Hibernation-Inspired Innovations in Biomedicine: Addressing Aging, Chronic Diseases, and Critical Care

Abstract

This review explores hibernation-inspired innovations to address major healthcare challenges, including aging and chronic diseases. The study of hibernating mammals offers unique insights into extreme metabolism that could revolutionize treatments for various conditions. Hibernation provides natural examples of reversible mass gain, insulin resistance, hypothermia, and metabolic suppression, which have direct applications to diabetes management and ischemia-reperfusion injury. The ability of hibernating animals to emerge without neuronal, muscle, or bone loss highlights potential avenues for treating neurodegenerative and age-related diseases. This review discusses the journey from discovery to translation, emphasizing the importance of understanding the phenology and physiological ecology of target species. It highlights the challenges and advancements in developing tools for non-model organisms, which have opened new opportunities for hibernation-inspired drug discovery. Hibernators’ resistance to bone and muscle atrophy, combined with adaptive anorexia, offers insights for obesity. Nitrogen recycling provides strategies for treating sarcopenia and preventing ammonia toxicity. Applications of hibernation science in stroke and cardiac arrest include improvements in targeted temperature management and application of temperature-independent neuroprotection. Interbout arousals in hibernators offers insights into tolerance of rapid rewarming and reperfusion, which could inform treatments for ischemia-reperfusion injuries. This review synthesizes the potential of hibernation research in advancing biomedical innovations.

Graphical Abstract

Hibernation Science: From Arctic Ground Squirrels to Human Health. This graphical abstract illustrates the potential of hibernation research, centered on ground squirrels and bears, to address critical healthcare challenges. The figure illustrates 1. Extreme physiological adaptations during hibernation, including sub-zero body temperatures, pre-hibernation fattening followed by extended fasting, and resistance to muscle atrophy. 2. Biomedical applications inspired by hibernation, targeting age-related disease including frailty, stroke and cardiac arrest, obesity and diabetes, and neurodegenerative disease. 3. The importance of defining molecular mechanisms underlying aspects of the hibernation phenotype to identify druggable targets and other interventions to recreate the phenotype for therapeutic purposes; and 4. The translational research pipeline, from field observations to drug development, highlighting potential for hibernation-inspired biotechnology. This figure emphasizes how studying the remarkable adaptations of hibernating mammals can lead to innovative approaches in human medicine, particularly for age-related and chronic diseases.

Two significant healthcare concerns for the next century include aging populations and chronic diseases. The global population is aging; i.e., the proportion of the population over 65 years of age is increasing. An increase in the proportion of older people will be associated with an increase in age-related conditions such as dementia, cardiovascular diseases, and multimorbidity (multiple chronic conditions). Chronic diseases such as diabetes, obesity, and cardiovascular disease, all risk factors for stroke and cardiac arrest, continue to grow. Traditional drug discovery and development is slow, expensive and has not yielded significant breakthroughs in treating chronic or age-related disease(Mohs & Greig, 2017). An alternative approach is to look to animal adaptions, in particular, extreme physiology for novel perspectives and novel solutions to some of our most pressing biomedical challenges. By example, the study of the venom of gila monster Heloderma suspectum (Cope, 1869), a lizard that eats only 5 to 10 times a year, led to the discovery of exendin-4(Yap & Misuan, 2019). Exendin-4 is a hormone that mimics human GLP-1 but lasts longer in the body. This discovery revolutionized the treatment of type 2 diabetes and obesity by inspiring the development of drugs like exenatide (Byetta) and semaglutide (Ozempic, Wegovy).(Yap & Misuan, 2019) Like the gila monster, hibernating mammals have evolved extreme metabolic adaptations needed to survive extended periods of resource limitation. The arctic ground squirrel (AGS; Urocitellus parryii (Richardson, 1825)), for example, can double its body mass by doubling adiposity in a few weeks(Sheriff et al., 2013) and then hibernate for 8 to 9 months of the year without eating or drinking. From this prolonged period of inactivity, animals emerge fit and trim with no ill effects, all as part of the ordinary phenology of these animals.(Ma et al., 2005; Williams et al., 2011) These remarkable physiological feats raise an important question: what underlying genetic and molecular mechanisms make such extreme adaptations possible, and how might they inform novel solutions to some of our most pressing biomedical challenges.

Hibernators and humans share evolutionary conserved genes and pathways, reflecting common ancestral mechanisms that regulate metabolism and neuroprotection. Importantly, unlike artificial disease models, which simulate disease states, studying natural disease resistance in hibernators offers insights into intrinsic protective adaptations evolved over millennia that could inspire more effective human therapies. For example, hibernation offers a natural example of extreme mass gain with associated insulin resistance, reversible hypothermia and metabolic suppression with direct application to the clinical management of diabetes and ischemia and reperfusion injury such as occurs during a stroke, cardiac arrest, or hemorrhage. Moreover, the ability to emerge from hibernation without meaningful loss of neurons, muscle or bone highlights the relevance of hibernation science for novel nutrient recycling and regenerative medicine for the treatment of neurodegenerative and age-related disease, in particular Alzheimer’s disease and sarcopenia. Signs of reversable damage in lung, kidney and retina and plasticity in brain suggest capacity for regeneration. This extreme physiology provides novel insights into the regulation and plasticity of processes fundamental to healthy aging. Better understanding of the extreme physiology of non-model organisms has potential to vertically advance medical practice. Here we review hibernation-inspired innovation for critical care, metabolic disease including sarcopenia, diabetes, obesity, as well as cardiovascular disease and age-related disease. Table 1 offers examples of phenotypes found in hibernation, mechanisms underlying those phenotypes and potential applications for biomedicine. Translating these hibernation-derived insights into medical advances requires a systematic approach that begins with phenotypic observations and extends to rigorous, mechanistic investigation.

