Sex Differences in Caloric Restriction and Anti-Aging Diets

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• Sex Differences in Caloric Restriction Response
• Genetic Background Influence on Diet Effects
• Hormonal Mechanisms and Speculation
• Pharmacological Interventions and Sex
• Rapamycin's Unique Effects on Lifespan
• Future Research and Human Translation
• Full Transcript

Sex Differences in Caloric Restriction Response

Dr. Matt Kaeberlein, MD, PhD, addresses the significant differences in how male and female organisms respond to caloric restriction diets. He explains that these sex-specific responses are observed in laboratory mouse studies. Dr. Matt Kaeberlein, MD, notes that the same dietary intervention can produce vastly different outcomes depending on sex. This variability presents a major challenge for developing universal anti-aging dietary recommendations.

Genetic Background Influence on Diet Effects

The interaction between genetic background and dietary response creates additional complexity in aging research. Dr. Matt Kaeberlein, MD, PhD emphasizes that limited studies have specifically examined genotype-caloric restriction interactions. He notes that within a single mouse genetic background, males and females can show dramatically different responses to identical dietary interventions. This genetic variability underscores the need for personalized approaches to anti-aging nutrition.

Hormonal Mechanisms and Speculation

Dr. Matt Kaeberlein, MD, PhD discusses potential mechanisms behind sex-specific responses to caloric restriction. He speculates that hormonal differences between males and females may play a crucial role. Caloric restriction significantly affects growth-related hormones including growth hormone and testosterone. These hormonal changes might explain why anti-aging diets affect sexes differently, though more research is needed to confirm these mechanisms.

Pharmacological Interventions and Sex

The sex-dependent effects extend beyond dietary interventions to pharmacological approaches. Dr. Matt Kaeberlein, MD, PhD references the NIA interventions testing program which has identified eight or nine lifespan-extending drugs. Most of these compounds show significant efficacy in one sex but not the other. This pattern highlights the broader challenge of sex-specific responses in anti-aging therapeutics that researchers must address.

Rapamycin's Unique Effects on Lifespan

Dr. Matt Kaeberlein, MD, PhD identifies rapamycin as a notable exception among anti-aging compounds. Unlike most interventions, rapamycin demonstrates significant lifespan extension in both male and female mice. However, Dr. Matt Kaeberlein, MD, notes that females show greater sensitivity to rapamycin's effects at equivalent doses. This unique profile makes rapamycin particularly interesting for studying sex differences in aging interventions.

Future Research and Human Translation

Dr. Matt Kaeberlein, MD, PhD emphasizes the critical importance of understanding sex differences for human translation. He identifies this as a fascinating area for future research that could significantly impact clinical applications. Determining whether specific anti-aging interventions work better in men or women will be essential for developing effective treatments. Dr. Anton Titov, MD's questioning highlights the clinical relevance of these research directions for personalized medicine approaches to aging.

Full Transcript

Dr. Anton Titov, MD: 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?

Dr. Matt Kaeberlein, MD: I sort of put that under the same umbrella as genetics. Obviously, men and women at a superficial level are genetically different in the inheritance of an entire chromosome. Whether or not the observational differences between males and females in laboratory studies with caloric restriction—what the mechanisms are there—I think remains unclear.

In the mouse studies, and again, it's important to appreciate that there are 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, 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.

Again, the mechanisms underlying that are completely unclear. You could certainly speculate. In both mice and humans, there are big hormonal differences between males and females. We know that caloric restriction has a profound impact on many growth-related hormones like growth hormone or testosterone.

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 truly try to test that hypothesis. But I agree. This is 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. There have probably been eight or nine drugs now from the NIA interventions testing program that have been shown to increase lifespan in mice. 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 a very small effect in the other sex.

We don't understand 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 there, 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.

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. As we talk about translation to people, that's a critically important thing to figure out. You would want to be able to understand in humans if a given intervention is more or less likely to have a positive effect in men versus women.

I think that would be a really interesting area of research over the next few years.