It cannot be said of many people that they wish to emulate the naked mole-rat. Yet inspired by the creature’s extraordinary longevity and robustness, a Ukrainian-Israeli collaboration has taken the first step toward doing that very thing.
The scientists placed regular mice in conditions of low oxygen and high carbon dioxide, like in naked mole-rat tunnels – and achieved something no one has ever done before: they managed to significantly lower the rodents’ body temperature and slow their metabolism for as long as months.
It was the first time science achieved a more or less permanently slower metabolic rate in any warm-blooded animal.
And why is this good? Because, they postulate, the lower body temperature and slower metabolism could significantly extend mouse longevity, based on the observation that metabolically slow naked mole-rats live eight times longer than similar rodents.
Why would we want mice to live longer? We may, we may not, but many of us harbor an aspiration to live forever, and the discovery could have broad application to mammalian life span. It may even have implications for the treatment of obesity, the scientists suggest.
How did they slow down the mice’s metabolism and lower their body temperature? Theorizing that chronic oxygen deprivation is one key to the naked mole-rat's extraordinary physiology, the mice were placed in a hypoxic-hypercapnic environment, i.e., chronically high in carbon dioxide and low in oxygen, explain the research groups from the Institute of Gerontology in Kiev, headed by Prof. Khachik Muradian, and Prof. Vadim Fraifeld’s Lab for the Biology of Aging at Ben-Gurion University of the Negev, Be’er Sheva.
The findings are contained in their report “Metabolic Remodelling of Mice by Hypoxic-Hypercapnic Environment: Imitating the Naked Mole-rat,” published in the journal of Biogerontology.
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Not only did the mice living in mole-rat conditions involving chronic hypercapnia/hypoxia have slower metabolisms and lower body temperatures: they voluntarily ate less. Unexpectedly, their skin wounds healed faster too, the team reports.
It’s long been known that slower metabolism, and dietary asceticism, can translate into longer life. Why hadn’t something like this been done before? Fraifeld says it’s probably because people assume that high concentrations of CO2 are toxic and that slow metabolism reflects CO2 toxicity. So they didn’t go there. This team did.
So, did the metabolically slowed mice live longer? “We did not check their life span – but I can say for sure that not less,” Fraifeld tells Haaretz. “The reduced metabolic rate and body temperature should, with a high probability, extend the life span.”
Asked if the mice weren’t half-suffocated, Fraifeld explains that according to the laws of chemistry, two things determine the metabolic rate: the organism’s input (of oxygen) and its output (CO2). “If there is less oxygen and more CO2, the metabolism slows. The respiration rate is faster under less oxygen and more CO2 but after passing some boundary in the organism – because of adaptation or some other reason – the organism begins to live normally,” he says.
Driving home the question and asking if the mice exposed to the low-oxygen high-CO2 environment were viable and frisky like regular mice, or were stumbling about half-dead besqueaking their bitter lot, Fraifeld reassures Haaretz that they were fine. If anything, they were friskier, he says, adding that they evinced no significant changes in expression of stress-related genes.
Of mice, men and mole-rats
Noble denizen of the netherworld it may be, but the mole-rat is more known for evoking vomitus than veneration. That is because it is very ugly and many people don’t appreciate how special it is.
Fact is, the naked mole-rat (Heterocephalus glaber) – which exists in Israel too, though most people don’t realize it – lives about eight times longer than other rodents its size. Procreation actually extends its life span even more, in contrast to every other animal. It barely gets cancer, and famously doesn’t age until it suddenly flops over and dies.
Let us unpack this a little. First, naked mole-rats do get cancer, though very rarely, like sharks. Second, naked mole-rats can live well beyond 30 years in captivity, compared with 2-4 years for mice. Third, not aging – what about those all-too-familiar signs of senescence, from gray hairs (they have no hair to speak of), wrinkled skin (they always have wrinkled skin), losing visual acuity (their eyes are degenerated)? Forget it. By any normal standards, the naked mole-rat does not age. It “exhibits delayed and/or attenuated age-associated physiological declines,” meaning scientists could not, to their astonishment, demonstrate that mortality hazard accelerated with age.
Since that is insane, scientists have been trying to figure out why. “Clearly physiological and biochemical processes in this species have evolved to dramatically extend healthy life span,” Rochelle Buffenstein wrote in 2008. But what processes?
It’s likely that slow metabolism and clammy body temperature are among the reasons naked mole-rats live so long. Low body temperature has been associated with longevity in other animals, too. Separate work in engineered mice with reduced core body temperature showed they live longer. “The change in body temperature in the engineered mice was 0.3 degrees and they lived 20 percent longer,” Fraifeld comments. “Small differences in temperature can lead to major changes in life span.”
He also mentions the echidna, which maintains a body temperature of 30 degrees Celsius (86 degrees Fahrenheit) and can live half a century; bats, which power down metabolically during the day and live relatively long lives for their size; and the relatively cool body temperature of the bowhead whale – the longest-living cetacean insofar as we know, though as Ben-Gurion University points out, whales can’t be studied in the lab. But mice and naked mole-rats can.
‘Boy do I have a tunnel for you!’
Science is still working on why exactly the naked mole-rat trucks on until suddenly it stops trucking on (or until it gets killed, likely by another naked mole-rat – they can have vile tempers). We can say this: Naked mole-rats live exclusively underground in colonies of up to hundreds that are dominated by a queen, who does all the breeding with just one to a few males. The rest of the colony consists of hormonally suppressed, non-reproducing workers. When the queen dies, the higher-ranking females fight one another viciously for the right to replace her.
We also know that the naked mole-rat’s body temperature ranges from about 30 to 33 degrees. That is the range in their burrows, giving them little need to control their body temperature (making them functionally “thermoconformers” rather than “thermoregulators”). The mouse’s normal body temperature is like ours: 36.5 to 38 degrees.
Since mice can thrive in the naked mole-rat environment, after adaptation, the team concludes that, all in all, chronic exposure to a hypoxic-hypercapnic environment offers the potential of being a life span-extending intervention, as well as a tool for treating human obesity and associated metabolic disorders.
Maybe. At least we would apparently not have to eschew sex, like the vast majority of the naked mole-rat population, because the queen also survives for decades without demonstrating the physiological deterioration typical of senescence. So if we dig a burrow, move in, stop eating hamburgers, prefer raw roots and bugs to chips and breathe less, maybe we can live longer in our subterranean tunnels. Suffering alone. In the dark.
Fraifeld stresses that while they achieved proof of concept in the mice, none of this is anywhere near human application. Anyway, instead of emulating the naked mole-rat, perhaps people could pick the bat as a physiological role model and not spend 24/7 hunkered down, barely breathing and hankering for hamburgers.
It bears adding that you shouldn't assume the high levels of CO2 in our atmosphere are therefore a good thing because they portend future bouts of unsurvivable temperature. But, one day, this breakthrough discovery could even serve SpaceX and its ilk when sending people to Mars, if they ever go, as a method for creating hypometabolism, Fraifeld suggests. Elon Musk, over to you.