Naked mole-rats can teach us about treating cancer

Naked mole-rats seem to defy ageing and appear immune to cancer. Scientists are studying these strange creatures to understand how humans can live healthier, longer lives.

It’s no secret that naked mole-rats, wrinkled, nearly hairless rodents with long buck teeth protruding from their mouths, are not the most attractive animals on Earth. But what these creatures lack in beauty, they make up for in a miscellany of extraordinary characteristics that are intriguing zoologists and medical researchers around the world.

Despite their small size – they measure between three and 13in (7.6 and 33cm) – naked mole-rats live to an average of 30 years, are resistant to chronic diseases, including diabetes, and have an intriguing reproductive system. The animals also provide environmental benefits by acting as “ecosystem engineers” and improving biodiversity in the soil when burrowing to make nests.

BIODISCORVERIES

This article is part of Duduspree Future’s Biodiscorveries World series, which explores the disproportionate contribution that certain important, but unappreciated species make to ecosystems, biodiversity and our own human lives. From starfish, to ants, dung beetles and fungi, these are the creatures that keen the world running and why they deserve our attention.

Immune to ageing and pain, these strange-looking creatures have long fascinated scientists. Now research is revealing that they may hold the key to understanding a range of human conditions, such as cancer and ageing.

Although we have historically studied mice and rats to understand the secrets of human biology, scientists believe naked mole-rats have special advantages for medical research.

Heterocephalus glaber, the species’ scientific name, which essentially means “different headed bald thing”, is native to the hot tropical reaches of north-east Africa. In the wild, they live in large underground colonies numbering up to 300, with a maze of tunnels and chambers the length of several football pitches.

The harsh low-oxygen conditions in which naked mole-rats live might be a clue to some of the species’ unusual traits. Most aerobic life would struggle to survive in such low oxygen environments, yet naked mole rats are the longest living rodents. A similarly sized mouse might live two years, next to the mole-rat’s 30 years or more – if you scaled that relationship up to our size, roughly speaking, it would be like humans having a wrinkly cousin capable of living to 450 years.

Found in the wild in Kenya, Ethiopia and Somalia, naked mole-rats live in colonies of around 70-80 members, with some home to as many as 300 animals. Highly social, these colonies are ruled by one queen and follow a strict hierarchy. Members oversee different jobs, such as those who bring back the underground parts of plants, such as bulbs, roots and tubers, which they eat, alongside faeces.

The species’ biology is incredibly unique. Naked mole-rats are considered “extremophiles” which are able to thrive in extreme environments underground, says Ewan St John Smith, a researcher who studies the sensory nervous system, at the University of Cambridge in the UK.

One of their most unique features is that it’s hard to tell exactly how old a naked mole-rat is, as they show limited signs of physical decline. Whereas humans might become progressively wrinkled, grey, or more susceptible to chronic diseases, “the standard signs of ageing you would expect to see in most mammals don’t really seem to occur”, says Smith. There are no significant changes in cardiac function, body composition, bone quality or metabolism.

At the University of Cambridge, Smith’s team keeps five colonies comprising around 160 naked mole-rats in a room heated to around 30C (90F) at 60% humidity. “I’ve had my animals in Cambridge for 10 years and I’ve never had an animal simply die of natural causes,” says Smith. In captivity, he says fighting between naked mole-rats tends to be the leading cause of death.

Their underground lifestyle may increase their chance of survival, protecting colonies from cold, rain and climate extremes. In the wild, the main cause of death is predation from animals such as snakes.

It’s a very different picture to the common causes of death in humans. “One in two humans are likely to get cancer,” says Smith. “Mice and rats have a similar likelihood of developing cancer, but by contrast, naked-mole rats almost never get cancer – it’s very rare,” he says.

The reason naked mole-rats evade cancer is still a mystery. Numerous hypotheses have been put forward over the years, with scientists struggling to provide a robust explanation. According to one theory, naked mole-rats have a particularly effective form of an anticancer mechanism called cellular senescence – an evolutionary adaptation that prevents damaged cells from dividing in an out of control way and developing into cancer. Another theory suggests that naked mole-rats secrete a complex “super sugar” that stops cells from clumping together and forming tumours.

