There aren’t many animals uglier than the naked mole-rat. It is so ugly, that some people find it cute. It has even become a star in the popular cartoon show, Kim Possible. But apparently, the gods felt sorry for this weird animal and endowed it with a quite unusual trait: It can survive without oxygen, a state known as anoxia.
If you exposed an ordinary mouse to anoxia, it will die within a minute, and even re-exposure to normal atmosphere oxygen levels of 20% will not resuscitate it. If you do the same to the naked mole-rat, it will lose consciousness but will regain it—even after 18 minutes of complete anoxia—when re-exposed to normal atmosphere. We could just file away this factoid as “interesting” and move on, or we could ask: How on earth can they do that? This is not just an academic curiosity but may have relevance to human beings. Cardiac arrest and stroke can cause complete brain anoxia. Is there something we can learn from the naked-mole rat that could help people recover?
Curiouser and curiouser
Naked mole-rats live in subterranean burrow systems and hardly ever see the light of day. Another curious trait of theirs is their longevity. They can live longer than 30 years, the longest reported lifespan of any rodent. Compare this with a mouse of a similar body mass, which lives up to 4 years, and you realize that biology of this curious animal has valuable secrets to reveal if we just paid attention to it. These rats also have unusual resistance to cancer. Not only don’t they get cancer, but if cancer cells are implanted in them, they simply die out.
But let’s get back to the first curiosity we described: Their incredible resilience to anoxia. As Einstein famously said, in another context, “God doesn’t play dice with the universe“. Or, as Darwin would have said, “there must be a survival advantage.”
Indeed. These social animals live in a matriarchal society, constantly burrowing and enlarging their tunnel system. All this social living and constant activity have an environmental consequence: The atmosphere in the tunnel contains 5% oxygen and is high in carbon dioxide. No other mammal could survive very long in these conditions, yet they seem to thrive.
Why should it be of practical interest? I already mentioned the brain’s dependence on a continuous supply of oxygen, and the dire fate it meets in cases of cardiac arrest and massive stroke. But solid tumors are also relatively hypoxic. And so are diabetic foot ulcers caused by blood supply insufficiency; in short, hypoxia is of great medical interest.
How do the naked mole-rats do it?
Most mammals, including us, adapted to low oxygen environments by “tinkering around the edge”, modifying existing systems. For instance, Inca Indians living in the Andes simply make more hemoglobin so that their blood can bind more oxygen. This is why competitive long-distance runners train in the mountains before an event. But naked rat-moles evolved a much more radical solution. Let me explain (hang in there, we have a bit of biochemistry to review, but I promise I will make it painless).
We need oxygen to survive because we use it to oxidize glucose and thus form ATP, which provides the energy needed to fuel biochemical reactions. If we, and every other aerobic animal, are exposed to conditions in which there isn’t enough oxygen to satisfy the body’s requirements, sooner or later we will slow down or stop altogether. Actually, the very first steps of glucose metabolism, called anaerobic glycolysis, produce a few (2-4) molecules of ATP without use of oxygen. But that’s not enough for sustained activity. Try to run at your full speed and it’s guaranteed that you’ll “run out of breath”. Compare that with the 32 ATP molecules that we get from oxidizing glucose using oxygen.
So how can the naked mole-rats sustain their activity in 5% oxygen? Park, et al. discovered that they use fructose as a source of energy rather than glucose. Yes, the same maligned molecule that is in high-fructose corn syrup as well as in many fruits. So why can’t we use the same metabolic trick? Because unlike the naked mole-rat, the only way we are able to utilize fructose is by first converting it to glucose. The clever little mole-rat, on the other hand, found a way to metabolize fructose directly without first converting it to glucose. This allowed it to evade a regulatory enzyme called PFK, sort of a traffic cop that slows down glycolysis when oxygen is in short supply. Without that regulation, the naked mole-rat is able to accelerate its anaerobic glycolysis, allowing it to operate in a low oxygen environment, and supply enough ATP for its strange lifestyle.
What’s this got to do with humans?
To compensate for the lack of the metabolic ingenuity of the naked mole-rat, people have something even more valuable: human ingenuity. Now that this novel metabolic trick has been elucidated, it opens the possibility of designing drugs that will allow fructose to enter hypoxic brain cells, cardiac cells, and diabetic ulcers and bypass the PFK regulation to provide much needed ATPs to tissues in distress.
Further, I suspect that the mole-rats adaptation to living in low oxygen, resistance to cancer, and inordinately long lifespan are not merely coincidences. High activity of another molecule IGF1, an insulin receptor which controls the cellular glucose metabolism, is associated with cancers such as breast, prostate, pancreas, and colon. Conversely, low activity of IGF1 is associated with a longer lifespan. Perhaps studying IGF1 in naked mole-rats could be a key to the naked mole-rat’s other unusual traits?
Although at first glance, it may seem far-fetched to think that studying this bizarre little creature could have profound implications for human beings, but as we have seen, there is, in fact, a lot we can learn. So there you have it: From a strange animal, with a bizarre lifestyle, we learned something that could help us save lives and maybe live a bit longer. Who would have guessed?
Dov Michaeli, MD, PhD
Dov Michaeli, M.D., Ph.D. (now retired) was a professor and basic science researcher at the University of California San Francisco. In addition to his clinical and research responsibilities, he also taught biochemistry to first-year medical students for many years.
During this time he was also the Editor of Lange Medical Publications, a company that developed and produced medical texts that were widely used by health professionals around the world.
He loves to write about the brain and human behavior as well as translate knowledge and complicated basic science concepts into entertainment for the rest of us.
He eventually left academia to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early-stage biotech company that developed products to improve post-surgical pain control.
Now that he is retired, he enjoys working out for two hours every day. He also follows the stock market, travels the world, and, of course, writes for TDWI.