Table 1.

Hibernation phenotypes, mechanisms and potential applications of manipulating that mechanism for therapeutic benefit

Phenotype	Mechanism	Application in preclinical model
Synaptic contacts are lost in hibernation but return when temperature increases.(Magarinos et al., 2006; Popov et al., 1992; von der Ohe et al., 2007)	Cold-shock RBM3 is upregulated during hibernation.(Fedorov et al., 2009) Impaired synapse regeneration in mouse neurodegenerative models is linked to a lack of induction of RBM3.(Peretti et al., 2015)	Overexpression of RBM3 restores synaptogenesis.(Peretti et al., 2015)
Metabolism is suppressed and core body temperature decreases during onset of torpor(Buck & Barnes, 2000; Geiser, 2004; Jastroch et al., 2016; Jinka et al., 2010; Karpovich et al., 2009)	CNS A 1 adenosine receptor stimulation is necessary and sufficient to induce hibernation.(Jinka et al., 2011)	A 1 adenosine receptor agonist suppresses shivering better than standard antishivering drugs during targeted temperature management in rat(Laughlin et al., 2018), but outcome post cardiac arrest is similar to standard antishivering drug combination.(Laughlin et al., 2024)
Hibernating mammals preferentially metabolize lipids and ketones and upregulate melatonin during hibernation.(Andrews et al., 2009; Hao et al., 2024)	Ketone bodies and melatonin are neuroprotective(Andrews et al., 2009; Schwartz et al., 2015).	β-hydroxybutyrate and melatonin infusion enhances survival after hemorrhagic shock.(Perez de Lara Rodriguez et al., 2017)
Hibernating mammals resist disuse muscle atrophy during prolonged inactivity during hibernation.(Harlow et al., 2001)	Nitrogen is recycled into essential and anabolic amino acids.(Regan et al., 2022; Rice et al., 2020) Upregulation of RBM3 and anabolic genes.(Fedorov et al., 2009; Goropashnaya et al., 2020)	not yet demonstrated in a clinical model.
Hibernating mammals resist brain and hindlimb injury caused by ischemia/reperfusion.(Bhowmick & Drew, 2017; Frerichs et al., 1994; Osborne et al., 2005)	Sumoylation is necessary for ischemic preconditioning and hypothermia cytoprotection(Karandikar et al., 2023), AGS brain resists peroxynitrite toxicity(Bhowmick & Drew, 2017), AGS plasma Iodide increases in late torpor and IBA.(Morrison et al., 2020)	Druggable targets identified for drug discovery. Iodide protects against myocardial infarction(Morrison et al., 2018)
During hibernation torpor, coagulation is inhibited, and fibrinolysis is accelerated.(De Vrij et al., 2023) Clots do not form in hibernation despite immobility.(Thienel et al., 2023)	Rapid and reversible anti-thrombotic shift by the reduction in circulating platelets, Von Willebrand factor, and coagulation factors(De Vrij et al., 2023) HSP47 down-regulation.(Thienel et al., 2023)	not yet demonstrated in a preclinical model.
Hibernating animals do not eat during IBA(Florant & Healy, 2012)	hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia.(Mohr et al., 2024)	not yet demonstrated in a preclinical model.

The journey from discovery to translation begins with foundational understanding of the phenology and physiological ecology of target species. Confidence in the model is then established by the ability to replicate field observations of phenology and physiology in captivity. Further characterization of physiology, biochemistry and behavior in captive populations opens opportunity to discover novel signaling molecules, metabolic pathways and targets that might be druggable, or responsive to supplemental nutrients or gut microbiome manipulation. This pipeline of discovery has historically been challenging due to a dearth of cell and molecular tools for nonmodel organisms. However, progress in gene therapy towards human applications has led to new tools to pursue cause and effect relationships to establish mechanisms that underlie remarkable feats of physiology that stretch our understanding of mammalian biochemistry and physiology and offer insights to reverse pathology and to treat disease. Fauna Bio is an example of a successful biotech company that is leading hibernation-inspired drug discovery using a biobank of genetic data and a novel bioinformatics platform to identify targets for drug development. The innovative approaches pioneered by companies like Fauna Bio are made possible by the remarkable diversity and evolutionary history of hibernation in endotherms. This phenomenon is not restricted to a single group, but is widespread among mammals and birds, providing a rich tapestry of species and adaptations to study (Geiser, 2021, pp 133–136.).

