In a small room in the lab-animal wing of the University of Illinois at Chicago, biologist Thomas Park peers into a plastic box full of naked mole rats. "You guys are so cute," he says softly, in a voice usually reserved for babies or puppies.

Park is mistaken. Naked mole rats are not cute. They're bald, wrinkled and purply pink, with tiny near-blind eyes and huge yellow teeth. Ranging from the size of a large mouse to that of a small rat, these odd rodents are among the strangest looking mammals on the planet. But don't judge a naked mole rat by its unfortunate appearance. These bizarre creatures could help us tackle all sorts of human maladies, from cancer and stroke to pain relief and aging.

A dozen species of mole rat exist, all native to sub-Saharan Africa. Naked mole rats stand out, though, not least because they appear completely bald. They're also extremely social, living underground in elaborate networks of tunnels and chambers in groups of up to 300. Here in the lab, Park mimics their burrow system by connecting several dozen plastic boxes with long tubes. The animals spend their days pushing bedding around the tubes and nibbling on bits of sweet potato.

"Naked mole rats are a really odd mammal species," Park tells me. "Their social structure is like that of insects." Akin to bees and ants, they live in a eusocial society in which a single breeding queen churns out all the offspring, with help from between one and three kings. The rest of the animals work for a living: soldiers defend the colony against predators and rivals, while housekeepers forage for root vegetables and tidy up the tunnels.

This unusual social arrangement is what first drew scientists to study the wrinkled rodents. "For many years, most of the studies were on their behavior," says Rochelle Buffenstein, a physiologist at the University of Texas Health Science Center, San Antonio. In time, though, researchers couldn't help but notice another intriguing aspects of naked mole rat biology. "They are incredibly long-lived creatures," she says.

In general, lifespan tends to correlate with body size. Large animals, on average, live longer than small ones. However, while mice and rats are lucky to survive three years in captivity, similar-sized naked mole rats live three decades, making them the longest-lived rodents on Earth. That's not all. They also maintain excellent health well into their sunset years. Their bones remain strong, their bodies stay fit and they don't show signs of heart disease or mental decline. Breeding females continue to produce pups right up to the end and, to top it off, naked mole rats don't even get cancer.

Naturally, scientists are eager to understand the secrets of this small, bald Methuselah. Buffenstein, who has been studying naked mole rats for 30 years, is among those looking for molecular explanations for their astounding longevity. She began by investigating their response to oxidative stress, one of the leading theories of how the aging process works.

According to this theory, oxygen-containing free radicals damage the molecules of the body, causing them to deteriorate over time until they stop functioning altogether. This oxidative damage, as it is known, is apparent as extra molecules that attach to DNA and proteins "like chewing gum stuck to the bottom of a shoe," Buffenstein says. If oxidative stress is truly an important mechanism of ageing, she predicted, naked mole rats should have lower rates of oxidative damage than more short-lived species.

To her surprise, Buffenstein found the opposite: more telltale oxidative damage in 6-month-olds than in mice of the same age. Remarkably, however, the damage had no obvious impact on the their well-being.

KEEPING IN SHAPE

Why is this? To find out, Buffenstein took a closer look at the 3D structure of proteins, which is critical to their functioning. Mouse proteins begin misfolding very quickly after suffering oxidative damage, a kind of anti-origami that causes them to stop working properly. But naked mole rat proteins can withstand significantly more damage before they lose their shape (Proceedings of the National Academy of Sciences).

"We think (protein stability) is a very important component of their extraordinary longevity," she says. "If your proteins maintain their integrity, if they have the mechanisms to protect themselves, it doesn't matter what stress comes along."

Another factor that helps naked mole rats reach an advanced age is their remarkable ability to avoid cancer. Nearly all mice have cancerous cells lurking in their bodies by the time they die but cancer has never been seen in a naked mole rat.

"Every time one of our animals die, we try to figure out what they die of," Buffenstein says. "We haven't seen a tumor, we haven't seen lesions, we haven't seen signs of lymphoma. We know they don't get age-related cancer."

To understand why, Buffenstein and her colleague Peter Hornsby introduced cancer-causing genes into cells from rats, mice, humans and naked mole rats. They then inserted the altered cells into immune-compromised mice. In two to four weeks, the mice injected with modified cells from rats, mice and humans developed highly invasive tumors. "In the case of naked mole rats, six months lapsed and there were still no tumors," Buffenstein says.

The abnormal cells were still alive but had stopped replicating. "We think mole rats have better surveillance mechanisms to assess what's going on in their DNA," she says. When things go awry, the deviant cells are essentially locked away, unable to replicate and cause tumors (Aging Cell).

This is probably just one of several tricks that allow these animals to avoid cancer. Another possible mechanism being investigated centers on how cells multiply. When cultured in a Petri dish, cells from both mice and humans multiply until they form a single dense layer. At that point, they stop dividing, halted by a process called contact inhibition. In cancerous tissues, however, the abnormal cells continue to multiply, piling up and growing out of control.

By contrast, when Vera Gorbunova at the University of Rochester in New York tried to grow naked mole rat cells to study their contact inhibition, she had trouble getting them to grow at all.

"The cells of the naked mole rat would never completely fill the plate," she says. That's because they stop multiplying at much lower densities than mouse or human cells. "They don't like touching each other too much," she says.

In humans, a gene called p27 is behind contact inhibition. But in naked mole rats, Gorbunova and her colleagues found that a second gene, p16, also plays a part. This unique early contact inhibition "is one extra barrier that prevents these cells from becoming cancerous", she says (Proceedings of the National Academy of Sciences).

