Tag: hibernation

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Synthetic Torpor has the Potential to Redefine Medicine

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A team of researchers at Washington University in St. Louis is in pursuit of translating induced, or synthetic, torpor into potential solutions for humans, such as when there is reduced blood flow to tissues or organs, to preserve organs for transplantation or to protect from radiation during space travel. (Credit: Chen lab)

Nature is often the best model for science. For nearly a century, scientists have been trying to recreate the ability of some mammals and birds to survive extreme environmental conditions for brief or extended periods by going into torpor, when their body temperature and metabolic rate drop, allowing them to preserve energy and heat.

Taking inspiration from nature, Hong Chen, professor of biomedical engineering in the McKelvey School of Engineering and of neurosurgery at WashU Medicine, and an interdisciplinary team induced a reversible torpor-like state in mice by using focused ultrasound to stimulate the hypothalamus preoptic area in the brain, which helps to regulate body temperature and metabolism. In addition to the mouse, which naturally goes into torpor, Chen and her team induced torpor in a rat, which does not. Their findings, published in 2023 in Nature Metabolism, showed the first noninvasive and safe method to induce a torpor-like state by targeting the central nervous system.

Now, the team is in pursuit of translating induced, or synthetic, torpor into potential solutions for humans, such as when there is reduced blood flow to tissues or organs, to preserve organs for transplantation or to protect from radiation during space travel.

Conventional medical interventions focus on increasing energy supply, such as restoring blood flow to the brain after a stroke. Synthetic torpor seeks to do the opposite by reducing energy demand.

“The capability of synthetic torpor to regulate whole-body metabolism promises to transform medicine by offering novel strategies for medical interventions,” said Chen in a Perspectives paper published in Nature Metabolism July 31, 2025. 

Synthetic torpor has been used successfully in preclinical models with medications and specialised targeting of the neural circuit, but there are challenges to adapting these methods for humans. Previous human trials with hydrogen sulfide were terminated early due to safety concerns.

“Our challenges include overcoming metabolic differences among animals and humans, choosing the correct dose of medication and creating ways to allow a reversible torpor-like state,” said Wenbo Wu, a biomedical engineering doctoral student in Chen’s lab and first author of the Perspectives paper, a collaboration between Chen’s team and Genshiro Sunagawa from the RIKEN Center for Biosystems Dynamics Research in Japan. “Collaboration among scientists, clinicians and ethicists will be critical to develop safe, effective and scalable solutions for synthetic torpor to become a practical solution in medicine.”

Chen’s team, including Yaoheng (Mack) Yang, who was a postdoctoral research associate in her lab and is now assistant professor of biomedical engineering at the University of Southern California, targeted the neural circuit with their induced torpor solution in mice. They created a wearable ultrasound transducer to stimulate the neurons in the hypothalamus preoptic area. When stimulated, the mice showed a drop in body temperature of about 3 degrees C for about one hour. In addition, the mice’s metabolism showed a change from using both carbohydrates and fat for energy to only fat, a key feature of torpor, and their heart rates fell by about 47%, all while at room temperature.

“Ultrasound is the only noninvasive energy modality capable of safely penetrating the skull and precisely targeting deep brain structures,” Chen said. “While ultrasound neuromodulation lacks cell-type specificity compared with genetic-based neuromodulation, it provides a noninvasive alternative for inducing synthetic torpor without the need for genetic modifications.”

Chen and her team indicate that synthetic torpor offers a promising therapeutic strategy with additional applications, including inhibiting tumour growth and potential development of new therapies for tau protein related diseases, such as Alzheimer’s disease. However, much remains unknown about how brain regions, peripheral organs and cellular pathways coordinate metabolic suppression and arousal. Researchers also need to study the long-term risks and potential side effects and call for more preclinical studies and technological innovations that will facilitate a dual approach, which would include modulating neural circuits associated with hypometabolism and influencing peripheral metabolic pathways through systemic interventions, such as with drugs or peripheral neuromodulation.

“Synthetic torpor is no longer just a theoretical concept – it is an emerging field with the potential to redefine medicine,” Chen said. “Bridging fundamental neuroscience, bioengineering and translational medicine will be key to overcoming current challenges and advancing synthetic torpor toward real-world applications. Synthetic torpor could transition from a scientific curiosity to a human reality through interdisciplinary collaborations.”