Many different types of endotherms hibernate, ranging from mammals to birds. Within mammals, there are a significant number of hibernating species. Some notable examples include rodents such as most species of marmots, ground squirrels, and chipmunks, all different genera within the family Sciuridae, commonly known as the squirrel family. Others include several species of bats, bears, hedgehogs and primates. The widespread presence of hibernating species across the deepest branches of mammals suggests that all mammals likely share the genetic basis necessary for hibernation.(Carey et al., 2003) Two recent papers report that hibernators have evolved specific changes, mainly in noncoding cis-regulatory elements, that break genetic constraints enabling aspects of metabolic flexibility (Ferris et al., 2025; Steinwand et al., 2025). With this new fundamental understanding additional work is needed to dissect the most relevant gene expression modulation for a variety of adaptations with biomedical significance.

Building on these fundamental genetic insights, ongoing research in Alaska leverages local hibernators, especially the arctic ground squirrel [Urocitellus parryii Richardson, 1825 (formerly Spermophilus parryii)] and black bear (Ursus americanus, Pallas, 1780), to illuminate the physiological and phenological adaptations that underpin extreme metabolic flexibility in natural environments.(Barnes, 1989; Chmura et al., 2023; Tøien et al., 2011) Similar phenomenon are observed in free-ranging, semi-natural, and captive conditions.(Buck & Barnes, 2000; Richter et al., 2015; Toien et al., 2022; Zhang et al., 2020) The arctic ground squirrel (AGS) offers accessible, cost-effective animals, 500–1000g that tolerate transmitters, chronically implanted cannulas and other technologies developed for laboratory rodents. The AGS also exemplifies extremes relative to other rodent hibernators; core body temperatures below freezing,(Barnes, 1989) torpor bout lengths as long as two to three weeks(Karpovich et al., 2009), and hibernation seasons as long as nine months(Sheriff et al., 2010). The American black bear serves as a human sized hibernator. Although far more expensive to house, the black bear decreases metabolic rate to 25 percent of basal metabolic rate at core body temperatures that humans can tolerate (30°C and higher)(Tøien et al., 2011), with potentially greater influence of temperature-independent means to suppress metabolism than the smaller sized rodents. Hibernating bears resist muscle atrophy despite an absence of food intake and prolonged inactivity(Berg von Linde et al., 2015; Fedorov et al., 2012; Harlow et al., 2001; Lohuis et al., 2007) and can accommodate multiple physiological monitoring devices. Captive bear research facilities allow for measures of metabolic rate and manipulation of environmental variables that cannot be achieved in free-ranging animals.(Rigano et al., 2017; Tøien et al., 2015) While these examples highlight the diverse physiological strategies of hibernators, from the extreme cold tolerance of AGS to the moderate but human-relevant adaptations of black bears, understanding their biomedical significance requires that observations in captivity faithfully reflect the natural seasonal patterns seen in the wild.

The rigor of hibernation science is enhanced when studies confirm that the phenology of captive animals replicates the phenology of free ranging populations. By example, conditions of captive husbandry should support the same pattern of body mass and body composition as is seen in free-ranging animals.(Buck & Barnes, 1999) In free-ranging AGS, body mass increases dramatically over the 3–4 month summer season. Data show the greatest increase in body mass in juveniles that reach lower limits of adult body mass within the first few months of life. Reproductively active adult males demonstrate a rapid decrease and increase in body mass in spring and fall that differs from yearlings and from adult females where body mass decreases slightly during the last two weeks of the pre-hibernation season. Adult males also differ from juveniles that show a steady increase in body mass throughout the summer and pre-hibernation seasons.(Buck & Barnes, 1999) Of biomedical significance, free ranging male AGS double fat mass while maintaining lean mass over the summer and pre-hibernation season.(Sheriff et al., 2013) Other aspects of the pre-hibernation phenotype in free-ranging AGS is a gradual decrease in core body temperature beginning 45 days prior to the first torpor bout(Sheriff et al., 2012) and a decrease in resting metabolic rate at the very end of the pre-hibernation season.(Sheriff et al., 2013) Similar pre-hibernation fattening is seen in captive AGS and thirteen-lined ground squirrels (13-LGS, Ictidomys tridecemlineatus (Mitchill, 1821)). In 13-LGS Lanaspa et al. saw evidence of fatty liver during the summer months and fall transition period that reversed during the hibernation season (Lanaspa et al., 2015). Sonsalla observed a loss of insulin sensitivity during the progressive increase in fat mass, with rapid return of insulin sensitivity just prior to hibernation after animals began to show torpor test drops.(Sonsalla et al., 2021) Studies show that fattening and reversible insulin sensitivity occurs in multiple species of Sciurids,(Florant et al., 1985) though this has not been well characterized in AGS.

Muscle, bone and anorexia

Beyond these metabolic preparations, hibernators display additional physiological adaptations during the hibernation season itself that are equally striking in their biomedical relevance. The remarkable resistance of hibernating ground squirrels to bone and muscle atrophy, combined with their adaptive hibernation anorexia, offers valuable insights for addressing human metabolic challenges. Studies using unilateral neurectomy in captive AGS confirmed their unique capacity to maintain musculoskeletal integrity despite prolonged inactivity(Bogren et al., 2016). Transcriptomic analyses reveal suppressed protein catabolism pathways and enhanced biosynthetic capacity during hibernation(Goropashnaya et al., 2020). This preservation of muscle occurs alongside rapid fat use(Sheriff et al., 2013), contrasting sharply with human physiology where decreases in body mass (particularly in aging or GLP-1 agonist treatments) disproportionately affects lean mass.(Colleluori & Villareal, 2021; Linge et al., 2024) Resistance to bone and muscle loss is concurrent with hibernation anorexia.

