First, I want to discuss 3 main micronutrient deficiencies for two reasons. One is their widespread prevalence as deficiencies or inadequacies. The second is that I think they play a very important role in a lot of physiological processes in our body that affect the way we age. So, first, we're going to talk about vitamin D. And most of you guys probably have already heard enough about vitamin D, but it's important to talk about because it's more than a vitamin. So vitamin D gets converted into a steroid hormone, and it goes into the nucleus of cells and interacts with DNA. It recognizes a specific DNA sequence called the vitamin D response element. And this is encoded in our DNA.

And that interaction then either turns genes on and activates them, or it does the opposite. It sort of turns them down and represses them. So it's very important for orchestrating gene expression. I mean, we're talking about over 5% of the protein-encoding human genome is regulated by vitamin D, which is quite a lot. And so, you can imagine that if you're running a car and your pistons are firing out of sync with each other, that's what's happening when you don't have adequate levels of vitamin D. Your genes aren't being regulated in the way they're supposed to be. Things aren't being activated when they're supposed to be or repressed when they're supposed to be. Things are going awry.

As I mentioned about its widespread prevalence in terms of inadequacy, about 70% of the population has inadequate levels of vitamin D, which we'll talk about in a minute. That means about 30 nanograms per milliliter or less. And it's a very simple solution. And that's also why I like to talk about it, because it's almost just as simple as taking basically a supplement that costs a penny a pill. Vitamin D supplements are one of the most affordable supplements out there. And there's really just no reason other than lack of, you know, education about vitamin D for people to be so deficient and insufficient. There are a lot of reasons for the widespread deficiency. You know, we make vitamin D3 in our skin. So UVB radiation is essential to make vitamin D3.

Anything that blocks out UVB radiation is going to stop that production of vitamin D. So we're talking sunscreen, melanin, which is the dark skin pigment that protects us from the burning rays of the sun and also is a natural sunscreen. Where you live also matters. At northern latitudes, enough UVB radiation cannot reach the surface for vitamin D production during several months of the year. So when you combine some of these factors, let's say you take someone with darker pigmentation from, let's say, East Asia, and they move somewhere like Chicago or they move to Sweden where you are not getting that UVB radiation for 6 months of the year, you're talking about a compounding effect on vitamin D deficiency. There have been studies out of the University of Chicago that have shown that, for example, African-Americans have to stay in the sun anywhere between 6 to 10 times longer than Caucasians with fair skin to make the same amount of vitamin D3 in their skin. So you're talking— I mean, it's a compounding effect with respect to the melanin production as well. And then age plays a role. So, as we age, you know, everything is less efficient. So, you know, a 70-year-old makes about, I think it's 4 times less vitamin D3 in their skin than their former 20-year-old self. And then, of course, there is modern-day society.

We're indoors, we're at our computers, we're in our cubicles, we're surrounded by technology, you know, we're not outside. It's not an agricultural society. We're not outside as much as we used to be. Vitamin D is just not being made in our skin like it was 100 years ago. There's a lot of reasons why it's widespread. I like to show this slide. This study was published in 2009. It shows that knocking out the vitamin D receptor in mice affects the way they age. At the top of the panel, the wild-type mouse and the vitamin D receptor-knockout mouse are aging similarly. Four months later, the vitamin D receptor-knockout mouse shows an accelerated-aging phenotype.

It looks terrible, but aging was accelerated across organs and tissues. So it's just kind of a nice visual to see. But of course, we're not mice. And I've often wondered why mice even need vitamin D because, you know, they're nocturnal and they have— it's just one of those things where it's like, I don't know how much of that actually translates to humans. So let's talk about some human studies. A large body of observational data correlates low vitamin D levels with higher all-cause and cancer mortality. But there's always that question of healthy user bias. Maybe people with higher vitamin D are outside and more physically active.

And of course, you try to correct for as many, you know, confounding factors as possible, but you never really can establish causation. That's where Mendelian randomization comes into play. So this is— we, you know, we have a variety of genes that are responsible for converting vitamin D3 into 25-hydroxyvitamin D, which is the main circulating form of vitamin D, and then subsequently into the steroid hormone, which is 1,25-dihydroxyvitamin D. We differ in some of the genes that encode these enzymes, and some variants do not perform these conversions as efficiently. Mendelian randomization uses these single-nucleotide polymorphisms as naturally assigned genetic proxies.

Researchers can identify people whose variants predict lower 25-hydroxyvitamin D levels and compare those variants with outcomes such as all-cause mortality. It is a way of approximating random assignment. People with genetically lower vitamin D levels, independent of lifestyle, have a much higher all-cause mortality. They have a higher cancer-related mortality, and they have a higher respiratory disease mortality with very little or no effect on cardiovascular mortality. Randomized controlled trials cannot practically follow people for an entire lifetime to measure mortality, but they can examine other biomarkers.

One is epigenetic aging, which I'm sure you guys heard about yesterday. One study enrolled people who were vitamin D deficient. It is important to start with participants who are deficient, right? Because if you already have someone that's sufficient, giving them a vitamin D supplement really shouldn't do much because they're already at a sufficient level. So these were African-American individuals that were also overweight. They were very vitamin D deficient. They were given a vitamin D supplement with 4,000 IUs of vitamin D a day. And it decreased their epigenetic age by almost 2 years. The question is: what constitutes deficiency, insufficiency, and adequacy?

Definitions depend on the organization, but the Endocrine Society defines deficiency as 25-hydroxyvitamin D levels less than 20 nanograms per mL. Sufficiency begins around 30 nanograms per milliliter. Below 30 is insufficient, while above 30 is sufficient. And it seems as though the sweet spot for vitamin D is between 40 and 60 nanograms per milliliter. And, you know, there are also all-cause mortality studies looking at vitamin D levels. There are meta-analyses of studies ranging from the 1960s through about 2015.

It seems that 40 to 60 is a good range for the lowest all-cause mortality with vitamin D. I mentioned 4,000 IUs of vitamin D a day because that's the tolerable upper intake for vitamin D. So it's quite safe. And in general, 1,000 IUs of vitamin D generally raises people's blood levels by about 5 nanograms per mL. So the key is to just get a vitamin D blood test. Do it, you know, after you're supplementing, and make sure your levels are adequate. This is important because, again, a lot of these single-nucleotide polymorphisms in genes that affect our enzymes that are metabolizing vitamin D also affect how we respond to supplemental vitamin D. And some people can require a much higher dose than other people. So really the key here is blood tests and measuring. You don't know what you don't measure, right?