Rhonda: Do you personally think that the epigenetic clock plays a causal role in aging? Do you think...?

Steve: Yeah, let me answer it in two ways. It clearly relates to a process that plays a causal role, and so to use a metaphor, is it the face of the clock, you know, or is it the clockwork of aging, you know? And no doubt the epigenetic clock must relate to at least one causal process because it predicts lifespan. If it didn't relate to a causal process, it wouldn't be able to predict how long you live. But the real question is perhaps what if you changed the methylome, you know, if you had an intervention, you change DNA methyltransferases, you kind of...I want to call it the superficial way of perturbing the clock, would that have a benefit? And personally, I don't have an answer to it yet.

These locations are not unique, you know, and when you look at the genome, we have, in principle, 28 million locations in the genome as cytosines, you know, and I want to say a quarter of them change with age. Some of them gain methylation, some of them lose methylation. So, these methylation changes like almost globally, you know. And in that sense, epigenetic clocks look at perfect representatives of the entire what is known methylome.

They represent everything that's going on. But you can see that maybe looking at only 300 locations is not ideal, you know.

Having said this, we certainly did look at it and say, "Are these locations enriched, you know, with certain pathways?" And no doubt they are. So, sites that gain methylation with aging are known to be located in so-called polycomb group protein target sites, so certain proteins that play a very important role in maintaining stem cells, you know, or conversely, sites that play a role in cell differentiation and development. So, these sites tend to gain methylation with aging, you know. The sites that lose methylation also are enriched with certain themes, for example, so-called enhancer regions, you know. So, the field of epigenetics has very much characterized the genome, which parts change with aging. There is wonderful review articles on it.

Rhonda: And then, I just got on the stem cell thing. That's just so interesting that a lot of those are regulating stem cell functioning because it's just...

Steve: Yeah. Coming back to the mechanism of the clock, that's really a profound insight, you know, that when you look at the data, you keep seeing themes related to development, tissue differentiation, organ development. And it is a profound insight because if you had asked an aging researcher five years ago whether developmental processes matter in aging, they would have said no. Many people think of aging as noise, right, wear and tear, you know, but these epigenetic clocks have really linked development to tissue dysfunction in a direct manner. An epigenetic clock is a continuous readout that links prenatal tissues directly to very old samples.