Extraordinary creatures: naked mole rats

What do naked mole rats look like?

Thomas Park: Most people describe them as looking like sausages with teeth. They have short legs, a short tail, small (or no) external ears – so their ear holes don't get filled with dirt – and they have no fur. A huge amount of the sensory brain is devoted to the teeth, but we don't really know why. Some people have proposed that maybe they put their teeth against the tunnel walls to communicate by vibration, but really, we don't know. One interesting thing is that the front teeth can move independently, which is bizarre. They use the teeth for digging and their teeth grow through the lips, so they can keep their lips closed so they don't get a mouthful of dirt while digging. They also use the teeth to break pieces off whatever vegetable they're eating.

Can you describe naked mole rat burrows?

Rochelle Buffenstein: The burrow system is a multi-dimensional maze. There are superficial burrows which go to the surface. That's where the sun's heat will penetrate, so sometimes animals go and lie in them to get warm, and here they find tubers and small bulbs to eat. They also eat a disgustingly poisonous tuber called pyrethrium, which can make a 30 kg tuber that can go really deep, so they have burrows at different levels to search for food. Interestingly, when they find a large tuber, they only eat part, returning next season after the tuber regenerates; so in a way, they're farmers. Their nest areas are usually very deep. When excavating, they kick soil backwards and push it out as a little volcano through a tiny opening on the soil surface and once they've finished, they seal that opening because they don't want snakes or other predators, coming in. The superficial burrows are much more aerated, through the little gaps between soil particles, so those burrows might have a higher level of oxygen, but when you get down to the deep nest, the oxygen there is pretty depleted and you may have as many as 300 animals piled in sleeping together, so the air becomes hypercapnic (has high levels of CO₂). The burrows are a little bit wider than their bodies, so, when they are running around, they can push air in front of them, ventilating the nest to some extent, but in general the nest is pretty hypoxic (low oxygen levels).

Can you tell us about their social structure?

TP: In every colony there is a breeding queen and one to three breeding males. None of the other animals breed, because the males have immature sperm that couldn't fertilize an egg and the vaginas of the females are sealed, so they cannot have sex unless they become the queen. The non-breeders are divided into two castes. Pups become adults around the age of 1 year when they take on housekeeping chores; they dig, keep the tunnels clean and bring food back to the nest chamber. They also carry the pups if the pups need to be moved. After about 6 years, they double their body mass, stop housekeeping and become soldiers. Soldiers spend 99% of their time sitting around, but if there's a threat to the colony – usually when they open a hole to kick dirt outside, they're vulnerable to attack from snakes – the soldiers come into play. They latch onto the snake with their teeth and the housekeepers fill in the tunnels so that the snake can't come after them; it's the ultimate sacrifice. And if you remove the queen from a colony, the three females that have the highest oestrogen level at that time begin to fight, they actually kill each other, and when they are dead, the next three with the highest oestrogen level have a further rise in oestrogen, and they too begin to fight. Eventually, one of the females survives, but there's a lot of collateral damage.

How did this extraordinary social structure come about?

RB: I think eusociality [with a single queen producing every member of the colony, like bees and other insects] came about primarily because of how difficult it is to find food in a desert below ground. If you all live together and you branch off, with animals going in different directions, one of you will hit the jackpot and bring food home. If it was just you, the cost of digging on your own is extremely high – it's five times basal metabolic rate in the lab, which isn't as harsh an environment as the natural burrows. Having lots of animals digging, taking turns and working cooperatively to kick the soil out of the burrows makes it easier to extend the burrow in search of food. I think that's why they have eusociality with strict division of labour culminating in the presence of a single breeding female.

Can you tell us about the air quality in the burrows and how naked mole rat cope with such a challenging atmosphere?