In 13-LGS, hibernation anorexia, a state of negligible hunger during periodic interbout arousals, is mediated by hypothalamic thyroid hormone deficiency that desensitizes arcuate nucleus neurons to both orexigenic (ghrelin) and anorexigenic (leptin) signals(Mohr et al., 2024). It remains to be determined if this metabolic adaptation could be functionally linked to muscle preservation,(Greenhill, 2025) but the coordinated suppression of appetite and maintenance of lean mass presents a novel therapeutic paradigm; a physiological “package” preventing the muscle wasting typically associated with caloric restriction. This dual mechanism holds particular biomedical relevance for developing interventions that simultaneously address obesity and sarcopenia, particularly in aging populations. By mimicking the natural integration of hypothalamic-endocrine regulation and cellular anabolic resistance observed in hibernators, researchers could pioneer therapies that maintain muscle mass during mass loss regimens or age-related metabolic decline.

This ability to maintain muscle mass despite prolonged fasting is closely linked to remarkable metabolic adaptations, including nutrient recycling processes mediated, in part, by the gut microbiome. During hibernation, nitrogen, presumed to originate from skeletal muscle breakdown, is recycled into essential amino acids and those known to stimulate protein biosynthesis. This recycling occurs through both microbial and non-microbial processes,(Regan et al., 2022; Rice et al., 2020) The phenomenon offers an opportunity to identify microbial communities involved in nutrient recycling(McKee et al., 2025; Sadowska et al., 2024) and to identify other mechanisms that underlie nutrient recycling and could be leveraged to reverse or to prevent sarcopenia. It is hypothesized that this nitrogen recycling serves two purposes: It supports protein synthesis and muscle regeneration throughout the hibernation season, and it helps prevent ammonia toxicity that could result from excessive muscle breakdown(Regan et al., 2022; Rice et al., 2020). While nutrient recycling safeguards muscle and protein integrity during prolonged fasting, other hallmarks of hibernation, including controlled cooling and rewarming, intrinsic resistance to ischemia-reperfusion injury, and a capacity for repairing or regenerating damaged cells, offer a broader framework for mitigating the metabolic and ischemic stresses inherent to acute neurological injury. These mechanisms, discussed in later sections, form the basis for exploring hibernation-inspired strategies in neurocritical care, in particular for treating stroke, cardiac arrest and neurogenic fever associated with brain injury.

Controlled cooling and rewarming

Stroke and cardiac arrest remain significant global health challenges. Stroke is the second leading cause of death worldwide, accounting for 11.6% of total deaths in 2019.(Virani et al., 2021) It’s also the third leading cause of death and disability combined, responsible for 5.7% of global disability adjusted life years(Feigin et al. 2021). Cardiac arrest, in particular, out-of-hospital cardiac arrest (OHCA), affects nearly 1,000 people daily in the U.S. alone, with a survival rate of only about 10%, and a high proportion of death due to brain injury. Both conditions disproportionately impact low- and middle-income countries, which bear 83.3% of new strokes and 87.2% of stroke deaths. The global burden of these conditions is expected to increase, with stroke deaths projected to reach 12 million annually by 2030.(Martin et al., 2025; Virani et al., 2021) Given the high mortality rates and the prevalence of neurological injury in survivors of stroke and cardiac arrest, there is a critical need for strategies that limit brain damage during and after ischemia. One such approach is Targeted Temperature Management (TTM), a therapy that controls body temperature to mitigate metabolic and inflammatory injury.

Targeted Temperature Management (TTM) is a medical treatment that involves controlling a patient’s body temperature to achieve specific therapeutic goals, often to reduce tissue injury following conditions like cardiac arrest or stroke. It is commonly used to improve neurological outcomes by lowering the body temperature. For decades guidelines for post-cardiac arrest care were to cool the core body temperature to between 32°C and 36°C, thereby reducing brain metabolic demand, inflammation, and oxidative stress, hallmarks of ischemia/reperfusion injury. More recently, a large clinical trial found no benefit of cooling compared to reduction of fever, with fever defined as body temperature greater than 37.8°C(Dankiewicz et al., 2019). Taken in the context of other temperature management trials, an American Heart Association science advisory committee concluded that temperature management is beneficial, but that the range of temperatures which the brain can be protected is broader than previously thought.(Perman et al., 2023) Capitalizing on thermoregulatory adjustments that occur during hibernation,(Arai et al., 2005; Jinka et al., 2011; Morrison et al., 2025; Olson et al., 2013; Sheriff et al., 2012; Shiomi & Tamura, 2000) fasting-induced torpor or synthetic torpor,(Hrvatin et al., 2020; Machado et al., 2023; Takahashi et al., 2020) better understanding of how these adjustments are achieved is expected to improve temperature management including treatments for neurogenic fever.(Tupone & Cetas, 2021) Furthermore, the therapeutic benefit of lower core temperature is expected to be enhanced by suppressing the cold-defense response.(Laughlin et al., 2024; Moreda et al., 2021) Cooling and rewarming may also activate regenerative processes.(Jackson & Kochanek, 2019; Peretti et al., 2015) In addition to the benefit of low body temperature, Kyo et al., found that synthetic torpor, specifically Q-neuron induced torpor in mice, ameliorates acute kidney injury caused by circulatory arrest even when mice are kept warm during synthetic torpor.(Kyo et al., 2022) Hibernation includes a variety of central and peripheral neural, and cellular mechanisms that work together with cold tissue temperatures to lower metabolic demand.(Buck & Barnes, 2000; Lewis et al., 2024; Staples et al., 2022; Tøien et al., 2011) Engaging these temperature-independent mechanisms may also improve outcome in conditions where blood flow fails to meet the metabolic load of vulnerable organs. Synthetic torpor for emergency medicine or even space travel is transitioning from science fiction to an area of active research, with two primary approaches under consideration: enhancing current medical practices like therapeutic hypothermia, and mimicking the metabolic processes found in natural hibernation. The evidence suggests that replicating natural hibernation mechanisms will be essential to address the inherent physiological challenges humans face during extended space missions(Drew et al., 2023; Nordeen & Martin, 2019).

