As the novel coronavirus cuts its relentless swath across the globe, doctors have identified one grim constant: COVID-19 has men, more than women, in its sights.
In Italy, men account for at least 70 percent of all coronavirus deaths. While South Korea has seen more confirmed COVID-19 cases in female patients than in males, a higher percentage of men have been felled by it. Here in New York City, more men than women are testing positive for coronavirus, with 55 percent of all cases. They also are dying of it at even higher rates. As of Friday, 1,159 men in the five boroughs had been killed by COVID-19 — 62 percent of the city’s 1,867 deaths.
The phenomenon has stumped medical experts. In their rush to make sense of the data, many are pointing fingers at men and their behavior. Some speculate that higher male smoking rates leave them vulnerable to the respiratory infection. Others guess that men are blowing off social-distancing guidelines, or are neglecting to wash their hands.
“I find that so offensive,” genetic researcher Sharon Moalem, MD, told The Post. “Talk about blaming the victim.”
“Sure, there are some behaviors that might affect the number of infections,” he said. “But why should poor hand-washing lead to death for a patient who’s already in intensive care? It’s ridiculous.”
In fact, the coronavirus’ bull’s-eye on men is consistent across age groups, regardless of underlying risk factors.
“What we are actually seeing is that males do not do well once infected,” Moalem said. “So it comes down to genetics. There is a genetic component to this illness.”
As a clinical researcher studying genetic disease, Moalem spent years working with patients at both ends of the human life span — from babies in the neonatal intensive care unit to seniors grappling with Alzheimer’s. In both groups he noticed that his female patients were more resilient than males, better at fighting off infections and recovering from injuries.
“The hardest thing a human being can do is surpass the age of 110,” he noted. “And 95 percent of those supercentenarians are women. Meanwhile, around the world, more girls than boys make it to their first birthdays.”
That brought Moalem to a startling conclusion contradicting centuries’ worth of conventional wisdom: Men, not women, are the weaker sex.
In “The Better Half” (Farrar, Straus and Giroux), out Tuesday, Moalem explains that from the time they are still in the womb to their final breaths, women’s immune systems outperform those of men — an inherent advantage that lengthens their lives and improves their overall health.
And when it comes to outwitting COVID-19, Moalem says, women’s genes provide an even bigger edge.
With this virus, there is immense risk simply due to the fact of being male.
“It’s not just that females have a stronger immune system to fight this infection,” he said. “It’s that their genes give them a better defense at the cellular level.”
Every human, male and female, carries a set of 46 chromosomes in our cells. One of those 23 chromosome pairs determines a human’s biological sex. A man’s cells contain an X chromosome inherited from his mother and a Y chromosome provided by his father. A woman’s cells carry two X chromosomes — one from each of her parents.
The genes within our chromosomes contain the code that builds our bodies. The Y chromosome, with only about 70 genes, is a specialist that fashions the male reproductive system. But the X chromosome, with nearly 1,000 genes, does much more.
“The X chromosome has the genes that go into making the brain and the immune system, the two crucial things you need to survive as a human being,” Moalem said.
Both of a female’s X chromosomes are present in all her cells. But within each cell, only one of the X’s calls the shots. Half of a woman’s cells are dominated by the X chromosome that came from her mother, half by the X contributed by her father.
“That genetic diversity is really valuable,” Moalem explained. “One of the immune system’s most important weapons is the ability to recognize a virus. Well, genes on the X chromosome are involved in viral recognition. Right away, women have two different populations of immune cells that are best at spotting invaders.
“Meanwhile, maybe the other X has a gene that’s very good at identifying and killing infected cells,” he said. “So women’s immune cells function like a tactical unit. They specialize, then they interact and cooperate to fight the invaders.”
Men, with their single X chromosome, have a far less nimble immunological army at their command.
“As a man, I don’t have all those options,” Moalem said. “I can only hope that my one X has the genes that can recognize the virus — and can kill it, too.”
It gets worse for men in the age of COVID-19: The new coronavirus takes direct aim at their single-X vulnerability.
