Rhonda: But to kind of shift into, you mentioned the exercise, and we're talking about age reversal and kind of slowing...like, so, exercise is also associated with the slowing of epigenetic age. And then I think the other thing you kind of alluded to for a moment was genetics, and I had a question here because you were saying, "Genetics," it seems as though...10% to 20% you mentioned?

Dr. Levine: Yeah.

Rhonda: Pretty small, pretty small in terms of epigenetic aging. Like...

Dr. Levine: But even in terms of lifespan, it seems to be on par with that.

Rhonda: So, only a small percentage of the way you age is controlled by genetics?

Dr. Levine: Yeah.

Rhonda: Now, this is my caveat, or my question, what if you are a super centenarian or a semi super centenarian, like there's obviously you're an outlier, right, like, that's an outlier but it exists and it's thought to be under genetic control, I think...

Dr. Levine: Yeah, yeah. So, they're probably not just randomly making it to that. So, for most of us, our aging is going to be less under genetic control but there are definitely people you might think win the genetic lottery. Right? So, they're very unique and they have the perfect combination. It's probably not one gene, they just have the perfect combination of different gene variants and that somehow enables them to live much longer than the rest of us, it seems even despite having bad health behaviors. So, these super centenarians don't necessarily smoke less or eat better or exercise more than people in the general public but they're somehow able to overcome that and survive to extreme ages. And that's probably more under genetic control.

But for most people, unless you have, you know, a string of grandparents that all survived to 110, you're probably not going to be able to rely on your genes to get you there. And actually, my PhD dissertation was on long-lived smokers and thinking, you know, smoking decreases people's life expectancy by about 10 years but you have these people who survive to 100 or beyond still smoking, and, you know, what is it about their genetics that allows them to kind of overcome that?

Rhonda: And what was it?

Dr. Levine: I mean, the stuff that came up was major aging pathways like insulin IGF-1 pathway, but again, we haven't proven this out causally. But yeah...

Rhonda: Did you read that Japanese semi or super-centenarian study that came out, I don't know, a few years ago?

Dr. Levine: I don't know if I...

Rhonda: It was a study where they looked at...

Dr. Levine: Was that the men, where they looked at...

Rhonda: Yes, men, and they looked at elderly and then they looked at, you know, going from elderly to a centenarian, from a centenarian to a semi-super centenarian, which is 105, and then to a super centenarian, which is like 110. And they looked at all battery of biomarkers, I don't think epigenetic clock was in there, but they looked at, you know, like, telomere length, immunosenescence, all the bloodwork stuff, the metabolic and, you know, lipids and stuff. And then they looked at inflammatory biomarkers.

And it was fun, it was interesting because the suppression of inflammation was the only thing that could predict going to the next age group or age...I don't know what it's called but transitioning to surviving to the next...right, just being able to like low inflammation, basically. So, that was sort of interesting as well.

And also it kind of goes back...you mentioned smoking and, of course, genetic control there, typical pathways, it kind of brings to mind we recently had Dr. Bill Harris on the podcast, and he's probably one of the world experts on omega-3 fatty acids and just been doing decades and decades of research. And he has all this interesting data. He does a lot of work using the omega-3 index, which he co-developed, where they measure omega-3 and red blood cells. It's a long-term marker of omega-3 rather than, like, what you had the night before, you know And, you know, he's done all sorts of studies using Framingham data and has found that...so, a typical American diet is they have about a 4% omega-3 index. And that's kind of low, especially if you compare it to other countries like Japan where their average omega-3 index is like 10% or 11% or something, much higher.

Anyway, so, he did studies with Framingham data and he stratified people based on their omega-3 index. So, low was like lower than 4% and high was about 8%. And people with an 8% omega-3 index had a 5-year increased life expectancy compared to people with the 4% omega-3 index. Interesting. But what was also really interesting from this data was he looked at smokers. And smokers, as you would imagine, had a much lower life expectancy. But smokers that took omega-3, that had high omega-3 indexes did not have that same low life expectancy. But here's the really interesting thing is that the smokers that took high omega-3 had the same life expectancy as the non-smokers with low omega-3. So, in a way, low omega-3 was like smoking, you know, for your life expectancy. Right? I mean, to me, it was very interesting data. You should pair up with him. And I would be so interested to know the epigenetic age as it correlates with the omega-3 index.

Dr. Levine: I mean, yeah, depending on which samples, in Framingham, they do have methylation already measured.

Rhonda: Okay, there was also a really interesting study. This kind of gets into interventions as well, I kind of wanted that you touched on that for a moment, and there was an interesting study...and I don't know if I really have a question but I also just like to seed ideas, you know. The study was, like, women that were genetically predisposed to breast cancer, they were given 5 grams a day of fish oil. So, it was EPA, DHA omega-3, the marine omega-3 fatty acids, and this was like 6 months treatment. And, like, they had done some sort of methylation profiling, not epigenetic clock but profiling of their blood, PBMC's, their peripheral blood mononuclear cells. And there was like hypomethylation in I think it was like TNF-alpha or one of the major controllers of inflammation where it was like decreasing a lot of the pro-inflammatory pathways. So, you know, at the level of methylation, I thought that was so interesting.

I'm not sure what's going on there because there's lots of ways omega-3 regulate inflammation, they suppress it, they resolve it. You know, and so, I was like, "Wow, they're changing methylation patterns, like, how is that happening?" So, just sort of interesting, you know, potential research ideas there.

Dr. Levine: Yeah. No, I think there's a ton of things to start connecting and, you know, all these environmental things and just physiologically how are these things connected when you go up in this, how does that affect these other things downstream. And yeah, I think, as more and more data gets collected and we actually have good measures of all these different things, we can start doing that. But yeah, it's...