And this is very interesting about genetics. But there's also a difference in male versus female sex as to how the caloric restriction diets affect that based on genetics. So what is known about those differences and the underlying mechanisms and their impact?
Yeah, so I mean, I sort of put that under the same, you know, umbrella as genetics, right? Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. Obviously, you know, men and women at a sort of superficial level are genetically different in the inheritance of an entire chromosome, right. So, you know, whether or not the observation, observational differences between males and females in laboratory studies with caloric restriction, you know, what the mechanisms are there, I think, remains unclear. What I would say about that is that in the mouse studies, and again, I think it's important to appreciate that there are, you know, relatively few studies that have tried to address this question of interaction between genotype and response to caloric restriction. So it's a limited data set in the few studies that have looked at this. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. I think the take-home message is that in a given mouse genetic background, males and females sometimes show very different responses to the same dietary intervention. And, again, the mechanisms underlying that are completely unclear. I think you could certainly speculate, right? So in both mice and humans, there are big hormonal differences between males and females. And we know that caloric restriction has a profound impact on many growth-related hormones like growth hormone or testosterone. And so it seems possible, maybe plausible, that some of the sex-specific different effects of caloric restriction are due to those sort of more global hormonal changes, again, not very much work to really, truly try to test that hypothesis. But I do, I agree. I mean, and I think this is, you know, this is a case where that's not unique to caloric restriction. Even for many of the pharmacological approaches that have been shown to increase lifespan in laboratory mice, there are sex-dependent effects. So, you know, there have probably been, I don't know, eight or nine drugs now that from the NIA interventions testing program have been shown to increase lifespan in mice. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. And most of those, again, for reasons that are not understood, work in one sex and not in the other sex or work robustly in one sex and have it have a very small effect and the other sex. We don't understand, you know, what the underlying mechanisms are the one example of a drug, in my mind that works robustly in both males and females is a drug called rapamycin, where you get significant lifespan extension in both sexes. Still, even their females seem to be more sensitive to the effects of rapamycin. So at a given dose, the lifespan extension is larger, usually in female mice, than in male mice. So it's a really important and interesting question that I think the field appreciates is important and interesting that we just don't have a lot of answers at this point. Dr. Matt Kaeberlein, PhD. Dr. Anton Titov, MD. But, you know, As we talk about translation to people, that's a critically important thing to figure out. Because, you know, you would want to be able to understand in humans is a given intervention, you know, more or less likely to have a positive effect in men versus women. And so I think it's, you know, that would be a really interesting area of research over the next few years. Well, that is certainly true.