Elissa: So, Rhonda, can I ask you something? You are such a broad expert on aging, you've interviewed, you know, so many of the experts in the world on this. How much do sex differences come up? And I ask partly because we're at a meeting here on women's health and I've just, you know, recently been scouring the human literature trying to understand hormones, and aging, sex hormones. And what have you learned?

Rhonda: It almost never comes up and it's certainly a question that has remained unanswered in my mind for several years. And, you know, over the years I've heard a variety of hypotheses, you know, ranging from immune system differences to differential effects of testosterone on a variety of different tissues, particularly the immune system. But it... You know, you started out this podcast, you mentioned the average lifespan in United States for men was about 78 something and women was about 83, you said. And I did want to stop and ask you right there why? Why is that?

Elissa: So I've recently tried to read everything I could about this, to understand it. So, this sex gap in longevity is robust across cultures across countries. I mean, this is a fundamental thing about human biology.

Rhonda: Species yeah.

Elissa: Women live longer, why? You know, it's kind of obvious of like, well, there's two X chromosomes, there's something protective about that backup copy. There's estrogen which is protective in certain ways to the heart. And then there's like, kind of like psychology, behavior, sex differences, where men are more risky, they do more alcohol and abuse and risky things that lead to death. So, there's some that but that's just like tip of the iceberg. Like the truth is we don't really understand those differences.

So, here's what we know. Women have many cases when we look at the cells of women and men where their aging biology is more robust and slower. Examples, women have much longer telomeres, like hundreds of base pairs longer. And that starts at birth, and that's probably related to sex hormones. So twins, where there's a female and a male, don't have different telomere length, so there's probably a masculinization in the womb.

So the bottom line is this. Estrogen, when we look at these experimental models, and in vitro and mice, estrogen is protective and anti-aging in a sense, in that it upregulates telomerase. It improves mitochondrial health. Those energy stores in our cells, those batteries are more robust. They create more ATP, they leak less oxidative stress. So if you like, cause menopause in a rat, you're going to create more mitochondrial dysregulation in the brain and cognitive problems. And then if you replace estrogen, you fix it.

So all these beautiful models suggesting estrogen is super anti-aging. But the idea of like, okay, do we have a new drug, and it's estrogen, and we're all going to live longer? Absolutely not. The complexity of hormones in general, the different types, the different receptors, hormone therapy, it's appalling how little we know about aging and hormones in humans.

Rhonda: Are there any people that are really specializing in that field that you know about?

Elissa: So there are some people with very... you know, important programs of research. They're mostly not in humans. In humans, we know this. We know that if you have a longer reproductive life span, meaning your menopause is a lot later, you're likely to have longer telomeres. If you give birth later, like in your 30s instead of your 20s, sorry, your last birth, you have longer telomeres. Those are also related to longevity too, having a longer reproductive life span.

So there are clues, like this is really important, we should understand the sex differences. They're big, they're obviously related to hormones but we really don't actually...don't know how to act on them. We don't know you know...

Rhonda: I didn't know that the differences in telomere length between men and women were present at birth or male and female.

Elissa: Yeah, so I mean this literature is just changing so rapidly. So people have discovered that, and it's become somewhat of a consistent finding in recent years. Of course, there are differences with ethnicity and race. We also know that telomere length at birth is impacted by the mom's health, her mental health, her nutrition, her physical health. So that's another whole world of like fabulous, important knowledge for us to act on.