Why Vitamin D Deficiency Matters for Brain and Biological Aging

The reason vitamin D deficiency is so prevalent, which we will get to in a minute, is important because 70 percent is a lot of people. The name "vitamin D" is a little misleading because it is actually much more than a vitamin.

Vitamin D3 gets converted into a steroid hormone. It goes into the nucleus of our cells, interacts with DNA, and changes how genes are regulated. It activates important genes involved in immune function, brain aging, and cognition. It also turns down and suppresses certain genes with a particular rhythm and timing. If you are not getting enough vitamin D, about a thousand genes are affected. That is a lot of different processes.

I think this is important because there is a simple solution. Taking about 4,000 IU of vitamin D per day can bring most people up to a sufficient level, although there are outliers.

I like to start with this slide because we are going to talk about vitamin D's role in aging. These are mice, and we are not mice, but they highlight vitamin D's role in the aging process. In the top panel, the mouse on the left is a vitamin D receptor knockout mouse. Vitamin D cannot act on its receptor because there is no vitamin D receptor, so it is like being vitamin D deficient. The mouse on the right is a wild-type mouse.

The bottom panel shows the same rodents four months later. The vitamin D receptor knockout mouse is like an accelerated model of aging. Its skin starts to wrinkle, its hair falls out, its bones become brittle, and it develops organ dysfunction. The aging process accelerates even in rodents.

In humans, vitamin D is a hormone that affects more than 5 percent of the protein-encoding genome. That is a large percentage of important physiological processes that are not working optimally, and there is a simple solution.

Vitamin D3 also plays a role in how humans age and in disease risk. Countless studies have found associations between low vitamin D levels and increased all-cause mortality, cancer mortality, and disease risk. One might say that this is only an association and that people who are vitamin D deficient are less healthy overall. Maybe they do not go outside and exercise as much. You can find many possible reasons and say that this is probably not causation.

That is where Mendelian randomization comes in. We use genetics to look at vitamin D deficiency. Mendelian randomization looks at variations in genes and uses them like randomization to examine outcomes. We all have different gene variants, including variants in genes involved in converting vitamin D3 into 25-hydroxyvitamin D3 and the active steroid hormone. Some people have variants that make those enzymes less effective.

You can identify people with those variants and examine their mortality rate without first measuring their vitamin D. Other studies show that their genes give them genetically low vitamin D. They have increased all-cause, cancer, and respiratory mortality compared with people who do not have those variants in vitamin D-related enzymes. I think that is more causal evidence, and it goes hand in hand with the observational data. Together, the evidence suggests that vitamin D sufficiency is important for reducing disease and all-cause mortality risk.

We also know from this study, along with other studies that repeated and confirmed the finding, that vitamin D deficiency relates to epigenetic aging. The participants here were overweight or obese African Americans. African Americans are often among the most vitamin D deficient, particularly at northern latitudes, because melanin acts as a natural sunscreen.

A University of Chicago study published around 2009 found that African Americans had to spend about six to ten times longer in the sun to make the same amount of vitamin D3 in their skin as fair-skinned Caucasians. That difference results from natural sunscreen.

In this study, overweight and obese African American participants received 4,000 IU per day for a few weeks, and researchers measured their epigenetic age. Epigenetic aging is another way to look at biological age. Certain DNA methylation patterns occur with age, and scientists can use those patterns to estimate how old someone is. Sometimes a healthy person appears biologically younger than their chronological age, while another person appears older.

Here, the vitamin D-deficient participants appeared older. After taking 4,000 IU, their epigenetic aging reversed by almost two years. In other words, correcting vitamin D deficiency had a profound effect on this measure of DNA epigenetic aging. That is important to keep in mind.

Vitamin D also plays an important role in cognitive aging. Many of the genes among that 5 percent of the protein-encoding genome are involved in cognition and neurotransmitter synthesis. You may have heard of Klotho. Klotho is important for cognition. Studies show that people with variants that make Klotho more active are protected against Alzheimer's disease and dementia. They also appear to be smarter for some reason, so it plays a role in cognition.

Vitamin D deficiency is associated with dementia risk across many observational studies. Studies that measure vitamin D deficiency find an 80 percent increase in dementia risk. When genetic studies examine possible causation, the increased risk is about 50 to 54 percent.

That is still strong. If vitamin D deficiency increases dementia risk by 54 percent and a vitamin D3 supplement can correct that deficiency, it sounds like good value. Separate studies also show that people who supplement with vitamin D have a 40 percent lower dementia risk. You want to see the evidence pointing in the same direction, and that is what we see with vitamin D and dementia.

Studies also show that vitamin D deficiency structurally accelerates brain aging. People who are deficient often have white matter hyperintensities. These appear as small white spots on brain imaging and represent damage to the brain's white matter. For every 10-nanomole-per-liter increase in serum vitamin D, studies have found a decrease in white matter hyperintensity volume. That is strong evidence because it shows a dose-dependent effect.

Randomized controlled trials provide more evidence. Two large trials involved people with either mild cognitive decline or Alzheimer's disease. In both cases, participants received a fairly low dose of vitamin D3, around 800 to 900 IU. These were older adults who were probably severely deficient.

In the Alzheimer's disease trial, patients received 800 IU of vitamin D3 or placebo for one year. Vitamin D3 improved cognition and lowered markers of amyloid beta. Amyloid beta is part of Alzheimer's disease pathology.

The mild cognitive decline trial found something similar. It also lasted a year, and patients received either 800 IU of vitamin D3 or placebo. The people who received vitamin D improved their cognition over the year. This is strong evidence that vitamin D3 can be important for avoiding deficiency before Alzheimer's disease and can also help if someone already has it by improving cognition and lowering some Alzheimer's disease markers.

Vitamin D3 may improve cognition through several mechanisms. It is known to play a role in clearing amyloid beta and in immune function. Neuroinflammation is important in dementia and Alzheimer's disease, and vitamin D helps control inflammation and some of the inflammaging that occurs as we age. It also supports neurotransmitter synthesis, neuroplasticity, and mitochondrial health. People can explore many different mechanisms.

Ultimately, you have to measure your vitamin D level. Measure 25-hydroxyvitamin D, the stable circulating form. A clinician can order it, and online tests can send you a kit. It is easy and fairly inexpensive. Testing is the best way to know your vitamin D level and, after supplementing, whether you are taking the right dose.

I mentioned that 20 nanograms per milliliter or less is deficient. From 21 to 29 is considered inadequate, so below 30 is still inadequate. You want to be above 30 and, ideally, around 40 to 60 or even 80 nanograms per milliliter. Many studies associate those levels with the lowest all-cause mortality. A meta-analysis covering about 30 years of studies suggests that 40 to 60, or up to 80, is a good range. Four thousand IU per day will get many people there. That is the simple solution: a vitamin D supplement.