by Angela Saini
In South Asia then, the mortality figures should be in favor of girls. That they’re not even equal but so far skewed in favor of boys means that girls’ natural power to survive is being forcibly degraded by the societies they are born into. “If you have parity in your survival rates, it means you aren’t looking after girls,” says Lawn. “The biological risk is against the boy, but the social risk is against the girl.”
Elsewhere, child mortality statistics bear this out. For every thousand live births in sub-Saharan Africa, ninety-eight boys compared with eighty-six girls die by the age of five. A study that Lawn and her colleagues published in the journal Pediatric Research in 2013 confirmed that a boy is 14 percent more likely to be born prematurely and more likely to suffer disabilities, ranging from blindness and deafness to cerebral palsy, when he’s at the same stage of prematurity as a girl. In the same journal in 2012 a team at King’s College London reported that male babies born very prematurely are more likely to stay longer in the hospital, die, or suffer brain and breathing problems.
“I always thought that it was physically mediated, because boys are slightly bigger, but I think it’s also biological susceptibility to injury,” adds Lawn. One explanation for more boys being born preterm is that mothers expecting boys are, for reasons unknown, more likely to have placental problems and high blood pressure. Research published by scientists at the University of Adelaide in the journal Molecular Human Reproduction in 2014 showed that newborn girls may be healthier on average because a mother’s placenta behaves differently depending on the sex of the baby. With female fetuses, the placenta does more to maintain the pregnancy and increase immunity against infections. Why this is, nobody understands. It could be because, before birth, the normal human sex ratio is slightly more skewed toward boys. The difference after birth might simply be nature’s way of correcting the sex balance.
But the reasons could also be more complicated. After all, a baby girl’s natural survival edge stays with her throughout her entire life. Girls aren’t just born survivors, they grow up to be better survivors, too.
“Pretty much at every age, women seem to survive better than men,” confirms Steven Austad, international expert on aging and chair of the biology department at the University of Alabama, Birmingham. He describes women as being more “robust.” It’s a phenomenon so clear and undeniable that some scientists believe understanding it may even hold the key to human longevity.
At the turn of the millennium, Austad began to investigate exactly what it is that helps women outlive men at all stages of life. “I wondered if this is a recent phenomenon. Is this something that’s only true in industrialized countries in the twentieth century and twenty-first century?” Digging through the Human Mortality Database, a collection of longevity records from around the world and founded by German and American researchers in 2000, he was surprised to discover that the phenomenon really does transcend time and place.
The database now covers thirty-eight countries and areas. But his favorite example is Sweden, which has kept some of the most thorough and reliable demographic data anywhere. In 1800 life expectancy at birth in Sweden stood at thirty-three years for women and thirty-one for men. In 2015 it was about eighty-three years for women and about seventy-nine for men. “Women are more robust than men. I think there’s little doubt about that,” he says. “It was true in the eighteenth century in Sweden, and it’s true in the twenty-first century in Bangladesh, and in Europe, and in the US.”
I ask Austad whether women might be naturally outliving men for social reasons. It’s reasonable to think, for instance, that boys are generally handled more roughly than girls are. Or that more men than women take on risky jobs, such as construction and mining, which also expose them to toxic environments. And we know that in total across the world, far more men than women smoke, and that this habit dramatically pushes up their mortality rates. But Austad is convinced that the difference is so pronounced, ubiquitous, and timeless that it must mean features in a woman’s body underlie the difference. “It’s hard for me to imagine that it is environmental, to tell you the truth,” he says.
The picture of this survival advantage is starkest at the end of life. The Gerontology Research Group keeps a list online of all the people in the world who they have confirmed are living past the age of 110. I last checked the site in July 2016. Of all these “supercentenarians” in their catalogue, just two were men. Forty-six were women.
Yet we don’t know why.
“I’m absolutely puzzled by it,” says Steven Austad. “When I first started looking into this, I expected to find a huge literature on it, and I found virtually nothing. There’s a big literature on ‘Is this a difference between men and women?’ but the underlying biology of the survival difference, there’s very little on that. It’s one of the most robust features of human biology that we know about, and yet it’s had so little investigation.”
For more than a century, scientists have painstakingly studied our anatomy, even collected thousands of liters of horse urine to root out the chemicals that make men more masculine and women more feminine. Their search for sex differences has shown no boundaries. But when it comes to why women might be more physically robust than men—why they are better survivors—research has been scarce. Even now, only scraps of work here and there point to answers.
“It’s a basic fact of biology,” observes Kathryn Sandberg, director of the Center for the Study of Sex Differences in Health, Aging and Disease at Georgetown University, who has explored how much of a role disease has to play in why women survive. “Women live about five or six years longer than men across almost every society and that’s been true for centuries,” she explains.