Interbout arousals.

While hibernating animals demonstrate remarkable thermoregulatory adjustments to achieve body temperatures that in the arctic ground squirrel can fall to as low as −2.9°C,(Barnes, 1989) their physiology also tolerates rapid rewarming and reperfusion of tissue that becomes metabolically active during rewarming and subsequent periods of interbout arousals (IBA). IBAs in hibernating mammals are brief periods during which the animal’s body temperature and metabolic rate return to near-normal levels, and they play several vital roles despite their high energy cost. These arousals help restore normal physiological functions such as sleep, which is particularly important because prolonged torpor disrupts sleep patterns(Larkin & Heller, 1999). They also correct metabolic imbalances that build up during torpor, functioning like an “hourglass mechanism” that signals when arousal is required(Ruf et al., 2021). IBAs replenish blood glucose, and restore immune response, kidney function and gene expression(van Breukelen & Martin, 2002), which can be impaired during deep hibernation torpor (Galster & Morrison, 1975; Prendergast et al., 2002). In addition, tissue and cellular maintenance occur during these periods, including the rapid regeneration of synapses lost in torpor, and reinstatement of mitotic activity(Popov et al., 2011) thereby aiding in brain functional recovery(Popov & Bocharova, 1992). Interbout arousals also help prevent oxidative damage, as hibernators have adaptations to manage the reactive oxygen species generated during the increase in metabolism(Schwartz et al., 2015; Tøien et al., 2001). Although IBAs typically last only 10 to 20 hours they account for up to 86% of the total energy used during hibernation(Karpovich et al., 2009), and are therefore considered to be essential for maintaining vital physiological processes and ensuring the animal’s long-term survival through extended periods of low metabolic activity.(Geiser, 2021, pp 133–136.) Notably, studies on Madagascan fat-tailed dwarf (Cheirogaleus medius E. Geoffroy Saint-Hilaire, 1851) show that IBAs are needed only when body temperature drops below 30°C during torpor.(Dausmann et al., 2004) This finding provides insight into why bears, which maintain a body temperature of 30°C or higher during hibernation, do not exhibit interbout arousals(Tøien et al., 2011), suggesting that warm temperature torpor may obviate the need for these intermittent arousals. While the mechanisms behind IBAs are complex and influenced by various factors, understanding these processes is crucial for appreciating the physiological challenges that hibernating animals face during rapid changes in metabolic states, such as those occurring during IBAs. While the benefits of interbout arousals are well recognized, the underlying mechanisms that trigger these transitions are less well understood. Some evidence suggests that glutamate and histamine play roles in triggering IBAs. Glutamate NMDA receptor antagonists stimulate arousal through peripheral or circumventricular sites of action(Harris & Milsom, 2000; Jinka et al., 2012). Moreover, H₃ histamine receptor agonists administered into the CNS delay arousal.(Lin et al., 1990) Improved understanding of neural mechanisms that trigger arousal from hibernation could have clinical applications, particularly in stimulating arousal from coma.

Repair, regeneration and protection from ischemia reperfusion injury

Resistance to detrimental effects of reperfusion, or the ability to regenerate cells damaged by reperfusion is also an area ripe for biomedical insights. Evidence for reversal of pathologies and regeneration of damaged tissue during hibernation is well documented in several organ systems, particularly during the phases of torpor (metabolic suppression) and interbout arousal (IBA, metabolic restoration). In hibernating Syrian hamsters (Mesocricetus auratus Waterhouse 1839), the lung undergoes marked remodeling during torpor, characterized by increased smooth muscle actin, collagen deposition, and expression changes in remodeling-related proteins such as transforming growth factor-β and angiotensin converting enzyme(Talaei et al., 2011). These changes resemble pathological lung remodeling seen in chronic human lung diseases but are completely reversed during arousal (IBA), restoring normal lung tissue structure. This reversibility appears linked to endogenous hydrogen sulfide (H₂S) production through cystathionine beta synthase in lung smooth muscle cells.(Talaei et al., 2012) Studies in the 13-lined ground squirrel show degeneration changes in cone photoreceptor outer segments and mitochondrial changes in the inner segment during torpor. These alterations are fully reversed during IBA, indicating a regenerative process in retinal tissue linked to hibernation cycles.(Sajdak et al., 2019) During torpor, kidney function is reduced in 13-lined ground squirrel, and the brush border shows signs of injury. However, these functional declines reverse during IBA, with kidney function resuming normal activity, thus illustrating an efficient repair and functional restorative mechanism.(Jani et al., 2011) Cooling and rewarming may also activate regenerative processes.(Jackson & Kochanek, 2019; Peretti et al., 2015)

