BY ANTHONY KING
Inducing humans into a state of torpor or hibernation could boost chances of reaching the red planet, while keeping astronauts healthier. And it could also have medical benefits, reports Anthony King.
The thirteen-lined ground squirrel (Ictidomys tridecemlineatus) is well known for its hibernation abilities. Also known as the striped gopher, the creature enters burrows in October and doesn’t emerge until the following April. It rolls into a ball; its body temperature drops to below 10°C; and its heart rate falls from 200 beats per minute to as low as 10 beats. Meanwhile, its breathing slumps from 150 puffs a minute to a sluggish average of around one per minute.
‘They can go 20 minutes without even a breath,’ says Ryan Sprenger, a hibernation researcher who studied the squirrels for his doctorate in British Columbia, Canada.
Somehow, the squirrels do not need to drink water for six to seven months during their slumber. Their liver stays somewhat active, but they do not eat or urinate during hibernation, and their GI tract shrinks. ‘You don’t see any new transcription or translation in cells, so no new proteins are made during this period,’ says Sprenger. ‘We know they are not sleeping, but they’re actually in a true suspended animation state.’ It is estimated that sleep saves around 5% on energy usage, while hibernation cuts it by a whopping 85% in small mammals.
But hibernation isn’t only helpful for squirrels. ‘The European Space Agency [ESA] has looked into hibernation as a possible means to enable human spaceflight missions into deep space destinations for a while,’ says Jennifer Ngo-Anh, team leader in human and robotic exploration with ESA, while NASA is also funding research in the area. Putting astronauts at metabolic minimum on a trip to Mars would save on food, water and oxygen, as well as cut waste onboard, as outlined in a review of ESA’s hibernation strategy (Neurosci. and Biobehav. Rev., 2021; DOI: 10.1016/j.neubiorev.2021.09.054).
It could also reduce onboard conflicts and benefit astronauts’ health status. For every month in space, weight-bearing bones become 1% less dense, according to NASA. When people are confined to bed through illness, they rapidly lose muscle tone. After two weeks of immobility, healthy volunteers lose 30% of muscle strength and 5% of muscle mass. Likewise, once a squirrel bounces out of its burrow in Spring, it will have lost one-third of its body weight. What is remarkable, however, is that they preserve muscle mass. A hibernating animal runs on its fat reserves. Squirrels are able to use their gut microbes to recycle nitrogen from urea waste to maintain their protein balance (Science, 2022; doi: 10.1126/science.abh2950).
And there is one more accidental upside to torpor. Since the 1950s, research with hibernating squirrels has shown they are more resistant to gamma radiation. If people could be placed into torpor, perhaps harm from radiation could be substantially reduced. ‘Radiation for long spaceflights is something that we do not yet have a solution to,’ says Ngo-Anh.
Hibernation facility
To study hibernation in space, a collaboration in the US is designing a special facility to house squirrels aboard the International Space Station (ISS). ‘Torpor has never really been tested in microgravity,’ says Tobias Niederwieser, an aerospace engineer at BioServe Space Technologies in Boulder, Colorado. Microgravity can be achieved for seconds aboard a special aircraft or a few minutes aboard a rocket, but only a space station can subject animals to these conditions for days, weeks or months. BioServe specialises in custom-made equipment for experiments in space. Its Space Automated Bioproduct Lab (SABL) is a temperature-controlled incubator launched in 2015 for the ISS. Now, a prototype unit is being developed by California biotech Fauna Bio to house hibernating squirrels under NASA’s Innovative Advanced Concepts Program.
It is part of a collaboration between BioServe and Fauna Bio, which is interested in torpor in mammals for human interventions and therapies. Two chambers fit inside the SABL and monitor the animals’ movements, their temperature, consumption of oxygen and production of CO2. ‘We are building this habitat for thirteen-lined ground squirrels, but in such a way that we can also put other animals in there like mice or hamsters,’ says Niederwieser, who has teamed up with Sprenger – now at Fauna Bio – to develop an incubator for squirrels that can answer the question: ‘What does hibernation look like in space’?
‘We know that months-long torpor by squirrels protects against tissue atrophy and osteoporosis of their bones on Earth, but we don’t know if that’ll translate in space,’ notes Sprenger. The squirrels-in-space project seeks to monitor hibernating animals as they orbit the Earth.
‘Cells grow at different speeds and have different metabolism in space,’ says Niederwieser. ‘We want to better understand hibernation. If you bring a process to a new environment that stresses it, you may find new things.’ With NASA funding, the squirrels could blast off for ISS within three to five years, the researchers hope.
One big question in the hibernation field has been what triggers the start of torpor. ‘We don’t know specifically what it is that allows them or forces them to go into hibernation, or what strategies they are using to depress metabolism,’ says Sprenger. If we knew, perhaps animals that do not go into torpor such as rats and then humans could be triggered into similarly reducing their metabolism.
ESA is funding research into the brains of hibernating animals to unearth answers. It is a question others want answers to. ‘We would like to know which neurons in which neuronal networks are responsible for initiating hibernation,’ says Sprenger. ‘The next step would be to test or initiate hibernation in animals that do not naturally hibernate.’
Those first steps remain mysterious and debated. ‘It can start from different directions, and this makes it extremely complicated,’ says Alexander Chouker, an anaesthesiologist at Ludwig-Maximilians-University (LMU) in Munich, Germany, who works with ESA on space flight studies. Initially it was thought the first step was a fall in body temperature, but the opposite has been observed. ‘What we see in most hibernating species is that metabolism is depressed, by up to 50%, before body temperature even starts changing,’ says Sprenger. As energy production in cells slackens, the breathing rate of a hibernating squirrel slumps and its heart rate slows. However, they periodically reanimate – mostly to sleep – and then return to torpor, a reboot that is essential for survival.
