Rhonda: If you take cells from a younger donor and put it into an older recipient, so you're basically taking young cells and putting them into an older person, so the young cells will have a younger epigenetic age, obviously, than what was already there. The environment around the cells, the niche, so to speak, does that play a role in...do those blood cells, like, have more of an accelerated aging? Do they...?

Steve: Yeah. So, just to be clear, I want to distinguish parabiosis from these hematopoietic stem cell transplantations. I can comment on both, but let me start out with a hematopoietic stem cell transplantation. Some people have a very severe form of leukemia, and therefore their bone marrow stem cells have to be removed, and the procedure is dangerous, I'll start out with that. So, that's why I say only severe forms of leukemia patients get that treatment. But yes, let's say you take a 50-year-old and you give this person a bone marrow transplant from a 20-year-old. And so, after the transplant, the blood in the recipient reconstitutes itself. The person has now new blood. And the question is, what's the age of the blood? Does the blood have the age of the 20-year-old donor or the age of the 50-year-old recipient? And you can make a case for both scenarios. But there are now several scientific papers that really give an unequivocal answer, which is the reconstituted blood in the recipient has the age of the donor, you know, and that effect persists for decades, you know. So, if you take...again, the 50-year-old got a bone marrow transplant from a 20-year-old, you follow this 50-year-old, 30 years, now he's 80. Question is how old is his blood? Well, the age would be now 50, because 30 years have passed and you add that to the age of the donor, you know. And one would think that the stem cell niche in the bone marrow could possibly affect the aging rate, but it just isn't the case. And so, that's on some level a very exciting finding because it kind of hints to an idea that you could possibly rejuvenate people through transplantation. The reason why this is not yet a viable strategy is because people who get a transplant often get so-called graft versus host disease. So, there are all sorts of complications, you know. It's a dangerous procedure, but in theory, you know, it could work.

And talking about parabiosis where people have connected two mice, you know, where one mouse is much older than the other one or much younger than the mouse. We just recently analyzed parabiosis mice, you know, it's unpublished, and we found two results. One corroborates things and one refutes it, okay? But just to explain it, so we looked at cortex and also subventricular zone, deep white matter in the brain, and we found that a young mouse that was connected to an old mouse actually aged faster according to an epigenetic clock in mice. So, that part confirmed these parabiosis experiments. So, in other words, you can age a young mouse. But that's not what people are interested in. They're interested in the opposite. You take an old mouse and you connect it to a young mouse, and then you study the brain of the old mouse, and you want to see that the brain is rejuvenated, you know. And for that scenario, actually, our results were disappointing. We didn't see a rejuvenation effect, you know. And so, now we're trying to get additional data because our first study was underpowered, but one of these months we will have a definitive answer.

Rhonda: Yeah. You know, some of these animal studies are really good for trying to understand mechanism, and all this data suggest, you know, you've got a clock that can predict chronological age. You've got a clock that can look at your biological age and also predict time to death, lifespan, the GrimAge. I mean, something clearly is changing these methylation patterns. So, the question is, what is that? Is there a chronic signal that's doing it or is it just completely under genetic control? And maybe they're related, right? So, what are your thoughts on the aging process and even [crosstalk] ?

Steve: Yeah. Well, when it comes to these epigenetic clocks, this is the 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.

And yes, another group thinks that epigenetic clocks might relate to circadian rhythm, so there have been some theories. Now, I believe that also processes that play a role in development must be playing a role here and the reason is because my original pan tissue epigenetic clock works actually beautiful in prenatal brain samples. It works beautifully in various in vitro studies of so-called three-dimensional brains, you know, or in retina samples. So, really, it captures aging of gestational age during development, you know, and during development, there's really no noise. This is a highly coordinated process. And so, yes, these processes also must play a role.