Naked mole-rats survive in low oxygen by metabolizing fructose like plants

The discovery could lead to treatments for heart attacks and stroke.

Naked mole-rats were already impressive: they’re a cold-blooded mammal that outlives other rodents by decades, seldom get cancer, and are unfazed by many types of pain. Now researchers have added a new ability to the list with the discovery that naked mole rats can survive long periods with very little oxygen. Thomas Park and colleagues exposed naked mole-rats to low oxygen conditions, enough to kill a human within minutes, and found that they released large amounts of fructose into the bloodstream, enabling the naked mole-rat to survive for at least five hours. The discovery could have implications for humans during times of extreme oxygen deprivation, for example during a heart attack or stroke.

We spoke to Park about the study, which appears in the journal Science.

ResearchGate: What motivated this study?

Thomas Park: There were already several clues that the naked mole-rat could be extremely tolerant to oxygen deprivation. It has been known for some time that the hemoglobin in their blood is very sticky for oxygen, able to grab oxygen molecules out of atmospheres with very low oxygen levels. Also, they reduce their need for oxygen by not generating body heat—they are the only cold-blooded mammal. Keeping warm takes a huge amount of energy which normally requires a huge amount of oxygen. The naked mole-rats also have a much lower metabolism compared to other mammals. All of these traits suggest that naked mole-rat physiology is geared for being able to survive periods of low oxygen.

Our first experiment was with five percent oxygen, which would be deadly for humans and laboratory mice (regular air has 21 percent oxygen). We had no idea how the naked mole-rat would respond, so we were ready to abort the experiment if things looked bad. But the naked mole-rat appeared fine after 15 minutes and even an hour. After 5 hours, we realized that five percent oxygen was not a problem for these guys so we decided to make 5 hours our limit.

Naked mole-rats can survive extended periods of absolutely no oxygen (at least 18 minutes). During that time, they greatly reduce their heart rate and respiration rate and their activity. They also release fructose into their blood which is carried to the brain and other vital organs.

RG: How do they use fructose?  

Park: When exposed to oxygen deprivation, these animals are able to use the simple sugar fructose to directly supply energy to brain cells and heart cells. Other mammals like humans use a different sugar called glucose to make energy. Normally, glucose is a better choice because you get more energy out of glucose. But glucose requires oxygen to make energy, while fructose does not. 99.99 percent of the time, glucose is a good choice because we live in an oxygen rich environment. On the other hand, naked mole-rats live in an oxygen poor environment. Hence, they have a very exaggerated fructose pathway with many fructose transporters on their brain cells, and a great amount of the enzymes used to convert fructose to energy, even in very low oxygen conditions.

RG: Why do naked mole-rats need to survive in low oxygen conditions?

Park: The crazy thing about naked mole-rats that distinguishes them from other subterranean mammals is that they live in very large colonies with up to 300 members. Where they live in Africa, the food that they eat—potato-like roots the size of a basketball—are scattered far and wide. A small number of animals digging in random directions would starve before they found one. But a colony of 300 animals can divide into many teams and dig in many directions at the same time. The likelihood of finding a root goes up, and naked mole-rats are very community minded and willing to share.

The downside of living with so many colony mates in a closed, underground tunnel system is that the animals use up much of the oxygen and they produce a great deal of excess CO2. This is particularly true in the nest chambers where many animals gather to eat, groom, and sleep.

RG: What applications could this study have for people?

Park: We might be able to use the same strategy during times of extreme oxygen deprivation, for example during a heart attack when oxygenated blood cannot reach the brain. Normally, we would have only a few minutes to reach medical help before our brain cells begin to die. If we could activate the fructose pathway, we could significantly extend that time window. We already have the same fructose transporters and enzymes, but in amounts too small to be useful. Now that we know about the fructose pathway, we will try to find ways of increasing the amounts of transporters and enzymes. Another interesting question is how the naked mole-rats use fructose without experiencing any of the negative effects of fructose such as obesity.

Naked mole-rats have evolved in an extremely different environment from most other mammals and they have had millions of years to figure out how to survive dramatic oxygen deprivation. Now it’s up to us to figure out how to apply the naked mole-rat solution to people.

Featured image credit: Thomas Park/UIC.