Understanding Sex Differences in Longevity and Healthspan

Jump To Section

• Female Survival Advantage
• Hormonal Influences on Aging
• Genetic Factors and the X Chromosome
• Prenatal Sex Ratio Surprises
• Lifespan vs. Healthspan Disparity
• Full Transcript

Female Survival Advantage

Dr. Steven Austad, MD, begins by highlighting a well-known but profound observation. Women consistently outlive men in every country and every historical period with reliable data. This female survival advantage persists through extreme conditions like droughts, famines, and pandemics. Dr. Steven Austad, MD, notes that men die at higher rates from nearly all top causes of death. The single notable exception is Alzheimer's disease, which remains an area of active investigation.

Hormonal Influences on Aging

A primary hypothesis for this longevity gap involves reproductive hormones. The idea that estrogen is protective and testosterone might be toxic is a common theory. Dr. Steven Austad, MD, cites intriguing historical evidence from studies on castrated men. Research involving eunuchs from the Korean court and individuals in mental health homes showed a significant effect. Castrated males lived 10 to 20 years longer than their intact counterparts, suggesting a powerful hormonal influence on male lifespan.

Genetic Factors and the X Chromosome

Beyond hormones, Dr. Austad points to fundamental genetic differences between the sexes. Women possess two X chromosomes, while men have one X and one Y chromosome. This provides women with a genetic backup system; if one X chromosome has a defective gene, the other can often compensate. Dr. Steven Austad, MD, describes a fascinating phenomenon where one X chromosome is randomly inactivated in each cell of a female's body. He notes that as women age, one X chromosome begins to predominate in tissues, potentially indicating a selection for the healthier chromosome, which may contribute to their survival advantage.

Prenatal Sex Ratio Surprises

The conversation with Dr. Anton Titov, MD, shifts to prenatal development and its implications for longevity research. Dr. Steven Austad, MD, discusses the prenatal sex ratio, correcting a long-held belief that conception heavily favors males. New evidence shows the ratio at conception is nearly 50/50. However, the survival of male and female fetuses fluctuates throughout gestation. Male fetuses experience higher mortality rates at certain stages, making prematurity a significant risk factor for male infants. This prenatal survival bias offers crucial clues about the biological mechanisms that extend into postnatal life.

Lifespan vs. Healthspan Disparity

Dr. Steven Austad, MD, makes a critical distinction between lifespan (how long one lives) and healthspan (how long one lives in good health). While women live longer, they often experience worse health in later life compared to men. They are more likely to suffer from disabilities and have difficulty performing daily activities. Dr. Austad posits that the ideal goal for medical science is twofold. The first goal is to extend the male lifespan to match the female lifespan. The second, equally important goal is to extend the female healthspan to match the male healthspan, thereby improving quality of life for everyone.

Full Transcript

Dr. Anton Titov, MD: 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?

Dr. Steven Austad, MD: Yes, so differences in health and sex, and health and aging. 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.

It's true that women live longer. They've lived longer in every country and in every historical period that we have good evidence for. 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.

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. 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.

One of the interesting things about that study is you could compare those with other members of the court, so same socioeconomic 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.

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 is if there's more to it than that.

I mean, 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. 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.

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 active in some cells and the father's X chromosome 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.

Dr. Anton Titov, MD: 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?

Dr. Steven Austad, MD: 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. We now know of about half a dozen drugs that if we give to mice, they 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 and 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 work 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. But that during gestation, more male fetuses died so that by the time they were born, they were just about the same.

There were a few more males, like 105 males to every 100 females. Now there's been new evidence that shows that that's not true. At conception, it's 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. 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. 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 that kind of bias persists postnatally.

Because, like I say—and I think I discovered this; I don't think anyone knew this before—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.