Rhonda: What about in young people? So, it's really fascinating because, you know, like, when I think about mortality risk, I think of like an older person going in, doing a battery of tests, getting all their bloodwork done and, you know, trying to do their grip strength and breathing, to do that. You know, so, I think about more of, like, things that are being measured and aggregated together to come up with this frailty index. But for someone who's younger, like in their 30s, like, and they go and do all this stuff, like, I don't know that it's really going to be a good predictor of their mortality. They're young, you know, they've got pretty good lung function. You know what I mean? So, is this where GrimAge may shine? Like, if you have a 30-year-old or 25-year-old and they do their GrimAge, does it, like, accurately predict mortality risk?

Dr. Levine: Yeah. So, we don't have these really really long follow-up studies but at least the preliminary data seems that it's going to be much better for young people. Because, exactly as you said, these functional things are going to have, what we consider, either a floor or ceiling effect. So, for most people below some certain age, they're all going to perform well on it. They're not at a level where they're seeing dysfunctional decline yet, which goes back to this idea of biological age versus functional age. Whereas the epigenetic clocks are meant to capture more this biological molecular cellular aging that we think will, eventually, feed into that. So, if you can say, "Oh, you're aging faster at a molecular level than we'd expect. We'll also expect you, down the road, probably to have these functional manifestations earlier, even if we can't see them yet." So, I totally agree. In younger people, when these things haven't really emerged, this is kind of the only way to kind of proxy who might be heading in that direction.

Rhonda: Totally. I mean you can't look in the mirror and go, "I've got more DNA damage today," like, you know...

Dr. Levine: Exactly, yeah.

Rhonda: Like, but you could be. And lifestyle factors do play a role and you could have someone who is in their, you know, 30s and they're sort of just living a hard life and perhaps they wouldn't pick up on those sort of functional declines yet but this is where something that is more measuring, something biological, you know, at the molecular level that's going to kind of open their eyes.

So, I kind of wanted to shift gears and talk a little bit about this epigenetic age acceleration. I mean, we've been sort of talking about how people age at different rates. I think you were a co-author on one of the studies like a few years back, that was one of the big ones that came out where it was like, "People age at different rates," and there was like 18 biomarkers that were looked at. And I think it was PNAS or something, a PNAS paper.

Dr. Levine: Oh yeah, the Belsky paper.

Rhonda: Yes, yes. And it was like, "Look, people are aging at different rates, and you can even look at their faces and it correlates with their, you know, biological age more than their chronological age." And so, to me, you know, clearly there's lifestyle factors, environmental factors that play a role in the way you age. Can you explain to people what epigenetic age acceleration is and what some of the most robust biological, environmental, perhaps social causes of epigenetic age acceleration are?

Dr. Levine: Yeah. So, we usually use this term "age acceleration" to just mean kind of the discordance between your chronological age, so, the age you know that you are and your predicted age based on whether it's GrimAge or PhenoAge or any of these epigenetic clocks. And that, again, we think it's biologically meaningful. So, someone who's predicted much older than they are chronologically are people who are higher risk for disease or mortality.

And so, you know, the next question is why are some people predicted older and other people are predicted younger? And a lot of people think, "Oh, it's just genetic, you know, maybe my family is just high-risk." But actually it seems to have very little impact on your epigenetic age, so, I think they estimate like 10%, maybe at the upper most 20% impact, your genes have that kind of impact on your epigenetic aging rate. And actually probably the majority of it is environment and lifestyle.

And when we look, again, these are not clinical trials, it's looking at epidemiological data, so, just saying, "In the population, the people who are predicted to be older versus people who are predicted to be younger, what are their characteristics?" We find things that are not surprising, so, socioeconomic status is a big thing in terms of differences in epigenetic age but also behavior. So, smoking really accelerates your epigenetic age. Generally, exercise will tend to decrease epigenetic age. Eating we think probably plant-based diet is going to decrease epigenetic age. And then, yeah, a lot of the things, don't drink heavily, get, you know, good-quality sleep, minimize stress, all the things that everyone's mother and grandmother told them to do in life.

Rhonda: How does being a male affect epigenetic age? Because males live on average, what, four years...like, their life span's like four or so years shorter than females', right? Is that reflected in...

Dr. Levine: Yeah, it is reflected in epigenetic. So, on average, again, not across the board but, if you look at the distributions, females on average will have lower epigenetic age than same chronological age males.

Rhonda: Similar question, females undergo menopause when they reach like 50s or something like that, plus or minus, I don't know how many years, but how does menopause affect epigenetic aging?

Dr. Levine: Yeah, so, this is actually a study I did while I was in Steve Horvath's Lab. So, we looked at women who undergone menopause and how long since they'd undergone menopause. And it seems to be that menopause is actually an epigenetic-aging-accelerated event. So, before menopause, women are doing pretty well and then, when they go through menopause, it seems to accelerate their epigenetic age. And we didn't have the kind of data you would want where we'd have the same women pre and post but we can even look at surgical menopause and that seems to also show this kind of accelerated epigenetic aging kind of manifestation.

Rhonda: That kind of leads me into another question, which is do the changes in these methylation patterns, that you and others are measuring, is it pretty stable over the lifespan or are they, like, you know, like, once you hit mid-life...because, like, there's functional aging that really starts to hit you, you start to get, like, late to midlife and then it starts to go down, right? So, does the epigenetic clock mirror that or is it pretty stable?

Dr. Levine: So, it's not stable but it actually doesn't mirror what we think of in terms of functional aging. So, if you think of a frailty index or even mortality risk, it increases exponentially after, let's say, age 30. The epigenetic clocks show a totally different pattern, it's still not linear but actually most of the changes happen during development. So, you have this huge increase in epigenetic age between...we can even measure it in fetal samples...and then it kind of starts becoming more linear and steady around age 20 and then, interestingly, actually slows down again, you know, very late, so, after, let's say, age 80. We don't know why these patterns look this way but, yeah, it's not perfectly stable across the life course.

Rhonda: Okay, this leads to a couple of other questions that, you know, sort of came in my mind. One is then what about, when people get, you know, disease states, so, like, they do get type-2 diabetes or cardiovascular disease, you know, does that then, being in that disease state, in that functional decline, like, state, does that accelerate the aging clock?

Dr. Levine: So, I don't know if we actually know that because we don't have very good...the problem with epigenetic data right now is we don't have good kind of time course data. We're not following people longitudinally, there are very few studies that do this. There are more studies that are starting to but I don't think we've reached the point to say, "I can look at someone's epigenetic aging pre-disease state and then see what happens after they've developed some disease," but I would imagine that it would probably kind of snowball and accelerate. And we do know, not looking at epigenetics, that, once you get a disease, it's actually shorter time to each subsequent disease. So, there does seem to be this kind of accelerating event in aging that occurs.

Rhonda: Biobank data might be a good source, they do a lot of, you know, like, they've got just tons and tons of samples, you know, because they have people come in for, like, routine...

Dr. Levine: Yeah. So, we've talked to them, the problem is that the epigenetic data is not super cheap. So, you know, to do that many people that many times, yeah, you have to come up with quite a bit of funding to be able to do that.

Rhonda: It would be interesting, it would definitely be...

Dr. Levine: Yeah, I know. I'm all for this. The more data samples we can get, I think the better we'll be able to figure this all out.