Steve: When it comes to these epigenetic clocks, this is the number one weakness of these clocks that we don't completely understand the molecular mechanism. And coming back to telomere length, that's a great advantage of telomere biology. We really understand very well what regulates telomere length, you know. But yeah, with the epigenetic clocks, this is a very active area of research. Top biologists and labs are working on that very question, you know, and there are many theories. Some people think stem cell biology plays an important role and that's probably true for many tissues, you know. In certain ways, it could measure aspects of stem cells, for example, how often a stem cell divided. The problem with that interpretation is that the epigenetic clocks work beautifully in neurons, you know, which really don't rejuvenate over the lifespan. By now we know that there is a U-shape behavior. You don't want telomeres that are too short, and you don't want to have telomeres that are too long, you know. And so that's the first statement. The second statement is telomere length per se is actually not a good biomarker for predicting onset of various diseases. Most diseases don't have a strong relationship with telomere length. In particular, when it comes to predicting lifespan, you know, telomere length is actually a shockingly weak predictor of lifespan. For many years, people wrote articles where they claim there is no relationship to lifespan. By now, the field has moved on to say, well, if you have very large data, you do see a relationship to lifespan. But if we compared telomere length versus an epigenetic clock such as GrimAge when it comes to predicting lifespan, time to cancer, time to coronary heart disease, I mean, there would be no comparison, you know. In this sense, telomere length plays a very important role in certain disorders, you know, but it's just not a broad biomarker for aging.

Rhonda: Right. How does the epigenetic clock, whether we're talking about the PhenoAge or DNA GrimAge, relate to other biomarkers of aging? So, does it usually correlate? Like, if you have...So, there's immunosenescence which, you know, is associated with aging, DNA damage, inflammation, there's telomere length. Does it correlate typically, like, in the same direction?

Steve: Yeah, it would. So, talking about GrimAge or PhenoAge, they would correlate in a consistent fashion, you know, so they would have a weak correlation with telomere length to give you a number correlation 0.1. So, it's actually a weak correlation but, yes, if you have a thousand people, you pick it up. In general, telomere biology is really a different hallmark of aging compared to epigenetic changes, you know. So, they measure different aspects of aging, but yeah, there's consistency.

Rhonda: Telomere biology has been...I interviewed Dr. Elissa Epel on the podcast. She works closely with Dr. Elizabeth Blackburn. She's at UCSF, and she has published some studies showing that, like, stress plays a big role...it plays a pretty good role in tumor biology. So, you can find that, like, different types of stress can actually affect telomere length. So, lifestyle factors that affect the epigenetic clocks, so for example, diet, exercise, smoking, or even, you know...