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What naked mole-rats can teach us

about treating cancer

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(Image credit: Alamy)

By Frankie Adkins 21st December 2022

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.

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t's no secret that naked mole-rats,

I 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.

UNLOVED WORLD

This article is part of BBC Future's

Unloved 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.

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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.

Naked mole-rats' underground lifestyle helps protect

them from cold, rain and other climate extremes
(Credit: Alamy)

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 olen
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.

Naked mole-rats live in large underground colonies

numbering up to 300 (Credit: Alamy)

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.

Immune to ageing, pain and cancer, naked mole-rats

have long fascinated scientists (Credit: Alamy)

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
olen 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.''

A high-ranking queen rules over naked-mole rats

colonies, breeding with one to three males at a time
(Credit: Alamy)

As biologically mind-boggling as naked mole-rats

are, they aren't the simplest species to look aler 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 aler 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." 

--

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