TP: Nobody has successfully measured the oxygen levels in the burrows, but naked mole rat haemoglobin (which carries oxygen in red blood cells) has a much higher affinity for oxygen than most mammals, so their haemoglobin can grab oxygen from air with low oxygen that we wouldn't be able to. The challenge that nobody's understood yet is how they release the oxygen in the tissues. More recently, there's been a lot of studies, including from Rochelle's lab, showing that their resting metabolic rate is two-thirds that of other mammals; they're not using as much energy when they're just sitting around. When we looked at hypoxia tolerance in brain tissue, the first experiment that we did was phenomenal. We placed the tissue in nitrogen, which is as close as we could get to no oxygen, and it survived for 40 minutes at 37°C, which was amazing. And, if you take the temperature down to naked mole rat preferred temperature (30°C), then survival extends even longer. The brain has some intrinsic property to survive in low oxygen, but what that is, we don't know. And we found that live naked mole rats can survive 18 minutes without oxygen, which is phenomenal (mice cannot survive more than a minute in zero oxygen). One thing that happens very quickly in zero oxygen is that they stop moving so they conserve energy. The next thing that happens is the respiration rate goes from something like two breaths per second down to a breath every couple of minutes and the heart rate goes from 200–250 beats per minute to about 35 beats per minute for the entire exposure to no oxygen. When room air returns, the heart rate slowly comes back to baseline, the respiration rate recovers and then they stand up and walk away. Brain activity goes down to what looks like a human patient in a coma, so there is very little activity during the zero-oxygen exposure, and then it comes back to normal in regular air. All of these things conserve energy. Also, they switch from aerobic glycolysis, using glucose, to anaerobic glycolysis, using fructose, during zero oxygen.

They are tolerant of elevated CO₂ too. I believe that Rochelle has measured CO₂ levels in her captive colonies and in the nest chamber they get up to 5% which is phenomenally high. CO₂ levels in the atmosphere are ∼0.04%. If you give a person 1% or 2% it makes them feel as if they're drowning and makes them anxious. We have put naked mole rats in 50% CO₂ and they were fine, whereas mice get pulmonary oedema (fluid in the lungs) and die.

How do naked mole rats protect themselves from high CO₂ in the air?

TP: Acid in the upper respiratory tract and in your eyes, caused by high CO₂, is painful and causes inflammation and oedema in the lungs. Naked mole rats have a couple of adaptations to resist the pain and the pulmonary oedema. They lack a neurotransmitter, Substance P, which is specific to pain nerve endings; they don't feel acid pain and they don't feel the pain from capsaicin (the spicy ingredient in chilli peppers). The absence of Substance P limits the ability of nerves in the respiratory system to transmit pain to the spinal cord. The other adaptation, which probably has an even bigger effect, is that there is a mutation in the sodium channel that carries the action potential along the axon from the periphery to the central nervous system, which deactivates the channel in the presence of acid. So, the action potential cannot travel when there's acid in the tissue. It's brilliant, because that same neuron can respond to other forms of pain when there is no acid. The lack of Substance P and the mutation in their sodium channels is how naked mole rats cope with breathing high levels of CO₂ without pain or the inflammation that causes oedema in the lungs.

How do they sense their surroundings?

TP: Their eyesight is really bad. They can tell when the lights go on and off, so they can detect luminance, but little more. Anybody that works with naked mole rats knows that they're incredibly sensitive to vibration. I've seen them startle when you slide a key into the lock on a door. They've got to be sensing vibration, possibly through the teeth and/or their limbs, because their hearing is quite poor, about 40 decibels worse than ours. But they're quite vocal, which is an odd paradigm. Their calls can travel many metres through a tunnel, the sounds they make are quite loud, about 90 dB, and they sound like birds chirping. They have individual signature calls for themselves and alarm calls warning you to ‘get away’. A lab in Germany discovered that each colony has its own dialect. Their sense of smell is as good as that of rats and mice and there are two interesting things about their sense of touch. First, they have rows of sensory hairs – about 10 hairs in a row – which are extremely sensitive. If you deflect a hair at the shoulder, they orient their face towards the shoulder, if you do it towards the hip, they orient towards the hip; so, they bring their smell, their whiskers and their teeth to whatever is touching them. Secondly, they do not feel acid pain or the pain of inflammation because they lack Substance P in nerve endings in the skin. If the queen bites somebody during a fight, they feel the bite, because that's like a pinch, but then they don't feel the inflammation pain after the bite, so they don't lick it clean, which can be fatal.

How do naked mole rats live for so long?