Indeed, cold stress during torpor and hypoxic stress upon arousal may initiate regenerative processes. Synapses are known to retract during hibernation torpor and to rapidly blossom during rewarming,(Magarinos et al., 2006; Popov et al., 1992; Strijkstra et al., 2003; von der Ohe et al., 2006) a phenomenon mimicked by cooling and rewarming in mouse brain slices(Roelandse & Matus, 2004) and mice in vivo.(Peretti et al., 2015) Synaptogenesis in response to cooling and rewarming depends on the cold-shock protein RBM3 and over expression of RBM3 delays pathology in mouse models of Alzheimer’s and prion disease.(Peretti et al., 2015) In arctic ground squirrels (Urocitellus parryii), rewarming from torpor may improve cognitive capacity.(Weltzin et al., 2006) In mice cooling and rewarming clearly enhances learning and memory and hippocampal long-term potentiation, a crucial cellular mechanism that supports learning and memory formation.(de Veij Mestdagh et al., 2021) Neurogenesis may complement synaptogenesis and contribute to regeneration and repair. Hamsters (Mesocricetus auratus) show suspension of mitotic activity in the subgranular zone during torpor, however, regrowth of processes dominates over neurogenesis upon arousal(Leon-Espinosa et al., 2016). Additionally, numerous cellular mechanisms observed in hibernation, which enhance protection, repair, regeneration and metabolic regulation, align with hallmarks of aging as outlined by López-Otín (López-Otín et al., 2023). Better understanding of these mechanisms have immediate application to treatments for stroke and cardiac arrest, neurodegenerative disease as well as for translating torpor-like physiology for critical care.(Drew et al., 2023) .Together, these data underscore that hibernators tolerate and rapidly reverse significant structural and functional tissue remodeling induced by the extreme physiological stresses of torpor. This dynamic remodeling during torpor-IBA cycles represents a natural model of reversible pathology and tissue regeneration potentially valuable for therapeutic insights.

Capacity for regeneration together with resistance to ischemia reperfusion injury likely protect hibernating species during IBAs which in nonhibernating species would pose a substantial risk of injury. If in a rat or human, cerebral perfusion does not match the metabolic demand of the brain, spreading depression and brain death ensues within minutes.(Carton-Leclercq et al., 2023) To make matters worse, upon return of blood flow reperfusion initiates a web of events including release of reactive oxygen and nitrogen species, inflammation apoptosis and ferroptosis.(Lipton, 1999; Wang et al., 2021) These events then exacerbate the injury caused initially by insufficient blood flow to create ischemia-reperfusion injury. The decrease in cerebral blood flow measured in hibernating, torpid, ground squirrels is similar to the decrease that occurs during a stroke, yet blood flow returns without injury.(Frerichs et al., 1994; Ma et al., 2005)

Multi-organ resistance has been documented in the intestine(Kurtz et al., 2006), kidney(Jani et al., 2011), liver(Lindell et al., 2005; Otis et al., 2017), and brain(Bhowmick et al., 2017; Dave et al., 2006; Frerichs & Hallenbeck, 1998). In 13-lined ground squirrels (13-LGS), protection occurs in both cold and warm ischemia models and can persist at normal body temperature(Frerichs & Hallenbeck, 1998). In cases where resistance from injury was compared with rat and across the hibernation season, 13-LGS were more resistant than rat and resistance was greatest during the hibernation season; i.e., during IBA or torpor. The kidney represents a partial exception, as Jani et al.,(Jani et al., 2011) found tissues from animals during IBA to be more vulnerable than tissues from animals in torpor.

Direct comparisons between hibernating species have not been made although reports suggest some differences in protection from ischemia reperfusion between 13-LGS and AGS. In the brain, hippocampal slices from hibernating 13-LGS resist oxygen–glucose deprivation (OGD) more effectively than tissue from active 13-LGS or rats. Even at colder assay temperatures, active 13-LGS also outperform rats, suggesting that both species-specific traits and the hibernation state contribute to this resilience. Arctic ground squirrels (AGS) show an even more striking pattern: both active and torpid AGS resist OGD significantly better than rats, regardless of season or hibernation state. Moreover, summer-active AGS also withstand in vivo brain injury after cardiac arrest better than rats. These findings indicate that AGS possess a species-specific, stable tolerance that may reflect evolutionary adaptation to their extremely short summer season, reducing the selective pressure to lose protection outside of hibernation. Alternatively, it may be that the severity of injury has not been sufficient to reveal benefit of the hibernation season or state.