This finding could be an important step towards new cancer therapies. Gorbunova and her colleagues are now trying to decipher the extracellular signals that prompt early contact inhibition. In theory, such a signal might be co-opted to stimulate the process in human cells, and prevent tumors from forming. "If this is some kind of extracellular molecule, then we could actually apply it to people as an injection or a drug," she says.

Cancer and aging are only the tip of the iceberg as far as the naked mole rat's peculiar biology is concerned. The rodent's neurobiology is also of interest, as Park is discovering. Setting out to better understand their sense of touch, he stumbled across something surprising: they lack a receptor that transmits messages about chemical pain. Inject lemon juice or the essence of chili pepper, capsaicin, beneath the skin of a mouse's paw, and it will shake and lick it like crazy.

"If you do that with naked mole rats, they don't do anything," Park says. "They couldn't care less." Naked mole rats do feel acute pain such as cuts and burns, he says, but they're impervious to chemical pain (PLoS Biology).

This finding is particularly significant because the nerve fibers associated with chemical pain are also involved in post-traumatic pain in people -- precisely the type of discomfort researchers would like to eliminate.

"It's OK to have pain sensation to tell you to get your hand off the stove, or to stop exercising because your knee is in trouble," says Park. "But post-surgical pain, or joint pain after a knee injury, those types of pain we could do without. The naked mole rats are laying the groundwork for potentially finding new ways to treat the kinds of pain we don't want."

Though the applications are intriguing, Park's own interests are more basic: Why would naked mole rats lack this type of pain? The answer, he suspected, stemmed from their unusual habitat. Although many animals live underground, few live in such close quarters and in such large numbers as naked mole rats. The air in their burrows is rank, with low oxygen levels and extremely high levels of carbon dioxide and ammonia. While normal air is about 0.03 percent CO2, levels in naked mole rat burrows can easily reach 5 percent or more -- an intensity that would sting our eyes and noses and leave us gasping for air. The rodents, however, are unaffected.

"They will stay away from 10 percent CO2, but they're perfectly happy to wallow around in 5 percent," Park says. They are also unfazed by ammonia fumes. "It turns out that high levels of CO2 and ammonia affect the types of nerves that the naked mole rats have disconnected," he says. "I think that's the evolutionary driving force to disconnect these pain nerves."

This isn't the only effect the naked mole rat's burrows have on their physiology. The low oxygen levels are just as important. Fresh air contains about 21 percent oxygen, whereas levels in the burrows can be as low as 12 percent in captive colonies, and are probably much lower in the wild. Park has found that naked mole rat brains are incredibly resistant to oxygen deprivation, with their brain tissue able to bounce back after 30 minutes without the gas (NeuroReport). Understanding the protective mechanisms at play could lead to better treatments for people whose brains have been deprived of oxygen during a heart attack or stroke.

SOCIABLE BY NATURE

Medical benefits may even arise from continuing research into naked mole rat behavior. Previous studies in voles and other mammals have shown that behaviors such as monogamy and maternal performance can be explained, in part, by genetic differences that influence the patterns of certain hormone receptors in the brain.

To find out whether naked mole rats' sociability has a genetic factor, Chris Faulkes at Queen Mary, University of London and colleagues compared their brains with those of the solitary cape mole rat. They were looking for receptors that bind to the "cuddle chemical" oxytocin.

The team found that the naked mole rat has far more of these receptors in several brain regions including the nucleus accumbens, an area known as the brain's pleasure centre, and assume this is under genetic control (Journal of Comparative Neurology).

"It's a good example of a change in a gene giving a change in complex behavior," says Faulkes. Changes in the oxytocin receptor in humans are associated with certain kinds of autism, he adds, so the finding could have direct implications for humans.

The possibilities don't end there. Naked mole rats do not experience menopause or osteoporosis, so perhaps they could help researchers develop osteoporosis treatments without the side effects of hormone replacement therapy. And, as they spend 24 hours a day in the dark, naked mole rats don't follow normal circadian rhythms. Studies of their sleep patterns could feasibly help treat disordered sleep in humans.

Even their incisors are fascinating. Instead of staying put in their mouths, they grow right through the skin of the lips, something of great interest to prosthetics designers.

Traditional prosthetics put pressure on delicate soft tissue causing sores and cell death, so a team led by Gordon Blunn and Catherine Pendegrass at University College London are testing new prosthetics that are attached directly to the bone of an amputated limb. To avoid infection, however, there needs to be a permanent seal where the skin meets the metal implant. This is where naked mole rats come in. Understanding the interface between their teeth and skin may help in the development of new coatings or structures that can be applied to the prosthetics.

With so much to offer science, it is no surprise that naked mole rats are becoming more common in labs. But they're still a quirky choice, and not without their challenges. Unlike mice, the naked mole rat hasn't had its genome sequenced yet -- though it is in the works. "With naked mole rats, we have to start from scratch with many things," Gorbunova says. "It's not very convenient, but I think it's definitely worth it."

Before I leave Park, he plucks one of his animals from its box and sets her on a nearby table. She waddles awkwardly before falling over sideways, as if she has had one too many cocktails. They are used to being propped up by their tunnel walls, Park explains, and don't get around well in open spaces. I must admit, her ugly mug and comedic gait are endearing. Naked mole rats are growing on me. I might not go so far as to call them cute, but I am impressed. If these creatures live up to their promise, I certainly won't be the only one.

 

 

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