The latest research is focused on unique conditions in their bodies that stop cancer cells multiplying. Experts at the University of Cambridge are suggesting that interactions with the naked mole rat’s microenvironment – the complex system of cells and molecules surrounding a cell, including the immune system – is preventing the disease, rather than an inherent cancer-resistant mechanism. One experiment at the University of Cambridge saw researchers analyse 79 different cell lines, grown from the intestine, kidney, pancreas, lung and skin tissues of 11 individual naked mole-rats. Researchers infected the cells with modified viruses to introduce cancer-causing genes. To their surprise, the infected naked mole-rats cells began to multiply rapidly. This confirmed that it’s the environment of the naked mole-rat’s body that prevents cancer from developing, rather than a cell-level trait.

The jury may still be out, but what we do know is that “cancer is fundamentally the result of a mutation, which causes cells to proliferate in an uncontrolled manner”, says Smith. “Compared to lots of other species, naked mole-rats have very slow mutation rates.” Animals with shorter lifespans typically have faster mutation rates but, unusually, mole-rats’ mutation rates are on the same level as those of longer-lived mammals, such as giraffes. A slower mutation rate means the animal is less likely to develop mutations and get cancer in a given period of time.

Perhaps the strangest of the naked mole-rat’s quirks is that it is impervious to pain. “This is probably a result of evolutionary adaptation to [their] high carbon dioxide environment,” explains Smith.

The air animals breathe out is richer in CO2 than the air in the atmosphere. If this exhaled air is trapped in underground tunnels, the proportion of CO2 builds up. For most mammals, this would be a problem. “Carbon dioxide reacts with water to form an acid called carbonic acid which can activate nerves to cause pain,” he says.

In many inflammatory diseases, such as rheumatoid arthritis, the areas of tissue swelling can often become acidic and can cause pain.

Yet, “the naked mole-rat doesn’t feel acid as being painful, not in the way that lemon juice or vinegar splashed over cut skin feels painful”, says Smith. He studied the molecular basis for this tolerance, identifying a gene that causes acid to act like an anaesthetic rather than an activator of naked mole-rat sensory nerves.

Gisela Helfer, a professor in physiology and metabolism at the University of Bradford in the UK, says naked mole-rats are also the ”perfect model” for learning about human puberty.

Alongside the Damaraland mole rat, naked mole-rats are one of only two examples of eusocial mammals that live in colonies of overlapping generations where only one female is responsible for breeding and the rest work together to raise the brood.

Much like bees, a high-ranking queen rules over the mole-rat colony, breeding with one to three males at a time. Other individuals play different roles, such as workers who dig the colony’s burrows with their tusk-like teeth and forage for food, providing the queen with roots and bulbs to eat.Usually, there is one fertile pair per colony and the rest of the animals don’t go through puberty, Helfer explains. However, if a naked mole-rat is removed from its colony, it will promptly start making sex steroids and the animal experiences puberty.’

‘Humans have a long phase of pre-puberty of around eight to 12 years,” she says. ”When a child goes into puberty this triggers hormones in the brain, which lead to the production of sex hormones and allows the reproductive tract to mature.” This mirrors the progression of puberty among naked mole-rats when subordinate females are isolated from the queen (the dominant female) in a colony. In contrast, mice and rats go through puberty particularly quickly, within two weeks of birth, so they are a poor template for studying sex hormones. Helfer and other scientists are increasingly looking to naked mole-rats to investigate the influence of sex hormones, specifically oestrogen and testosterone, and sex chromosomes.

This information might shine a light on medical treatments such as puberty blockers, hormone replacement therapy, IVF and menopause. Issues which, Helfer says, ”are at the forefront of health right now”.

One in two humans are likely to get cancer, but naked mole-rats almost never get cancer – Ewan St John Smith

The naked mole-rats Helfer keeps at Bradford University fascinate her due to their ”incredible intelligence” and a few ”bonkers” habits. Inside their highly organised colonies, they have nesting chambers for sleeping and toilet rooms for keeping their habitats clean, she says. When pups were born, she was stunned to see the colony had created a “nursery”, for rearing young naked mole-rats.