Source: Washington University McKelvey School of Engineering

Categories : GeneticsTags :

Hibernation ‘Superpowers’ May Be Hidden in Human DNA

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Photo by Sangharsh Lohakare on Unsplash

Animals that hibernate are incredibly resilient. They can spend months without food or water, muscles refusing to atrophy, body temperature dropping to near freezing as their metabolism and brain activity slow to a crawl. When they emerge from hibernation, they recover from dangerous health changes similar to those seen in type 2 diabetes, Alzheimer’s disease, and stroke.

New genetic research suggests that hibernating animals’ superpowers could lie hidden in human DNA – with clues on how to unlock them, perhaps one day leading to treatments that could reverse neurodegeneration and diabetes.

Two studies describing the results are published in Science.

The genetics of metabolism and obesity

A gene cluster called the “fat mass and obesity (FTO) locus” plays an important role in hibernators’ abilities, the researchers found. Intriguingly, humans have these genes too. “What’s striking about this region is that it is the strongest genetic risk factor for human obesity,” says Chris Gregg, PhD, professor in neurobiology and human genetics at University of Utah Health and senior author on the studies. But hibernators seem able to use genes in the FTO locus in new ways to their advantage.

The team identified hibernator-specific DNA regions that are near the FTO locus and that regulate the activity of neighbouring genes, tuning them up or down. The researchers speculate that adjusting the activity of neighbouring genes, including those in or near the FTO locus, allows hibernators to pack on the pounds before settling in for the winter, then slowly use their fat reserves for energy throughout hibernation.
 
Indeed, the hibernator-specific regulatory regions outside of the FTO locus seem crucial for tweaking metabolism. When the researchers mutated those hibernator-specific regions in mice, they saw changes in the mice’s weight and metabolism. Some mutations sped up or slowed down weight gain under specific dietary conditions; others affected the ability to recover body temperature after a hibernation-like state or tuned overall metabolic rate up or down. 

Intriguingly, the hibernator-specific DNA regions the researchers identified weren’t genes themselves. Instead, the regions were DNA sequences that contact nearby genes and turn their expression up or down, like an orchestra conductor fine-tuning the volume of many musicians. This means that mutating a single hibernator-specific region has wide-ranging effects extending far beyond the FTO locus, explains Susan Steinwand, research scientist in neurobiology at U of U Health and first author on one of the studies.  “When you knock out one of these elements – this one tiny, seemingly insignificant DNA region – the activity of hundreds of genes changes,” she says. “It’s pretty amazing.”
 
Understanding hibernators’ metabolic flexibility could lead to better treatments for human metabolic disorders like type 2 diabetes, the researchers say. “If we could regulate our genes a bit more like hibernators, maybe we could overcome type 2 diabetes the same way that a hibernator returns from hibernation back to a normal metabolic state,” says Elliott Ferris, MS, bioinformatician at U of U Health and first author on the other study.

Uncovering the regulation of hibernation

Finding the genetic regions that may enable hibernation is a problem akin to excavating needles from a massive DNA haystack. To narrow down the regions involved, the researchers used multiple independent whole-genome technologies to ask which regions might be relevant for hibernation. Then, they started looking for overlap between the results from each technique.

First, they looked for sequences of DNA that most mammals share but that had recently changed in hibernators. “If a region doesn’t change much from species to species for over 100 million years but then changes rapidly and dramatically in two hibernating mammals, then we think it points us to something that is important for hibernation, specifically,” Ferris says.

To understand the biological processes that underlie hibernation, the researchers tested for and identified genes that turn up or down during fasting in mice, which triggers metabolic changes similar to hibernation. Next, they found the genes that act as central coordinators, or “hubs,” of these fasting-induced changes to gene activity.

Many of the DNA regions that had recently changed in hibernators also appeared to interact with these central coordinating hub genes. Because of this, the researchers expect that the evolution of hibernation requires specific changes to the controls of the hub genes. These controls comprise a shortlist of DNA elements that are avenues for future investigation.

Awakening human potential

Most of the hibernator-associated changes in the genome appeared to “break” the function of specific pieces of DNA, rather than confer a new function. This hints that hibernators may have lost constraints that would otherwise prevent extreme flexibility in the ability to control metabolism. In other words, it’s possible that the human “thermostat” is locked to a narrow range of continuous energy consumption. For hibernators, that lock may be gone.

Hibernators can reverse neurodegeneration, avoid muscle atrophy, stay healthy despite massive weight fluctuations, and show improved aging and longevity. The researchers think their findings show that humans may already have the needed genetic code to have similar hibernator-like superpowers—if we can bypass some of our metabolic switches. 

