Dr. Shinya Yamanaka discovered a group of proteins that can reprogram differentiated (mature) cells into pluripotent stem cells. These proteins, now called Yamanaka factors, are highly expressed in embryonic stem cells in mice and humans. Their short-term expression can ameliorate cellular and physiological hallmarks of aging and prolong lifespan by resetting the Horvath epigenetic clock. In this clip, Dr. David Sinclair talks about the discovery of genes that can reset the Horvath epigenetic clock.

David: We haven't published it yet. So my graduate student, Yuancheng, will probably kill me for saying too much. But we're both so excited. Even today, he sent me a text about, a new breakthrough is that we've found not only the genes that trigger them to move, but then the genes that reset the Horvath clock once they get there.

Rhonda: Really? You've identified the genes that can make them move...make the methyl groups move?

David: Methyl groups. Yeah, and reset the methyl groups and what gets them to go back.

Rhonda: Okay, okay. Wow.

David: Yeah. So, I'll give a hint to the viewers. And maybe this will be published and, shortly, we'll see. So we're using what's called the Yamanaka factors. And so, the first, person to do this...

Rhonda: Explain what that is.

David: Sure. Well, the first person to use these factors was Shinya Yamanaka, a Japanese scientist who looked through a lot of different genes and found a set of four factors that if you put them into an adult cell, say, a skin cell, they would go back to being very primitive, so primitive, what we call a pluripotent stem cell that you could then turn those cells into a nerve cell or even regrow an eye in the dish. It was a breakthrough that led to the Nobel Prize being awarded to him in 2012.

Rhonda: You just take a person's skin cell and turn it into a neuron. I mean, that's, like, amazing.

David: Why not? We do... I mean, a high school student can do that these days. It's not that difficult. Typically, with science, once you know how something works, it's pretty easy. Same with aging, I think. But what we've discovered is that... And first of all, I want to give a lot of credit to someone at the Salk whose name is Juan Carlos Belmonte, a professor there. A good friend of mine and he's...and he did the experiment that we were trying to do, so we were just slightly scooped on that. But he made a mouse where he could turn on these four Yamanaka genes. And that, for sure, they stand for O,S, K, and M. And that mouse, when he switched them on, died within a couple of days. So that's not great for those mice. But what he then cleverly did was he didn't give up or his postdoc didn't give up. What he did was he turned the genes on for a couple of days and then stopped, let the mice recover for a few days, and then turned them back on.

So, you know, I feel for the mice because they were headed towards death and they could recover and then they cycle, but actually, they ended up being healthier. The premature aging mouse model that he had lived, I think it was 40-plus percent longer. But also, he's shown since then that you can use these factors to improve wound healing and kidney healing.

Rhonda: So was he boosting their stem cell pools, and their... So he was, like, regenerating tissues or?

David: What I think he's doing is what we're doing in the lab, which is getting those proteins that have moved around and lost their way to go back to where they were when they were young and then reset the methylation clock. And now a cell doesn't just think it's young. It's literally young.

Rhonda: Was he using CRISPR to do this?

David: Well, he might've, but it was a transgenic mouse, which means he inserted those four genes into the mouse's genome with an on-off switch.

Rhonda: Yeah. Okay.

David: We don't do that. We use viruses that we can give to old mice. He has to start from a single egg. We can go into old mice and within a few weeks, figure out if we've reversed aging in a tissue or in the whole mouse. And we've also discovered that it's best if you don't use all four of those factors, we have to leave one of those off because it's toxic. It's the Myc gene, Myc is an oncogene, but the other three worked great. And the results that came in through the tech today use those three genes to protect neurons from dying in the mouse but also in the dish. And the gene that can restore the Horvath clock was required. And so we're very close, I think, to seeing the future of where maybe eventually we don't use viruses, maybe we have molecules that can do this that we can put in a drip or in a pill that can send us back another 20 years.

Rhonda: Wow. That's super exciting. I'm, like, very pumped up about this whole epigenetic clock research and linking it to, you know, basically, like, being able to reverse aging. I mean, I think that... Do you know... Is there any evidence that fasting has any effect on that epigenetic clock? Has that been shown, do you know?

David: I have not seen that. I think what I've seen from Steve's work and others is that you can slow the rate of the clock, but I haven't seen reversal yet. And I've shown Steve the results I just told you and he's pretty excited that someone's figured out... We think we've figured out why the clock ages, what's causing it, but also what's the first reset that's ever been found. But I would suspect that fasting can help, but probably, it's not enough to really do what these powerful genes are doing. One day, we'll figure it out but... So fasting, I still do that as much as I can for one main reason, and that is that it's going to activate these defenses that, at least, slow down and somewhat stabilize the epigenome decay that we call. But we're probably going to need something more potent to really go back 20 years. But do we slow down aging by fasting and running? Absolutely, no question.