Immune to cancer, long-lived and really ugly

Author: Jovana Drinjakovic, 06/27/17

Angry female naked mole rat.
Credit: Buffenstein/Barshop Institute/UTHSCSA c/o Wiki Commons

They could well be the ugliest animals on the planet, but naked mole rats don’t get cancer or suffer decrepitude from old age. No wonder scientists are working hard to unlock the secrets of these bizarre-looking creatures that could teach us how to stave off disease and repair brains.

With large protruding teeth, squinting useless eyes and wrinkly pale skin with no hair, the naked mole rats don’t exactly look like nature’s superheroes. Yet this is what they are! These rodents live to a ripe old age of 30 years – ten times longer than mice that are of similar size. And they don’t get cancer, based on autopsies of thousands of animals that have died in captivity with no sign of tumours – except for a handful of examples.

But escaping cancer only partly explains why the naked mole rats live so long. They also don’t seem to age; unlike in the human world, the passing of time is not measured by the brittleness of arteries and bones or harrowing decay in the brain. So, how did these creatures become so special?

It’s worth remembering here that “nothing in biology makes sense except in the light of evolution,” as was famously said by Theodosius Dobzansky, a trailblazing Russian-American evolutionary biologist from the last century.

Looking at the naked mole rats’ lifestyle, their unusual biology starts to make sense. Native to East Africa, they live in stifling mazes of underground tunnels that they share with 200-300 relatives. It’s not just their eyesight that disappeared while adapting to a life in the dark with close cousins. They also lost any sense of pain, presumably to cope with a build-up of acid and other burning chemicals in their muggy home.

But the naked mole rat’s perhaps most distinct feature is a hairless body covered by pasty skin that’s remarkably stretchy, making it easier to scurry through narrow tunnels. And while this stretchiness may have evolved to aid movement, it also, by pure chance, holds clues to cancer avoidance.

A few years ago, scientists at Rochester University, led by Professors Vera Gorbunova and Andrei Seluanov, were puzzled to find that the medium in which they cultivated naked mole rat skin cells would become gooey over time. This turned out to be due to the cells secreting hyaluronic acid, or hyaluronan, a long stringy molecule that can retain water and turn liquid to gel. Because it boosts skin elasticity, it has become a favourite ingredient in anti-wrinkle beauty products, although the evidence that these potions make any difference is scant.

Hyaluronan is part of the extracellular matrix, a jelly-like rich mix of molecules that fills the space between the cells. What’s astonishingly different about the naked mole rat’s hyaluronan is that it is 10 times longer and more plentiful than its mouse and human counterparts, and makes the jelly that the cells sit in far more viscous.

This helped explain not only the amazing stretchiness of the mole rat skin, but also something that scientists had already known—that their cells divide less often than human and mouse cells.

“In naked mole rats, the cells are sitting more tightly in the extracellular matrix,” explains Gorbunova “and this prevents them from hyper-proliferating.”

The high density of the extracellular matrix could also limit the travel of other molecules secreted by the cells, such as growth factors, that may call on other cells to start dividing. It basically dampens the molecular chatter that can spur uncontrolled growth—and eventually cancer.

Gorbunova is now testing if the longer version of the hyaluronan can help mice avoid cancer. They have bred mice that produce the naked mole rat’s hyaluronan, in addition to their usual shorter form. The bred animals are only one-and-a-half-years-old, halfway through their lifespan, and it will take more time to see if the longer hyaluronan delays tumours and prolongs life. But, early and unpublished data suggest that the naked mole rat’s hyaluronan does slow down the division of mouse cells, Gorbunova said.

The team is also beginning to study the naked mole rats’ stem cells in the bone marrow, which is loaded with hyaluronan and is where all blood cells are made. They think that the animals have more blood stem cells and they use them differently than mice, but Gorbunova warned that it’s still too soon to draw any firm conclusions because “methods to analyze stem cells are still in infancy for naked mole rats.”

Meanwhile, scientists in Japan have already reported unusual properties of mole rat skin cells that were reprogrammed into stem cells, or induced pluripotent cells. The mole rat’s reprogrammed cells did not form tumours when injected into mice, unlike those from other species. In this case, cancer resistance was not driven by hyaluronan; instead, the researchers found that the reprogrammed cells dialed up a tumour-supressor gene that stopped them from dividing.

What about the naked mole rats’ resistance to the usual ailments of old age?

Central to their underground life is the ability to cope with very little oxygen and they achieve this through a slew of metabolic and respiratory adjustments. Earlier this year, scientists from Chicago and Berlin discovered that naked mole rats can survive for an unbelievable 18 minutes without any oxygen, whereas most mammals suffer brain damage and die within a few minutes.

When oxygen is scarce, naked mole rats switch to an unusual arm of anaerobic, or oxygen-free metabolism. Instead of glucose, they start metabolizing another sugar, fructose, in a way that has never before been seen in animals. How naked mole rats stay intact during hypoxia could help guide the strategies to reduce brain damage in stroke patients, for example.

Curiously, another long-lived mammal that spends large chunks of time without oxygen is a blue whale, which can spend a couple of hours underwater and is thought to live 100 years. “There may be a link between hypoxic stress and longevity, but we don’t know what that is yet,” says Gorbunova.

Although oxygen metabolism gives animal cells the energy they need, it also produces byproducts known as free radicals that are harmful to the cells. It could also be that a lifetime of inhaling little oxygen protects the cells from this kind of damage.

Another unusual feature of naked mole rats is that their cells produce better proteins—molecules that make up cells and do most of the work in them. Diseases of old age, like Alzheimer’s for example, occur when proteins no longer work properly and clump together to gunk up the cells. Not only do their proteins have fewer miscues to begin with, but they also have heightened quality control mechanisms for purging busted proteins that could cause disease.

The list of wonders goes on and for more naked mole rat curiosities see here. It turns out that being ugly and never seeing the sun is not such a bad thing after all.

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Jovana Drinjakovic

Jovana Drinjakovic

Jovana Drinjakovic is a science writer with a background in cell and developmental biology. After completing her PhD in Cambridge (the old one) and a postdoc at the Hospital for Sick Children in Toronto, Jovana decided to switch gears and enrolled into a journalism course at the University of Toronto’s Munk School of Global Affairs. Her writing appeared in the Globe and Mail, the National Post, Dallas Morning News and U of T Magazine. Most days Jovana writes about discoveries at U of T’s Donnelly Centre, where she works as a communication specialist.
Jovana Drinjakovic

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