“What we researchers are seeing right now is the way this coronavirus gets into our lung cells,” Moalem said. “It has a key: a spike protein we think it uses to break in. And the lock it picks to enter is called ACE2” — an enzyme attached to the outer surface of the cell membrane.
“The gene that makes ACE2 is on the X chromosome,” he continued. “So if the coronavirus has the right key, it can unlock every one of a male’s lung cells. But females have two X’s — so half of their lung cells use one ACE2 lock, and the other half use a slightly different ACE2 lock. The chance that the virus has the perfect key to unlock both of them is not great. So that’s another enormous advantage for females.”
The virus’ lock-picking action damages the ACE2 so badly that it can no longer perform one of its crucial functions: preventing the buildup of fluid in the lungs during the infection.
“It’s the lungs filling up with fluid that happens in COVID-19 that can lead to the breathing difficulties experienced by so many,” Moalem said. “The severest lung injury we’re seeing with this infection is not likely to occur unless all your locks get picked. In females, the virus can’t usually get into enough of their cells to do that amount of damage — and that may be the reason why we’re seeing so many men dying.”
If that idea is correct, he said, we should expect more tragedies like that of the Fusco family of New Jersey, who lost four closely related members — 73-year-old matriarch Grace Fusco, two of her sons, and a daughter — to the coronavirus last month.
“We will likely see siblings or families that are particularly susceptible to this virus, because their cells share the same lock that the coronavirus is picking,” Moalem said. “We will see young people succumbing very quickly, very likely because they were born with a genetic version of the ACE2 lock that the coronavirus easily picks.”
And yet he sees reason to hope as research laboratories around the world home in on ACE2 to thwart the coronavirus’ attack.
“In that effort we can learn from the superimmunity of females,” he said.
Moalem’s own lab was in the midst of investigating new antibiotics when the crisis hit.
“We quickly switched our research efforts to find out if we can repurpose a drug that already exists,” he said. “There are a lot of drugs available, drugs whose safety profile we know, that could be used. I’m hopeful we can find something already in the toolkit that will be effective.”
Until then, he said, understanding the genetic risk factors of COVID-19 should spur us to safeguard those who are most in danger.
“We should be shielding all our seniors, but we should actually be protecting our male elders most of all,” he said. “With this virus, there is immense risk simply due to the fact of being male.”
DOUBLE X MARKS THE SPOT
The homogenous chromosomes benefit other animals too.
Human females are not the only ones that benefit from the double-X advantage. Across the animal kingdom, in all kinds of creatures whose sex is determined by their chromosomes, researchers are learning that the sex that has the doubled chromosome is almost always the one that lives longer.
“Essentially I’m proposing a new biological law,” genetic researcher Sharon Moalem told The Post. “The sex that gets two of same chromosomes will have an immense genetic advantage.”
Moalem calls it the “Law of Homogameity” (same-gene).
In a study published just last month, researchers from Australia’s University of New South Wales found new evidence to support his thesis. Biologists analyzed life-span data on 229 different animal species — mammals, birds, insects, fish, spiders, and more.
“We found that across that broad range of species, the heterogametic sex does tend to die earlier than the homogametic sex, and it’s 17.6 percent earlier on average,” lead researcher Zoe Xirocostas said.
It isn’t always the female of a species that gets the edge. Birds, some reptiles and butterflies don’t have the X and Y chromosomes that humans and other mammals share. Instead, they have what’s called a ZW sex-determination system. Female birds’ cells contain Z and W chromosomes; males get the double-Z.
Just as Moalem suspected, it’s the males in those animal species that gain the longevity edge.
Across the animal kingdom, these creatures benefit from a double chromosome hit …
- Female lions typically live to 15 years compared to male lions’ 12.
- Female chimps can expect to reach age 39, while males usually live 7 years less.
- Female purse-web spiders live to an average age 8, while males typically get to 4.
- Male chickens, like many other birds, have a double-Z chromosome, which extends their life span to 15 years while females reach age 8.
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