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.