The mechanisms of species-specific protection have potential to identify druggable targets for treating ischemia reperfusion injury in the clinic. In AGS brain slices we found that creating an environment of hypoxia led to the same cascade of events known to occur in rat and human during hypoxia-induced cell death, stroke or cardiac arrest. AGS brain slices lost ATP, depolarized, released glutamate, but cells did not die, even at low pH meant to mimic ischemia-induced acidosis.(Bhowmick et al., 2017) Downstream of these events we found that AGS resist the damaging effects of a highly toxic and reactive nitrogen species, peroxynitrite.(Bhowmick & Drew, 2017) In vivo, additional protections from ischemia/reperfusion injury are expected to come from inhibition of the innate immune response(Bouma et al., 2010), and prevention of blood clot formation and accelerated fibrinolysis during the hibernation season.(De Vrij et al., 2023; Drew et al., 2001)

An ability to resist ischemia-reperfusion injury, in brain and other tissues and organs(Jani et al., 2011), may be a critical adaptation that enables survival through IBAs. The physiological or biochemical functions served by IBAs are many,(Galster & Morrison, 1975; Heller & Ruby, 2004; Prendergast et al., 2002) suggesting that hibernating mammals have evolved robust mechanisms to mitigate reperfusion injury. During peak metabolic load in AGS, rectal pulse oximetry measurements indicate a decline in arterial blood oxygen saturation (sO₂) to a minimum of 57%, suggesting reduced arterial oxygenation(Ma et al., 2005). Similar results are seen in 13-LGS(Duffy et al., 2025). Furthermore, near-infrared spectroscopy (NIRS) measurements reveal an increase in deoxyhemoglobin and a corresponding decrease in oxyhemoglobin in both the brain and hindlimb during arousal(Drew et al., 2023; Ma & Wu, 2008). However, direct focal measurements of brain tissue oxygenation using an implanted oxygen electrode in the brain do not show a significant decline in brain tissue O₂ partial pressure (PtO₂) during arousal.(Ma & Wu, 2008) This apparent preservation of PtO₂ despite declining oxyhemoglobin concentrations suggests the involvement of an alternative oxygen storage or transport mechanism that may contribute to resistance to ischemia/reperfusion injury. The arctic ground squirrel (Urocitellus parryii), is highly protected from ischemia/reperfusion injury, and offers a promising model for studies on protective mechanisms. In this species, plasma levels of iodide increase in late torpor and IBA compared to summer active and early torpor time points. This was one of many observations supporting a role of iodide as a cardioprotective catalytic antioxidant, catalyzing conversion of hydrogen peroxide to oxygen and water(Morrison et al., 2020). Iodide is now in clinical trials to test its ability to improve outcome following myocardial infarction.(Morrison et al., 2020) While antioxidant defenses and alternative oxygen delivery strategies may contribute to the remarkable resilience of arctic ground squirrels, these mechanisms do not act in isolation. Increasing evidence points to fundamental adaptations at the mitochondrial level, which endow these animals with an exceptional ability to cope with metabolic stress and support tissue survival during the profound energetic transitions of hibernation. Among these adaptations, recent research has highlighted the pivotal role of mitochondrial ATP synthase in neuroprotection and cellular resilience.

Evolutionary Adaptations in Mitochondrial ATP Synthase.

In AGS neuronal progenitor cells increased spare respiratory capacity plays a role in resisting injury from hypoxia and metabolic stressors. Mitochondrial ATP synthase plays a crucial role in cellular energy production, and recent studies have highlighted its importance in neuroprotection. Specifically, Singhal et al.(Singhal et al., 2020) found that a single amino acid substitution in ATP5G1, a subunit of mitochondrial ATP synthase, significantly influences neuroprotection in ground squirrels. The leucine-32 residue of ground squirrel ATP5G1 is unique relative to the highly conserved proline seen in other clades. Replacing a leucine with proline eliminates the neuroprotective effect, while the reverse substitution, proline for leucine, confers protection. This neuroprotective effect is linked to the concept of spare respiratory capacity, which is a key indicator of cellular metabolic reserves and resilience(Nicholls & Budd, 2000). Spare respiratory capacity is a function of the electron transport chain (ETC) complexes embedded in the mitochondrial inner membrane. These complexes, including Complex I (NADH dehydrogenase), Complex II (succinate dehydrogenase), Complex III (cytochrome b-c1 complex), and Complex IV (cytochrome c oxidase), work together to generate a proton gradient across the membrane. This gradient is utilized by ATP synthase (Complex V) to synthesize ATP from ADP and phosphate. The function of the ETC reflects an organism’s ability to respond to increased energetic demands or metabolic stress. Notably, AGS neuroprogenitor cells exhibit marked elevations in spare respiratory capacity, which likely underlies their ability to tolerate metabolic challenges that lead to mitochondrial stress. This enhanced metabolic flexibility is particularly beneficial during energetically demanding phases of hibernation, such as arousal from torpor. The ATP5G1 variant, associated with this increased spare respiratory capacity, enhances mitochondrial function in ways that support metabolic resilience, suggesting a critical role in the survival strategies of ground squirrels during hibernation.