“Humans already have the genetic framework,” Steinwand says. “We just need to identify the control switches for these hibernator traits.” By learning how, researchers could help confer similar resilience to humans.

Source: University of Utah Health

Categories : GastrointestinalTags :

Probing the Gut’s Ability to Change Size According to Nutrient Intake

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Source: CC0

The gut has considerable plasticity among animals, shrinking as much 50% in cases of fasting such as hibernating and able to rapidly return to normal size on refeeding. Now, scientists from the University of Copenhagen used fruit flies to investigate the signalling mechanisms and cellular changes that regulate this rapidly renewable tissue, which could reveal insights into diseases such as colorectal cancer. Their results are published in Nature Communications.

“Taking advantage of the broad genetic toolbox available in the fruit fly, we have investigated the mechanisms underpinning nutrient-dependent gut resizing,” says Dr Ditte S. Andersen.

The results show that nutrient deprivation results in an accumulation of progenitor cells that fail to differentiate into the mature cells causing the gut to shrink.

Upon refeeding these stalled progenitor cells readily differentiate into mature cells to promote regrowth of the gut.

Ditte S. Andersen continues: “We have identified activins as critical regulators of this process. In nutrient restrictive conditions, activin signalling is strongly repressed, while it is reactivated and required for progenitor maturation and gut resizing in response to refeeding. Activin-dependent resizing of the gut is physiologically important as inhibition of activin signalling reduces survival of flies to intermittent fasting.”

Regulators of organ plasticity are essential for host adaptation to an ever-changing environment, however, the same signals are often deregulated in cancers. Indeed, mutations affecting activin signalling are frequent in cancer cells in a variety of tissues. This study provides a starting point for investigating the link between aberrant activin signalling and the development of colorectal cancers and sets the stage for exploring the efficiency of anti-activin therapeutic strategies in treating colorectal cancers.

Source: University of Copenhangen

Categories : Cardiovascular DiseaseTags :

Scientists ‘Poke the Bear’ to Gain a Better Understanding of Blood Clotting

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Photo by Mark Basarab on Unsplash

It’s generally good advice not to “poke the bear” as they say, but that’s exactly what a multinational team of scientists have been doing, to discover the secrets of blood clotting. Hibernating bears, paralysed humans, and pigs kept in small enclosures all avoid dangerous blood clots, despite being immobile for extremely long periods.

Their new study published in Science shows that reduction of a key protein inhibits the formation of blood clots in all three mammal species when they are immobile for days, months or even years.

Passengers on long haul flights run the risk of developing deep vein thrombosis if they do not take some time to walk around and use compression socks. Some people are predisposed to blood clots, due to genetic factors.

Yet, when humans – and other mammals such as bears – are immobilised for a much longer period than a flight, the researchers found that a protein known as Hsp47 is reduced by 55 times. This could lead to new medicines to help those who have inherited blood clotting disorders that put them at risk for pulmonary embolism, heart attack, and stroke.

Professor Jon Gibbins led the work at the University of Reading. He said: “It seems counterintuitive that people who have severe paralysis don’t appear to be at higher risk of blood clots. This tells us that something interesting is happening. And it turns out that reducing levels of Hsp47 plays a key role in preventing clots, not just in humans, but in other mammals, including bears and pigs.

“When we see something like this in multiple species, that reinforces its importance. Having Hsp47 must have been an evolutionary advantage.”

Hsp47 is released by platelets – the sticky blood cells that trigger blood clotting.  Usually clotting is an important response to an injury, to prevent blood loss, and Hsp47 is one of the necessary ingredients to enable platelets to do their job. Examining the role of Hsp47 in clotting function the team found that when released into the blood of bears, mice and humans that it promoted conditions that may give rise to deep vein thrombosis.

Professor Gibbins said, “We aren’t totally sure how, but it appears that there is something about movement that keeps Hsp47 at an appropriate level. It could be that the mechanical forces involved in moving around actually have an impact on gene expression, dramatically increasing the amount of Hsp47 that circulates in the blood.”

The team took blood samples from bears in winter, while hibernating, and in summer, while awake and moving around. They also compared people who were immobilised with those who can move and walk. And finally, pigs kept in small pens were compared with others that were free to move around in barns. In all three cases, proteomics experiments showed that the absence of movement was associated with having far less Hsp47.

Professor Gibbins continued: “Now we know that Hsp47 is so important, we can begin to look for new or existing medicines that might be able to inhibit the function of this protein in blood clotting and protect mobile people who are prone to clots.”

Source: University of Reading