Naked mole rats are the superheroes of lab animals. They show few signs of aging, are resistant to some types of pain, and almost never get cancer. Now, scientists have discovered another superpower: The animals can survive more than 18 minutes without oxygen. They do that by essentially switching their bodies from using one fuel to another—a strategy that might point to new ways of combatting strokes and heart attacks in people.
“This is an exceptional feat for a mammal,” says Grant McClelland, a comparative exercise physiologist at McMaster University in Hamilton, Canada, who was not involved in the work.
Naked mole rats are unusually resistant to air containing high levels of carbon dioxide or little oxygen. The mouse-size hairless mammals live in colonies of up to 300 individuals in underground burrows where oxygen can be scarce.
To find out just how little oxygen they need, Thomas Park, a neuroscientist at the University of Illinois in Chicago, and Gary Lewin, a physiologist at the Max Delbrück Center for Molecular Medicine in Berlin, put naked mole rats and mice in a chamber with no oxygen. Mice died in less than a minute. Not so for the naked mole rats. Their heartbeat slowed from 200 to 50 beats per minute, and they quickly lost consciousness. But even after 18 minutes in the chamber, they recovered completely when exposed to normal air, the researchers write today in Science.
The trick may have to do with how naked mole rats metabolize sugar. Humans and other mammals break down the sugar glucose to generate energy in a multistep process called glycolysis. That process requires oxygen; without it, byproducts such as lactate build up that inhibit the first steps of glycolysis, and energy production ceases. Energy stores are quickly depleted, especially in the brain, and cells start dying.
Looking for chemical changes in the oxygen-deprived naked mole rats, the researchers found sharply higher levels of two sugars in the blood, fructose and sucrose (a molecule consisting of fructose and glucose). And compared with other mammals, those mole rats also had higher levels throughout the body of both GLUT5—a molecule that transports fructose into cells—and an enzyme that converts fructose into a form that can enter glycolysis. “Together this allows the naked mole rat to use fructose as fuel instead of glucose when there is no oxygen,” Lewin says.
Because fructose enters glycolysis at a later stage, energy production can go on if no oxygen is present and the first steps of glycolysis are blocked. According to McClelland, even fish or turtles that can survive long periods without oxygen have not modified glycolysis in that way. “It is a great example of evolution finding different solutions for the same or similar environmental challenges,” he says.
“I’m fascinated by this glucose-to-fructose switch,” says Rochelle Buffenstein, a biologist at Calico, a research company in South San Francisco, California, that former Google board member Arthur Levinson founded to combat aging. Buffenstein has studied naked mole rats for more than 30 years and says the animals still manage to surprise her. Researchers should start to look whether other animals in low-oxygen environments have evolved to use fructose that way, she says, adding, “there’s a whole world of wonderful, crazy critters out there.”
Still, how important the switch to fructose is for the animals’ survival isn’t clear, cautions Göran Erik Nilsson, a comparative physiologist at the University of Oslo. Other mechanisms such as slowing down metabolism play a role, as does the mole rats’ unusually low body temperature, a cool 30°C.
Better understanding the mole rat’s energy switchover will be key to any hope of somehow using it to help humans. During a stroke or a heart attack, for example, oxygen flow to the brain is interrupted and brain cells begin to die within minutes, Park says. “If we could activate the fructose pathway, we could significantly extend that time span,” he predicts.
“I’m very excited by this paper,” Buffenstein says. “I’m looking forward to seeing what happens next.”
With reporting by Elizabeth Pennisi.