Horvath altering enzymes_12 dan Rhonda: So, the question is, there's a group of demethylases that can take off the methyl group that become active and take it off of this gene, and they're activated by inflammation. So, what I'm wondering is, is anyone looking at...Obviously, these methyl groups are changing, and so the enzymes that are pulling off methyl groups and the demethylase is the enzymes that are putting them on their methyltransferases, they must be doing something.

Steve: Yes. And people are looking at it. Yeah. I mean...

Rhonda: Okay. What's changing those enzymes? Like, is there a signal there or is it a gene? Is it genetic control or what is it, you know, that can change?

Steve: Yeah. You make very good points. So, if you want to understand the epigenetic clock clearly, you start with so-called DNA methyltransferases or these TET enzymes. Why? Because they, on the one hand, add methyl groups or remove methyl groups. So, that's a low hanging fruit. And just recently, we and others, several groups have actually found no doubt when you interfere with these enzymes you affect epigenetic age. There are very exciting findings where people studied certain developmental disorders where mutations deactivated DNA methyltransferase or mutation rendered it overactive, you know. And sure enough, all of these mutations in humans, you know, affect epigenetic age. And so, at that level, we know it has an effect as expected, and the effect is pronounced. It could add 5 or 10 years to a person or the opposite, you know.

Rhonda: And does that correlate with the life span of whatever disease?

Steve: You see, we don't know exactly. That's the question. So, some of these children have a developmental disorder, and there is various syndromes, you know, one is the so-called Sotos syndrome. Anyways. And so, we see strong deviations in blood in both directions plus five years, minus five years. So, at that level, it's all confirmed, plus right now, we do mouse crosses, you know, where we knock out these DNA methyltransferases just to very carefully study it in a very controlled setting. But I can already tell you you'll find strong effects. But the question you really ask is, well, on this upstream of those, you know, what regulates the clockwork? What tells the DNA methyltransferase, "Go to this location and deposit and work your magic," you know? And that's where we don't have an understanding yet.