Sex differences in health and aging, a dialogue between the brain and gonad. This is the title of your paper. It's very intriguing. What are sex differences in health and aging? Yes, so differences in health and sex, and health and aging. So I kind of think of my scientific career as sometimes consisting of pointing out what everybody knows, but nobody's observed. In the case of sex differences, I think, you can ask anybody do men or women live longer. They would say that women live longer. But that's just the beginning of the story. Dr. Steven Austad, PhD. Dr. Anton Titov, MD. It's true that women live longer. And they've lived longer in every country and in every historical period that we have good evidence for. And they live longer when there's drought, and they live longer when there's famine. Women live longer when there are pandemics, and they live longer even right after birth. Dr. Steven Austad, PhD. Dr. Anton Titov, MD. So there's some fundamental feature of female biology that we don't understand yet that makes them superior survivors to male biology. It has nothing to do with just heart disease. If you looked at all of the top causes of death, all men die at higher rates of all of them, with one exception. And that exception, interestingly enough is Alzheimer's disease. Again it's something that we don't understand. Now, does that have something to do with the reproductive hormones? That's one obvious hypothesis that estrogen is somehow protective. And maybe testosterone is somewhat toxic. Again, we don't know that for sure. But there are some very crude but intriguing observations or two studies of men, who, for one reason or another, have been castrated, sometimes, at a young age. One of them is in homes for people that are mentally disturbed. And another one was from Eunuchs in the Korean court. A nice thing about the Eunuchs study is that the men were castrated there because they were taking care of the king's harem and didn't want any difficulties. Dr. Steven Austad, PhD. Dr. Anton Titov, MD. One of the interesting things about that study is you could compare those with other members of the court, so same socio-economic setting. Like I say, the data are very crude. The interesting thing is the magnitude of the difference. The ones that were castrated were living 10 to 20 years longer than the intact males. And that's in both of those studies. And we're not talking about a small number of individuals. We're talking about hundreds of individuals. So that suggests that there may be a hormonal influence. But what we don't know yet, if there's more to it than that. I mean, the women have two X chromosomes. That means all of the genes on the X chromosomes have two copies of them. Men have one X chromosome. And so, if they have a defective copy of an important gene on the X chromosome, they don't have any backup. Whereas women do. That might also play a role. Dr. Steven Austad, PhD. Dr. Anton Titov, MD. One of the things that we do know is this. As women age, one of the sex X chromosomes, is turned off in every cell of a woman's body, and it tends to be random. So when women are young, it's 50/50. They have the mother's X chromosome in some cells and the father's X chromosome. It's active in other cells. As women get older, though, one or the other of those X chromosomes starts to predominate in the blood and tissues. So is it that the better of the two X chromosomes is surviving better? And does that have something to do with women's survival advantage? We don't know. It's an intriguing question. And it's just started to be investigated. While we're talking about the different lifespans between different sexes, you also published on the prenatal sex ratio. 'Sex ratio: a major surprise' was the title of your paper. What are the surprises in prenatal sex ratios? And why is it important for longevity research? Well, so yeah, let me go into that. Let me mention one thing that I forgot to mention before, which reinforced the interest in sex differences. So we now know of about half a dozen drugs that if we give to mice, their food will make the mice live longer and stay healthy longer. Of those, all of them show a sex difference. Many of them only work in one sex don't work at all in the other sex, and even some genetic manipulations, where we knock out a gene and both sexes have a life-extending effect only in one sex. 

So there are some fundamental features. Now, prenatally the evidence for a long time has been that at conception, there were three male to every female embryos at conception time. Dr. Steven Austad, PhD. Dr. Anton Titov, MD. But that during gestation, more male fetuses died so that by the time they were born, they were just about the same. There was a few more males, like 105 males to every 100 females. Now that there's been new evidence that shows that that's not true. That at conception is pretty close to a 50/50 ratio. But during some parts of gestation, the sex ratio will fall, male fetuses will be dying more frequently. And in other parts, it's reversed. And it only reaches its final ratio just before birth. And this is interesting because it's been known for a long time that females survive better when they are born prenatally. For prematurely born infants, it's considered a risk factor to be a male infant. Again, that's something that seems to happen only just before birth. Dr. Steven Austad, PhD. Dr. Anton Titov, MD. But there's a clue there potentially for why women have this survival advantage. It turns out that understanding how survival varies prenatally can potentially tell us something about how it also that kind of bias persists postnatally. Because like I say, and I think I discovered this. I don't think anyone knew this before. that females survived better from zero to five, as well as later in life. It's very intriguing. The other intriguing part, though, brings up something you mentioned before, which is the difference between lifespan and healthspan. It turns out that later in life, women have worse health than men. They're more likely to be disabled or more likely to have difficulty with a lot of the activities that we need to do in later life. So one idea is that if we could make men live as long as women, there's about a five-year to six-year difference between that in the US. But if we could keep women as healthy late in life as men, that would be doing a great service to both sexes. Dr. Steven Austad, PhD. Dr. Anton Titov, MD.