“First of all, you have differences in the age of onset of disease. So, for example, cardiovascular disease occurs much earlier in men than women. The age of onset of hypertension, which is high blood pressure, also occurs much earlier in men than women. There’s also a sex difference in the rate of progression of disease. If you take chronic kidney disease, the rate of progression is more rapid in men than in women.” Even in laboratory studies on animals, including mice and dogs, females have done better than males, she adds.
By picking through the data, researchers like Kathryn Sandberg, Joy Lawn, and Steven Austad have come to understand just how widespread these gaps are. “I assumed that these sex differences were just a product of modern westernized society, or largely driven by the differences in cardiovascular diseases,” says Austad. “Once I started investigating, I found that women had resistance to almost all the major causes of death.” One of his papers shows that in the United States in 2010, women died at lower rates than men from twelve of the fifteen most common causes of death, including cancer and heart disease, when adjusted for age. Of the three exceptions, their likelihood of dying from Parkinson’s or stroke was about the same. And they were more likely than men to die of Alzheimer’s disease.
When it comes to fighting off infections from viruses and bacteria, women also seem to fare better. “If there’s a really bad infection, they survive better. If it’s about the duration of the infection, women will respond faster, and the infection will be over faster in women than in men,” says Sandberg. “If you look across all the different types of infections, women have a more robust immune response.” It isn’t that women don’t get sick. They do. They just don’t die from these sicknesses as easily or as quickly as men do.
One explanation for this gap is that higher levels of estrogen and progesterone in women might be protecting them in some way. These hormones don’t just make the immune system stronger but also more flexible, according to Sabine Oertelt-Prigione, a researcher at the Institute of Gender in Medicine at the Charité university hospital in Berlin. “This is related to the fact that women can bear children,” she explains. A pregnancy is the same as foreign tissue growing inside a woman’s body that, if her immune system was in the wrong gear, would be rejected. “You need an immune system that’s a
ble to switch from proinflammatory reactions to anti-inflammatory reactions in order to avoid having an abortion pretty much every time you get pregnant. The immune system needs to have mechanisms that can, on one side, trigger all these cells to come together in one spot and attack whatever agent is making you sick. But then you also need to be able to stop this response when the agent is not there anymore, in order to prevent tissues and organs from being harmed.”
The hormonal changes that affect a woman’s immune system during pregnancy also take place on a smaller scale during her menstrual cycle, and for the same reasons. “Women have more plastic immune systems. They adapt in different ways,” says Oertelt-Prigione. Many types of cells in the body are involved in immunity, but the kind that come into closest contact with viruses and bacteria are known as “T cells.” T cells inject substances into bacteria to kill them or secrete other substances that call more cells to action, some of which “eat up” infected cells and bacteria, like Pac-Man in the video game, she explains. Researchers know that a certain type of T cell that’s crucial to managing the body’s response to infections becomes more active in the second half of a woman’s menstrual cycle, when she’s able to get pregnant.
The discovery that sex hormones and immunity might be linked is fairly recent. In men, scientists have explored connections between testosterone and lower immunity, although the evidence is relatively thin. In 2014 Stanford University researchers found that males with the highest levels of testosterone, for example, had the lowest antibody response to a flu vaccine, which meant they were the least likely to be protected by the jab. As yet, though, it’s an unsubstantiated link. In women, the connection is far clearer; so much so that patients themselves have noticed these fluctuations. For years, doctors assumed that a woman’s immunity couldn’t be changing during her menstrual cycle. If she did report a difference in pain levels, doctors might dismiss it as premenstrual syndrome or some vague psychological complaint. It was only when these links were increasingly backed up by hard research that scientific interest was sparked and more research began to flourish.
This problem runs all the way through research into women’s health. If a phenomenon affects women and only women, it’s all too often misunderstood. And this is compounded by the fact that even though they’re good at surviving, women aren’t healthier than men. In fact, quite the opposite.
“If you could add up all the pain in the world, all the physical pain, I suspect that women have way, way more of it. This is one of the penalties of being a better survivor. You survive, but maybe not quite as intact as you were before,” says Steven Austad. Statistically, it could even explain why women seem proportionally sicker than men. “Part of the reason that there are more women than men around in ill health is to do with the fact that women have survived events that would kill men, and so the equivalent men are no longer with us.”
Another reason is that women’s immune systems are so powerful that they can sometimes backfire. “You start regarding yourself as foreign and your immune system starts attacking its own cells,” explains Kathryn Sandberg. Diseases caused in this way are known as “autoimmune disorders,” the most common of which include rheumatoid arthritis, lupus, and multiple sclerosis. “It’s kind of a double-edged sword with the immune system. In some ways it’s better to have a female immune system if you’re fighting off infection of any kind, but on the other hand, we are more susceptible to autoimmune diseases, which are very problematic,” she explains.