RB: My oldest animal lived more than 40 years in captivity. An animal weighing 35–45 g is expected to live about 7 or 8 years, but mole rats live at least five times longer than their predicted maximum lifespan. They're the longest living rodent known. For an animal to reach a long lifespan, all organs have to remain healthy, you can't have one maintain function at the expense of the others. I've studied predominantly heart function. We looked at animals all the way up to 36 years of age. By the time humans reach ∼35 years (about a third of their maximum lifespan potential) you're already showing changes in heart function, but in mole rats we see no change; they maintain cardiac output and they don't show any signs of irregular heartbeats. We've looked at muscle mass and fat mass and metabolic rate, and everything that we've looked at doesn't really change with age, although they show very slight declines in activity. I think all of their physiological systems are well maintained, which tells me that their health is also good at the molecular level. They seem to be able to maintain mitochondrial function throughout life and they get rid of unfolded and damaged proteins very efficiently. They maintain many neonatal or juvenile features throughout their lives; the proteins in their heart tissue are what you usually see in human foetuses – so that helps them deal with hypoxia – and they also seem to be better at regenerating heart cells, skin fibroblasts and other types of cell as they become nonfunctional. We've had very little success in figuring out the main cause of death in these animals. The biggest sign that they've died is they've got periodontal disease, and I think that's because when they stop eating the bacteria in their mouths haven't got much food, so they go for the animals’ gums. And naked mole rats don't go into menopause. They maintain their fertility and fecundity way beyond the expected time they should. Mice start becoming less fertile when they're a year old, but we have mole rats still breeding at 36 and 37 years of age. My best breeding female became a queen at 11 years and died at 23. She had 1100 pups and the biggest litter I've ever seen in captivity was 29 individuals. Litter size depends to a large extent on how established the breeding female is. A new breeding female has between one and nine pups in a litter and over the first six litters her body shape changes, her lumbar vertebrae grow, she becomes disproportionately longer, so she can carry more pups. If she did not extend her length, having more pups would make her wider, with the danger of getting stuck in a tunnel.

Naked mole rats are believed to never get cancer, is that true?

RB: That's a myth. They do get cancer, but the incidence of cancer is very low. I've had 10 cases in my colony over 40 years and we found that no particular type of cancer is prevalent, it's just very rare. They have a whole suite of mechanisms that seem to protect them from developing cancer. First and foremost, they have very low levels of IGF1 (insulin-like growth factor 1), which is one of the main causes of cells over-proliferating, leading to cancer. They have very low levels of growth hormone and we know that growth hormone also promotes cell proliferation. They have much better DNA repair processes and they seem to resist mutations when you try to induce them experimentally. When you try to cause skin cancer, the mole rats don't activate the acute phase of the inflammatory response, which is one of the drivers of cancer. I think all of those factors play an important role in preventing them from developing cancer.

What are the main impacts of living in the dark?

RB: Naked mole rats are naturally vitamin D deficient because they live in the dark. Their calcium metabolism seems to be independent of vitamin D status, so they are able to absorb as much calcium as possible from their food. If they take in too much calcium, they just dump it in their teeth, which they are constantly wearing down during digging. When we tried to supplement them with vitamin D to see what happened, we found that they immediately switched off producing it from 2,4-hydroxy vitamin D, so they like to keep the active form of vitamin D pretty low. We serendipitously did one very interesting experiment. We gave the mole rats 20,000 times the vitamin D dose that we intended, which should result in hypercalcemia, which is fatal in humans because it disrupts muscle and nerve function. But our animals didn't die. Instead, they deposited calcium in their skin along their mammary gland line, around the face and they had the thickest whitest teeth. They were able to cope with the excess vitamin D very efficiently, which surprised me. It's a sign that they pretty much resist all forms of toxins you give them. They have mechanisms to handle high levels of toxic drugs, heavy metals, vitamin D excess and the like.

Why are they so resilient to toxins that they do not encounter naturally?

RB: When they dig in soil, they potentially encounter high levels of arsenic or pesticides or heavy metals, such as cadmium. They also eat a plant diet which often have secondary defence mechanisms like cardiac glycosides or cyanide in the outer layers, and even though they peel the skin off usually, they do get exposed to a range of toxins in the wild. They have very high levels of NRF2 (nuclear factor erythroid 2-related factor 2), which is the magic ingredient in broccoli and cabbages that's meant to protect you from all sorts of illnesses. NRF2 regulates the cell's response to stress and poisons by increasing the level of heat shock proteins, antioxidants and protein degradation pathways; it regulates about 600 known protective pathways. Naked mole rats seemed to have 10 times higher levels of NRF2 even when they are not stressed, so they've got the army primed to deal with whatever poison comes along. Although they're not exposed naturally to chemotherapy or high levels of vitamin D, if something weird comes along, they've got this protective pathway ready to deal with it immediately. These little critters have a host of remarkable adaptations, and we believe there are many more still to be discovered.

Thomas Park and Rochelle Buffenstein were interviewed by Kathryn Knight. The interview has been edited and condensed with the interviewee's approval.