Induced torpor
Seasonal hibernation of some squirrels, hedgehogs and bears is not the only form of torpor. Animals such as birds, for example, can torpor overnight. Stop feeding lab mice for six to ten hours and they also reduce their movement, turn down their metabolic rate and lower body temperatures to as little as 20°C.
‘Fifteen years ago, there was just hibernation for many months or daily torpor, which was less than 24 hours,’ says ecologist Kathrin Dausmann at the University of Hamburg, Germany. Then we found all these animals in the field that go into torpor for 48 hours, maybe 60 hours, and we call this prolonged torpor.’ This flexibility feeds hope that perhaps people could be induced into a state of torpor.
One recent study identified neurons in the mouse hypothalamus that seem to regulate torpor (Nature, 2020; DOI: 10.1038/s41586-020-2387-5). In the US, meanwhile, the lab of Hong Chen at Washington University triggered a torpor-like state in mice using ultrasound stimulation of the hypothalamus (Nature Metabolism, 2023; DOI 10.1038/s42255-023-00804-z). Delivering ultrasound for 30s into a few mm2 of brain put the mice into torpor for around an hour.
This activated torpor-regulating neurons by opening ion channels – nano-switches sensitive to mechanical and thermal stimulation, but also ultrasound. ‘The moment ultrasound is applied, there’s an instant reduction in metabolism and body temperature,’ says Chen. Her preliminary evidence suggests downstream brain circuits that control brown adipose tissue, known for generating heat, are turned on. The Washington lab showed a similar, though lower impact in rats, which do not go naturally into torpor.
Another ray of hope comes from the island of Madagascar. There, as a doctoral student two decades ago, Dausmann investigated what happened to dwarf lemurs during winter. The fat-tailed dwarf lemur (Cheirogaleus medius) hibernates in tree holes for seven months of the year, relying on a flexible thermal response that depends on its tree hole. If the hole is poorly insulated, the body temperature of the little lemur fluctuates to reflect ambient temperature. ‘At night, they might be 10 degrees colder, which is amazing for a mammal,’ says Dausmann. ‘[In humans] our body freaks out if we go up or down by one or two degrees.’ If a lemur holed up in a well-insulated baobab tree, she found temperature remained constant and the primate experienced regular arousals (Nature, 2004, DOI: 10.1038/429825a).
Dausmann is intrigued that heating above a certain temperature means the lemurs do not need to arouse themselves. ‘For all the energy needed during hibernation, around 85% goes into these short phases of arousal. That is wasteful, so something important must be going on.’ She believes ancestral mammals were more flexible in regulating body temperature and that it remains within the ken of many mammal lineages, including primates, to evolve torpor.
‘If you look at the mammalian tree, almost every family has a torpor species,’ she says, except marine mammals. It is unlikely that each developed this independently, which has implications for triggering torpor in people.
‘Somewhere deep down in the mammalian genome, there might still be the answer to get humans in space to hibernate,’ says Dausmann.
Unlike mice, there is no way it will be safe to reduce the body temperature of people towards 20°C. But bears are a somewhat similar size to humans and do not depress their body temperature to levels considered dangerous to people. An Alaskan study of hibernating black bears (Ursus americanus) found they suppressed metabolism by a quarter while regulating temperature from 30°C to 36°C in multiday cycles, while heart rates fell from 55 to as few as 9 beats per minute (Science, 2011; DOI: 10.1126/science.1199435). A recent Norwegian study of dozens of wild brown bears (Ursus arctos) found that smaller individuals hibernated longer than large bears, with lower body temperature. The scientists pinned this on basic thermodynamics, the greater need for energy savings and lower cost of warming up a smaller body (Front. Zool., 2023; DOI: 10.1186/s12983-023-00501-3).
Humans and bears
While challenging to study, bears give the hibernation research community hope it will be one day possible to turn down the dial on human metabolism for space travel. ‘Black bears in Sweden hibernate, so we know that it works for larger animals, so why not in humans?’ asks Ngo-Anh, even though ESA realises there is little chance of short-term success.
When experts consider torpor for humans, they think about a mild form of bear-like hibernation, not the deep cold slumber of a ground squirrel, says Sprenger. ‘NASA is not necessarily looking for deep hibernation for humans, but they would be happy if we could cut metabolism by 20%.’
Some see vestiges of torpor even in humans. ‘There is absolutely no reason why this should not be working in humans, because we can probably do it as babies,’ says Chouker, citing the ability of newborns to cope with low oxygen conditions during birth. There is also the possibility some ancient humans entered torpor during winter. Mostly, this rests on one study of Neanderthal bones from a Spanish cave at a time of extreme glaciation (L’Anthropologie, 2020; DOI: 10.1016/j.anthro.2020.102797). Opinions remain divided. And hibernation is not entirely without risk, with concerns around whether some memories might be lost.
Nonetheless, it is unlikely we can get astronauts into torpor by the flick of a switch. ‘Early on in hibernation research, everybody thought that they would find the hibernation molecule or the hibernation signature,’ says Sprenger. ‘But it turns out it’s everything.’ Others are confident that we can wake up the hidden mechanisms of torpor within our own genomes. ‘I believe some drugs could help get us into this state,’ says Chouker, while others add that lowering the temperature is likely to be another part of the recipe.
For now, the big goal is a Martian mission. ‘With current technologies it would take a human crew two-and-a-half years to reach Mars,’ says Ngo-Anh. ‘Hopefully we will have [this technology] ready for a human mission to Mars.’
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