Pitch dark, dank, and seething with saber-toothed, sausage-shaped creatures, the world of the African naked mole-rat is a hostile habitat. In the 1980s, scientists made the remarkable discovery that naked mole-rats live like termites with a single, dominant breeding queen and scores of nonbreeding adult helpers that never leave their natal colony. But the bizarreness doesn’t stop there. Naked mole-rats, unlike other mammals, tolerate variable body temperatures, attributed to their lack of an insulatory layer of fur. Their pink skin is hairless except for sparse, whisker-like strands that crisscross the body to form a sensitive sensory array that helps them navigate in the dark. Both the naked mole-rat’s skin and its upper respiratory tract are completely insensitive to chemical irritants such as acids and capsaicin, the spicy ingredient in chili peppers. Most surprisingly, they can survive periods of oxygen deprivation that would cause irreversible brain damage in other mammals, and they are also resistant to a broad spectrum of other stressors, such as the plant toxins and heavy metals found in the soils in which they live. Unlike other mammals, they never get cancer, and this maintenance of genomic integrity, even as elderly mole-rats, most likely contributes to their extraordinarily long life span. In contrast to similar-size mice that only live 2–4 years, naked mole-rats can survive and thrive, maintaining normal function and reproduction, into their 30s.

Brain tissue of naked mole-rats remains functional with no oxygen supply for more than three times as long as brain tissue of laboratory mice.

The current hypotheses for the existence of this suite of unusual features center around the equally unusual lifestyle traits of the naked mole-rat. (See illustration on page 33.) Naked mole-rats live in large family groups in elaborate underground burrows. Although they are protected from large temperature fluctuations as well as from predators and pathogens, they have to contend with low oxygen and high carbon dioxide levels, due to the large number of individuals—usually 100 to 300—living and respiring in close quarters under poorly ventilated conditions. The unusual ecology and social structure of the naked mole-rat make this an exciting system for understanding evolution and specialization, and details of the molecular mechanisms underlying the mole-rat’s unusually good health are providing insights into human disease.

No oxygen? No problem!

Most mammalian brains, including those of humans, start to suffer damage after just 3–4 minutes of oxygen deprivation. This is because brain tissue does not store much energy, and a steady supply of oxygen is needed to generate more. Hence, when the oxygen supply to the brain is reduced or blocked, brain cells run out of energy, and damage quickly ensues. This is a major concern for victims of heart attacks and strokes, in which the blood supply to the brain is interrupted. Brain tissue of naked mole-rats, on the other hand, remains functional with no oxygen supply for more than three times as long as brain tissue of laboratory mice. And when the oxygen level is restored, brain tissue from naked mole-rats frequently recovers fully, even after several minutes of inactivity.1

This remarkable ability no doubt stems from the challenge that all subterranean animals face: low oxygen levels because of poor air exchange with the surface. Oxygen depletion is even more pronounced for naked mole-rats because they live in large groups, with many individuals sharing the same poor air supply, and gas exchange is limited to diffusion or air turbulence caused by animals moving in the tunnels. So how do mole-rats survive in such smothering conditions?

Naked mole-rats display several physiological adaptations for survival in a low-oxygen environment. The hemoglobin in their red blood cells has a higher affinity for oxygen than that of most other mammals, meaning that their blood is better at capturing what little oxygen there is. They also have a greater number of red blood cells per unit volume. In addition, their mass-specific metabolic rate is only about 70 percent that of other rodents, so they use oxygen at a slower rate. But when it comes to the brain, naked mole-rats protect themselves by borrowing a strategy used by the brains of infants.

Infant mammals, including humans, are known to be much more tolerant of oxygen deprivation than older juveniles or adults. It turns out that calcium is a key factor in this tolerance. Normally, calcium ions in our brain cells play vital roles, including helping memories form. But it’s a delicate balance: small amounts of calcium are essential for brain function, but too much calcium makes things go haywire. When nerve cells are starved of oxygen, they no longer have the energy to regulate calcium entry, resulting in an influx of too much calcium, which poisons the cells. This is the primary cause of neuronal death during oxygen deprivation.

In the last decade or so, researchers discovered that adult and infant brains express different calcium channels in their cell membranes. Calcium channels in infants actually close during oxygen deprivation, protecting the brain cells from calcium overdose in the womb, where the baby gets much less oxygen. After the baby is born, however, oxygen is plentiful, and these channels are largely replaced by ones that open in response to oxygen deprivation, often leading to cell death.

Recent studies on naked mole-rats show that this species retains infant-style calcium channels into adulthood.2 Accordingly, calcium-imaging techniques show that oxygen deprivation leads to much less calcium entry into the brain cells of adult naked mole-rats compared to other adult mammals.3 These findings suggest a new strategy that may help human victims of heart attack and stroke: increase the numbers of infant-style calcium channels in the brain. Brain cells of adult humans actually have some of these channels already, just not enough to protect them during oxygen deprivation. If a drug is designed to quickly upregulate production of infant-style channels in the brains of heart attack and stroke victims, it could provide valuable protection during a time when a steady supply of oxygen-rich blood is not reaching the brain.

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