Aging and Longevity

Lyman et al., found a positive correlation between the length of life and the amount of time spent in hibernation in Turkish hamster (Mesocricetus brandti (Nehring, 1898))(Lyman et al., 1981). This suggests that aging processes slow down during hibernation. In a study involving a large sample of yellow-bellied marmots (Marmota flaviventris Audubon and Bachman, 1841), specifically 149 blood samples collected across the lifetimes of 73 females, researchers found that hibernation slows or stalls epigenetic aging compared to the active season(Pinho et al., 2022). Inspired by these findings in hibernation, Hrvatin and colleagues showed that a prolonged, synthetic, torpor-like state in mice slows epigenetic aging and improves healthspan as measured by reduced frailty. Crucially, the slowed epigenetic aging effect is driven by decreased core body temperature (Tb), not by reduced metabolic rate or caloric restriction alone. Mice maintained in TLS with periodic arousals displayed sustained epigenetic age deceleration for months after TLS ended(Jayne et al., 2025). Wu and Storey note that hibernation suppresses many energy-intensive cellular processes like protein synthesis and activates protective pathways (e.g., FOXO and p53 signaling), that in principle should extend lifespan(Wu & Storey, 2016). The traditional approach to translate these insights into clinical interventions, is to dissect the underlying cellular and molecular pathways that confer resilience, regeneration or longevity in hibernators to reveal druggable targets to screen small molecule modulators. For example, identifying key mediators of oxygen storage and delivery, oxidative stress resistance, anti-inflammatory mechanisms, or cold-induced mitigation of aging may reveal potential druggable targets for therapeutic development.

Next steps after defining biological mechanisms

Target identification and validation.

In drug development, the concept of a druggable target refers to a biological molecule—typically a protein—that plays a critical role in a disease process and can be modulated by a therapeutic compound. These targets must have specific structural and functional properties that allow for interaction with small molecules or biologics (e.g., antibodies) to alter their activity in a way that produces a beneficial physiological effect. In hibernation science, insights from naturally evolved protective adaptations can inform the search for novel druggable targets. For example, by pinpointing the molecular mechanisms that confer resilience to metabolic challenges, hibernation scientists can guide the development of therapeutics for human conditions like stroke, cardiac arrest, or even trauma-related ischemia. Identifying targets begins with understanding the molecular pathways underlying a physiological or pathological condition. For example, in the context of ischemia-reperfusion injury (as seen in stroke, cardiac arrest, or even the intermittent arousals of hibernators), key proteins involved in oxidative stress resistance, metabolic suppression, and neuroprotection may serve as potential targets for intervention. These targets are validated through various assays and studies to ensure they are relevant to the disease process.

Lead compound identification.

Once a promising target is identified, researchers develop compounds that can bind to it and either enhance or inhibit its function. These compounds undergo rigorous testing, from initial biochemical screening to potentially testing the proposed role of the mechanism in the hibernating species. Small molecules are the most common compounds studied, but the concept of a lead compound could also be expanded to include nutrients or specific manipulations of the gut microbiome.

Preclinical development.

For small molecules, promising compounds are tested in cell cultures (in vitro) and animal models (in vivo) that mimic the condition or disease where the new therapeutic will be used to improve outcome, for example in a mouse or rat model of the condition, or disease. In vivo and in vitro testing is used to assess efficacy, safety, and pharmacokinetics (PK) and pharmacodynamics (PD). In addition, absorption, distribution, metabolism, and excretion (ADME) studies are conducted to understand how the compound behaves in biological systems.

Next steps include filing a new drug application with regulatory agency for clinical trials.

By example, in the US, an Investigational New Drug (IND) application is submitted to the FDA. The IND includes data from preclinical studies, manufacturing information, and proposed clinical trial protocols. Once approved for use in humans lead compounds make their way to clinical trials. This process applies to both small molecule drugs and biologics, though biologics may require additional considerations due to their complex nature and potential for immunogenicity. Biologics are a type of pharmaceutical drug that is manufactured in, extracted from, or semi-synthesized from biological sources. These sources can include microorganisms, plant cells, animal cells, or human cells.(Mohs & Greig, 2017) Biologics are typically large, complex molecules such as proteins, nucleic acids, or living cells, which distinguish them from small molecule drugs like aspirin. A gut microbiome transplant, specifically fecal microbiota transplantation, is considered a biological product by regulatory agencies like the FDA(US Food & Drug Administration 2022). Dietary supplements do not require FDA approval before they are marketed.(Bailey, 2020)

This standard practice of drug discovery may in the future be complemented by emerging techniques such as ASO (Antisense Oligonucleotides), AAV (Adeno-Associated Virus), antibody therapies, and tissue-specific delivery mechanisms that have potential to target diseases with greater precision. While classical drug discovery in hibernation research has focused on dissecting molecular pathways to reveal discrete druggable targets, the field is increasingly propelled by emerging molecular and genetic techniques. Approaches such as AAV-based gene delivery is enabling researchers to probe and harness the complex, multi-layered adaptations of hibernators without relying solely on single-target small molecules. The difficulty of isolating traditional targets has, in turn, spurred interest in these precision tools, which can directly modulate gene expression, metabolic states, and cellular resilience. In this way, hibernation biology both inspires and benefits from advances in gene therapy, offering the potential to translate nature’s strategies into durable, tissue-specific interventions for conditions involving ischemia, inflammation, aging, and metabolic dysregulation.

In summary, hibernation research is revealing a rich network of genes, proteins, and metabolic controls that could be harnessed for medicine. Traditional approaches can turn these insights into druggable targets for small-molecule therapies, while cutting-edge tools, such as gene therapy, offer new ways to directly reprogram protective pathways. By combining these complementary strategies, scientists can translate nature’s most extreme adaptations into innovative treatments for metabolic disease, ischemia, inflammation, aging, and organ preservation.

Data Availability:

This is a review article and does not include primary research data