They also ”move back and forwards equally fast” and rarely use their small beady eyes, instead relying on sensory whiskers for navigation when underground, she explains.

Naked-mole rats also have unique ways of communicating with each other, determining who is friend or foe through various dialects – much like humans.

Their classic ”chirp” call conveys information unique to the animal’s group, which one study suggests is learned culturally, rather than genetically. Noises are often related to the queen, with cross-fostered pups adopting the tone of the colony that raised them, which can change if the queen is replaced.One study charts 18 different vocalisations that include alarm calls, food recruitment calls, mating calls, toilet-assembly calls. When predators are in close range several distinct alarm calls are used to defend the colony.

Another way naked mole-rats cooperate as a colony is through sustainable farming. Meal times involve bringing back large tubers such as sweet potatoes to their burrows, with each meal weighing up to 50kg (110lb), to gnaw at with other members of the colony. The mole-rats remove the poisonous outer layers of the plant, eat their meal, and then plug the regions they have eaten with soil, allowing the tuber to regenerate and become another meal down the line.Indeed, with their complex communication, long lives, social cohesion and careful management of food resources, naked mole-rats exhibit strong signs of having high intelligence.

These creatures show a few other remarkable traits. Although research is limited, in South Africa the related common and cape mole-rat species have been heralded as ”ecosystem engineers”.

On the Wayland Flower Reserve in Darling, some 60km (37 miles) north of Cape Town, is one the world’s top-rated locations for biodiversity – bursting with wildflowers, bees and insects. As part of her post doctorate at the University of Pretoria in South Africa, Nicole Hagenah studied the role two different mole-rat species, the common and the cape mole-rat, play in contributing to the area’s rich and fertile soils.

In her study, which spanned three years, she found when burrowing their tunnels, these two mole-rat species got rid of excavated soil by depositing it as mounds on the surface.

These mounds had higher nutrient levels, especially nitrogen, compared with the existing soil on the surface. ”We believe that this was due to the below-ground soil that was pushed up containing decomposed uneaten plant material and possibly dung and urine,” she says.

The mound soil was also less compact than the surrounding soil.

The cape and common mole-rats therefore helped plants in two ways. ”Firstly, plants need nutrients to grow, and one of the most important nutrients for plants is nitrogen,” she says.

“Secondly, the less compact mound soil may have enabled the water to penetrate the soil easier, which is also beneficial for plants as they need water.”

As biologically mind-boggling as naked mole-rats are, they aren’t the simplest species to look after and work with, meaning that relatively few research groups worldwide study this incredible species.

“Although their extreme biology is very fascinating, and provides great insights, it’s not easy for everyone to set up their own research facility for this species,” says Smith. Apart from the logistics of replicating hot and humid environments, the lifecycle of a naked mole rat is longer than mice or rats. It usually takes 75 days to give birth and there is only one breeding pair – resulting in a long wait time when planning experiments.

For this reason, Smith set up the Naked Mole-Rat Initiative, to collaborate with experts in other medical fields, such as cancer, and use his animals to support new lines of research.

Smith’s naked-mole rat colony, if they live to their natural age, are likely to transcend his career.

“Very few people in the world have lots of naked mole-rats aged over 30 years. For example, the animals that were born in my colonies last week won’t reach their maximum life span until after I’ve retired,” he says.

If scientists can crack why these extremophile mammals live a long healthy life they can “translate” this knowledge into preventative treatments, or medication that treats cancer once it’s taken hold, Smith says. And there may well be other benefits to investigating these highly unusual animals, some of which may be hard to foresee.

Smith uses the example of PCR tests for detecting Covid-19. “The reason PCR tests work is because they use an enzyme that’s been extracted from a species of bacteria that lives in Yellowstone Park thermal vents,” he says. “Living at high temperatures means that the bacteria’s enzymes have evolved to be stable at high temperatures where biological reactions happen more quicky.

“If we don’t study extreme biology, we miss out on things.”