A growing body of evidence suggests that fat plays a role in the activation of stem cells. Fasting generates molecules such as fatty acids, ketone bodies and glycerol, providing a favorable environment for stem cell activation and renewal. While there is much to understand about the mechanistic details of the fasting-mimicking diet, the clinical benefits are clear. In this clip, Dr. Valter Longo discusses how fasting can play a role in the activation and renewal of stem cells by altering the metabolic profile.

Rhonda: And that is, at least, with the hematopoietic stem cells, like I'm not sure about with that, you know, others stem cells and other tissues. But I know that when they're quiescent, when they're not dividing, they are glycolytic, meaning they use glucose for energy because they don't want to damage themselves with reactive oxygen species being generated as a byproduct of mitochondrial function, right? But I do know that when they come out of quiescence, and they come out to either self-renew or differentiate into progenitor cells, oxidative phosphorylation becomes their source of making energy. And so, I'm wondering what's the signal... I know you've published some studies on looking at different signaling pathways that are required to cause this hematopoietic stem cells self-renewal mechanisms, but I'm wondering if possibly just not having the glucose available, and having just the fatty acids, the source of energy that can only be used by mitochondria, if that's somehow also is playing a role in making them self-renew more, or differentiate more?

Valter: I think so, and this is the work by David Sabatini, and others at MIT, and they're doing work on the fat, and the role of fat and fatty acids, etc., and self-renewal and the activation of stem cells, particularly in the gut. So, yeah, there seems to be a role for fat in that, and I think we're still beginning to understand it. I think, obviously, with fasting, you produce fat, and you produce fatty acids, and glycerol, and ketone bodies. So, the environment is there, and, you know, we need to maybe understand more, how each component that is changing is affecting the program, so yeah. So, we made the decision to try to, I think, things are going very slow, and we've always been very interested in people that have a problem now, right, instead of, you know...

Rhonda: Right.

Valter: A lot of people are always like, wow, in 20 years we'll have this. And we always said, you know, "There's people who have cancer now, they have multiple sclerosis now, so what do you do for them," right? And so, our decision has been always understand enough the mechanisms to be able to not, or minimize the chance of making mistakes, get to the clinical trial, and then, go back and fill it in, right?

Rhonda: Mm-hmm, yeah.

Valter: Rather than step, by step, by step, by step, you know, and then it'll take you 15 years to get to clinical trial.

Rhonda: Right. Yeah.

Valter: So, I mean, I'm not criticizing the other method, but I'm just saying that for us it has been get the mechanism, get enough mechanism, move to the clinical trial, and then make sure it's safe, and...

Rhonda: It's been fantastic. I mean, you've been able to translate so many different studies, I mean, it's really quite phenomenal. I'm just, sort of, thinking, in fact I just thought about it when you're mentioning the ketone bodies too. Well, ketone bodies are more, if you think about the stem cells, and if they need energy to differentiate or self-renew, ketone bodies would actually provide a very energetically favorable source because it takes less oxygen, actually, to convert beta-hydroxybutyrate into Acetyl-CoA, as opposed to glucose into pyruvate. So, if you think about it, it's more energetically favorable to have ketone bodies, and so, maybe it also helps just because it takes less energy to do this process. I mean, you know, it's possible, but...

Valter: Yeah. I think, there's also mechanisms. Again, the fasting imposes this new metabolic profile, and the new metabolic profile requires the stem cells for this regeneration that I mentioned. So, if you got to get rid of the health of your liver, let's say that you fast for a month-and-a-half, right? Then you must, you will produce tons of fatty acids and tons of ketone bodies, and that environment is gonna require the stem cell to be renewing, and being standing by for the day where you need to make a new liver, essentially, or health for the liver, right? So, this is why, I think, it's all a part of a coordinated response, where, you know, you have the fat... And by then, the fat is one of the few abundant sources of energy also for the stem cells, so they really have no choice but to be ready to respond to fat metabolites so that they can self-renew. Because there's not much sugar around, and the brain needs the sugar, by the way, right? So, the brain needs a lot of the sugar that is available, a lot of is made by gluconeogenesis, so it makes sense...

Rhonda: Red blood cells are needed since they have no mitochondria.

Valter: Right. And so it makes sense that you would have a system like that, that is fat in fatty acid and ketone body...

Rhonda: Yeah, yeah, absolutely.