation and DNA damage, as well as cell division. Every time a cell divides to give rise to daughter cells, the telomeres get shorter. We know that vitamin D activates DNA repair genes and anti-inflammatory genes to reduce damage at the telomere. This is a good thing for a whole host of reasons, but in the context of telomeres, it means extending their shelf life just a bit longer. Once the telomere runs out, the cells either die…or worse, they stick around in a “senescent” state, failing to do their normal function and instead becoming a source of damage to nearby cells by causing inflammation.


How can vitamin D intake affect our behavior and mood? What are other effects, physical and mental, of low levels of vitamin D?


This question touches on my own research that I did during my postdoctoral training. Among the 1,000 genes that vitamin D controls is a gene in the brain called tryptophan hydroxylase 2 (TPH2), which encodes for the rate-limiting enzyme that converts tryptophan into serotonin in the brain. It was my work that identified that this gene, TPH2, has a sequence that indicates that it is activated by vitamin D, suggesting that vitamin D may be important to producing serotonin in the brain from tryptophan. That’s pretty important! Serotonin regulates a broad range of cognitive functions and behaviors. It regulates social behavior, impulse control, decision making, anxiety, memory, impulse aggression, so-called “sensory gating,” and more.

We know that serotonin does these things because dozens of studies have teased out what serotonin does by depleting normal people of their serotonin temporarily. The way this is done is actually pretty clever and a little more harmless than it sounds: Tryptophan, the amino acid serotonin is made from, has to be actively transported into the brain. Another group of amino acids, however, will be transported preferentially before tryptophan if there’s enough of it sitting around. So that means you can actually give people a shake of branched-chain amino acids, a common component of bodybuilding supplements, and, in about 7 hours, around 90% of the serotonin in the brain is depleted. What happens then? People become impulsive, their long-term thinking shuts down, they become irritable, anxious, depressed, and their sensory gating, the ability to block out extraneous stimuli in the environment, becomes impaired. Aside from mood, serotonin is also important for many other things. We’ll get back to that in a second, however.


Can you explain how vitamin D is linked to our gut, inflammation, and autoimmunity?


This may surprise some people, but gut inflammation is also linked to serotonin: Not the serotonin in the brain, rather serotonin that is produced in the gut. Around 90% of the serotonin in the body is actually produced in the gut by a separate tryptophan hydroxylase gene called TPH1. This gene has a very important distinction from TPH2, the brain variety. Instead of being activated by vitamin D, TPH1 appears to have a sequence that is associated with repression. In other words, when vitamin D is around, it probably stops the conversion of tryptophan (in the dietary protein we eat) into serotonin in the gut. Don’t get too alarmed by that, however, serotonin made in the gut doesn’t have a lot to do with the amount of serotonin in the brain, since all of the serotonin in the brain is actually made in the brain by TPH2. In other words, serotonin does not cross the “blood-brain barrier.” We need just the right amount of serotonin in the gut because too much causes gut inflammation where serotonin serves to actually activate immune cells in the gut. In fact, it’s been shown that getting rid of serotonin in the gut in several different animal models of colitis and irritable bowl syndrome ameliorates the inflammatory symptoms associated with these inflammatory gut diseases. Since we now know that TPH1 is most likely repressed by vitamin D, this suggests that vitamin D deficiency may lead to excessive immune cell activation in the gut and, thus, inflammation.

My work also identified that vitamin D may be regulating autoimmunity through this same gut-serotonin pathway. Tryptophan, in addition to being converted into serotonin in the gut, can also be metabolized by another enzyme to generate a compound called kynurenine, which is essential for the production of regulatory T cells. Regulatory T cells are essential for telling the immune system, “Hey, this is my cell, it is not a foreign invader, do not attack this cell.” They play a very important role in dampening the immune response and preventing autoimmunity. Because tryptophan can be used in the pathway to make serotonin, through tryptophan hydroxylase 1 (TPH1), if that gene is hyperactive because there is low vitamin D, it may be sucking all the tryptophan into that pathway and producing a lot of serotonin in the gut, which then means less tryptophan is available to this other pathway that is essential to making regulatory T cells that keep autoimmunity at bay.


Can you talk a bit about the potential link between low levels of vitamin D and autism?


Low levels of vitamin D had been linked to autism and low levels of serotonin in the brain had also been linked to autism, however, until my work linking vitamin D more directly to serotonin, nobody had put the two together. Serotonin is so much more than a neurotransmitter. During early brain development serotonin actually acts as a brain morphogen because it shapes the structure and wiring of the brain. Serotonin tells neurons where they should go and what type of specific neurons they should become. It is literally acting as a growth factor in that sense during early brain development. Several studies have shown in mice that inhibiting the production of serotonin in early brain development causes functional and structural abnormalities in the brain, some of which manifest later in behavior that is said to resemble some autistic-like behaviors, insofar as mice can mirror the complexity of human behavior. Since vitamin D is required to activate this gene that produces serotonin, and the developing fetus depends on the mother’s vitamin D levels, if the mother is low in vitamin D then there may not be enough for the developing brain to produce serotonin. This could lead to abnormal brain development and autism, particularly in combination with other gene polymorphisms that already increase autism risk.

The other way in which the vitamin D-serotonin pathway may influence autism is by keeping the autoimmune response during pregnancy at bay. What is interesting is that mothers with autistic children are three times more likely to have high levels of antibodies against fetal brain protein in their blood cells. Said another way, they are three times more likely to show signs that their immune system was actively engaged against the developing fetal brain. There is really no good explanation as to why, but it suggests that the developing fetus may be recognized as “foreign” in these women. This may cause the immune cells to actually make antibodies that attack proteins in the developing brain, which could alter the way the brain develops. In fact, this has been shown in pregnant monkeys.


Is it possible to have too much vitamin D?


Yes, it is possible but not common. Data compiled from several different vitamin D supplementation studies reveal that vitamin D toxicity is obtained at doses higher than 10,000 IU. Toxic doses of vitamin D can result in exceedingly high serum levels of calcium, known as hypercalcemia and have been reported at doses higher than 50,000 IU.


How can we be sure we’re getting enough vitamin D? What are the best sources?


The best way to know if you are getting enough vitamin D is to get a blood test that measures your vitamin D levels. Meta-analyses of studies done ranging from 1966-2013 have shown that people with serum levels between 40-60 ng/ml have the lowest all-cause mortality, meaning they die less of all non-accidental diseases.

Supplementation with vitamin D3 is a good way to ensure you get adequate vitamin D. 1,000 IU of vitamin D per day, in most people, will raise serum levels by about 5 ng/ml. A good vegetarian source of vitamin D3 is lichen. Some foods have been fortified with vitamin D, including milk (100 IU per 8 ounces) and orange juice (100 IU per 8 ounces), but if we’re trying to fix inadequacy, these numbers are really a drop in the bucket. They’re not very much at all. Furthermore, dairy products are a sub-optimal choice for fortification for the approximately 50 million Americans who are lactose intolerant. If, like me, you are someone who decides to supplement, the upper tolerable intake level set by the Institute of Medicine is 4,000 IU. One study showed that people that were considered to be vitamin D deficient were able to raise their serum levels to sufficient levels after supplementing with 4,000 IU of vitamin D3 per day. Via Goop.



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