This isn’t to say autoimmune disease is always hardest on women. When men develop multiple sclerosis, they tend to get it worse. Women also survive with it longer than men do. Even so, of the roughly 8 percent of Americans who suffer from autoimmune diseases, estimates suggest that at least three-quarters are women.
“In autoimmune diseases, they almost all tend to get worse right before the menstrual cycle in women who are premenopausal,” says Sabine Oertelt-Prigione. There are theories postulating that the same way varying hormone levels may boost a woman’s immunity at different times of the month, they might also affect her experience of illness. According to some reports, for instance, women with asthma are at highest risk of an attack just before or at the start of their period. When estrogen and progesterone levels drop through the years following the start of menopause, a woman’s immunity advantage starts to drop away as well.
When it comes to viral infections, too, a woman’s strong immune response may be a problem as well as a benefit. Research on influenza by Sabra Klein, an immunologist at the Johns Hopkins Bloomberg School of Public Health, has shown that while women are generally hit by fewer viruses during an infection, they tend to suffer more severe flu symptoms than men do. She reasons that this may be because women’s immune systems mount sturdier counterattacks to viruses, but then suffer when the effects of these counterattacks upset their own bodies.
Women also tend to get more painful joint and muscle diseases in general, observes Austad. Part of this is due to autoimmune diseases that affect the joints, such as arthritis. The physical toll of childbearing and the hormonal changes of menopause may also leave women with more physical problems and disabilities, especially in later life. Bone density is known to fall in the short term after pregnancy and also after menopause. Weight gain is now, too, recognized as a symptom of menopause.
But the overall picture of pain and ill health is complicated. “Crossculturally women just report more physical limitations and more disabilities. It’s really widespread,” says Austad. When it comes to biological clues about the underlying reasons for this sex difference in disease or survival, however, he adds, “I don’t feel very confident of any explanation.”
It’s difficult to tear apart the effects of biology from other effects. Society and the environment can sometimes affect illness more than a person’s underlying biology. “Women are less likely to go to the hospital when they’re feeling chest pain than men,” explains Sandberg, who has looked at gender differences in heart disease in particular. Men’s and women’s health habits throughout the world differ in countless other ways. Oertelt-Prigione points out that where families eat collectively and food is scarce, women are sometimes the last to eat and the most likely to give up food, which can raise their risk of malnutrition. This in turn can affect their susceptibility to disease.
Not only a woman’s own behavior but that of others around her can also affect her health. From the second a girl is born, she’s placed in a different box. She may be handled differently, fed differently, and treated differently. This marks the beginning of a lifetime of differences in the way doctors and medical researchers approach her as well. Only recently, for instance, have doctors begun to acknowledge the severity of some women’s experience of period pain. In 2016, a professor of reproductive health at University College London, John Guillebaud, told a reporter that it can be “almost as bad as having a heart attack,” while admitting that period pain hasn’t been given the attention it deserves, partly because men don’t suffer from it. In 2015 a team of British researchers studying cancer diagnosis in the United Kingdom found that for six of the cancers that affect both men and women, including bladder and lung, it took longer for women to be diagnosed after going to doctors with their symptoms. For gastric cancer, a woman waited on average a full two weeks longer for a diagnosis.
If there are deep-seated biological sex differences in health, and the differences aren’t largely due to society and culture, then scientists need to go deeper inside the body to find them.
“Females get sicker but males die quicker,” says Arthur Arnold, a professor at the University of California, Los Angeles. It’s an old adage bandied among his undergraduates. It reflects what doctors all over the world have observed, and Arnold is convinced this betrays the long roots of sex differences in health. He runs a laboratory studying the biological factors that make females different from males and edits the journal Biology of Sex Differences. His work has taken him beyond looking at organs and sex h
ormones and down to the fundamental level of the gene.
The human body is made up of trillions of cells. Every one of them has genetic information stored in chromosomes, which explain to the body how to build itself from the subtlest hormones all the way up to skin and bone. We have forty-six chromosomes in total, split into twenty-three pairs, and the roots of the genetic differences between men and women lie in our twenty-third pair, the “sex chromosomes.” In women, these are called “XX,” with one X chromosome inherited from each parent. Men’s sex chromosomes are called “XY,” with the X coming from the mother and the Y from the father. For a long time scientists assumed that these sex chromosomes were mainly concerned with reproduction and not much else. Today some, including Arnold, believe that the consequences of this seemingly tiny genetic difference may stretch much farther.
Each chromosome in a pair carries the same genes in the same locations, known as “alleles.” For a female with two X chromosomes, the allele for eye color from her father will be matched by another one for eye color in the same place from her mother. For males with XY sex chromosomes, however, a matching allele isn’t always there. X and Y don’t have the same genes in the same locations. In fact, the Y is far smaller than the X.