stasis sleep reviews
Although adenosine plays a central role in the thermoregulatory aspects of torpor, other metabolites are also implicated in natural hibernation. Hydrogen sulfide (H2S) showed initial promise in inducing a hibernation-like state of metabolic depression (11), although the original results were obtained in mice, which naturally use torpor when food-deprived (72). A hypometabolic effect of H2S was not reproduced in other mammals (30, 105), and the hypothermia seen in the original mouse model now appears to have been a consequence of hypoxia rather than H2S (54). H2S is an endogenous gasotransmitter with a myriad of effects in multiple physiological systems (119), including playing a protective role in ischemia-reperfusion injury (33, 58, 86, 99, 121). Results from a plasma metabolomics screen using carefully timed samples from hibernating 13-lined ground squirrels supports a role for H2S in resistance to reperfusion damage during hibernation by depressing the activity of complex IV in the mitochondrial electron transport chain to reduce ROS accumulation during arousal (25). This and other metabolomics data sets underscore a pattern whereby arousals restore levels of metabolites that either deplete or accumulate during torpor (34). Metabolomic, proteomic and transcriptome data sets highlight a shift away from glucose toward fatty acids as the primary fuel during hibernation (3, 44, 45, 73, 81, 82, 97, 115), which may itself be protective against ischemia-reperfusion damage (13). Elevated beta-hydroxybutyrate, typical of hibernation, is also protective in a hemorrhagic shock model (87). Peripheral glutamate receptor activation is required for maintenance of torpor (63). The loss of glutamate signaling, perhaps caused by transamination and conversion to glutamine to protect against toxic nitrogen accumulation (34), results in arousal from torpor (63).
Engineering Human Stasis for Long-Duration Spaceflight
Suspended animation for deep-space travelers is moving out of the realm of science fiction. Two approaches are considered: the first elaborates the current medical practice of therapeutic hypothermia; the second invokes the cascade of metabolic processes naturally employed by hibernators. We explore the basis and evidence behind each approach and argue that mimicry of natural hibernation will be critical to overcome the innate limitations of human physiology for long-duration space travel.
After decades of learning from manned missions in low earth orbit, governmental agencies, including the U.S.’s National Aeronautics and Space Administration (NASA) (32), the European Space Agency (35), and Roscosmos (24), in addition to private enterprises (94, 102), are poised to begin moving humans back to the moon and from there on to Mars and other deep-space destinations. Manned spaceflight, however, presents numerous challenges at the interface of astrophysics, engineering, and human biology (42). Placing humans into synthetic torpor 1 would reduce both engineering and psychosocial stresses for long-duration spaceflights (23, 42, 55, 57). A metabolically quiescent human requires substantially less oxygen, food, water, waste removal, and living space than an active human, and bypasses potential psychosocial difficulties incurred by interacting in a restricted, high-stress environment with other travelers. NASA has reported detailed designs that estimate a 52–68% reduction in mass required to sustain 96 humans in synthetic torpor together with four active astronauts for a mission to Mars (FIGURE 1) (101).
FIGURE 1.Illustrated concept for Mars transporter with torpid humans
Illustrated concept for Mars transporter with torpid humans based on NASA-proposed design. Figure modified from Ref. 16.
There are currently two parallel and conceptually disparate approaches under pursuit to achieve synthetic torpor in humans. The first employs existing technology to induce hypothermia as currently practiced in medicine (94), extending this practice to new applications. The second proposes to utilize the metabolic cascade naturally occurring in mammalian hibernators and actuate it in humans (42). This review aims to present the background, strengths, and weaknesses of these two approaches for achieving metabolic depression in humans. Although the necessity of synthetic torpor for long-duration space travel is agreed upon, learning how to reversibly induce this physiology in humans would also positively impact the treatment of various medical pathologies, including cardiac arrest, stroke, traumatic brain injury, newborn hypoxic-ischemic encephalopathy, hemorrhagic shock, refractory seizure, open heart surgery, and cerebrovascular surgery (6, 8, 15, 19, 21, 48, 61, 89, 104, 109).
The therapeutic potential of hypothermia has been recognized since the 4th century BCE, when Hippocrates described the application of hypothermia in the treatment of tetanus and recommended packing wounded soldiers with snow and ice (90). During the Napoleonic campaigns in Russia, physicians noted that, even in “apparent death occasioned by excessive cold . . . animation [has been] brought about after having been suspended for several hours” (46). With these fundamental observations in mind, in 1950 William Bigelow advanced the scientific study of hypothermia with experiments on dogs, showing a profoundly decreased metabolic demand (measured as oxygen uptake) in animals induced to deep hypothermia. By the mid-1950s, several cardiothoracic surgeons were routinely employing the use of hypothermia for open-heart surgeries, with the goal of “excluding the heart from circulation without arrest” (90). Using temperatures around 28°C without cardiopulmonary bypass, ventricular fibrillation occurred in 38% of patients, and the procedures still carried significant (10%) mortality, but that many survived these hitherto lethal conditions and operations neurologically intact was a marked advance (70). In 1963, Christiaan Barnard and Velva Schrire successfully combined cardiopulmonary bypass and deep hypothermic cardiac arrest for aortic arch operations, improving outcomes even further (90).
The understanding of mechanisms behind hypothermia and its therapeutic applications in medicine have expanded over the past 50 years. Hypothermia exerts its therapeutic effects through both protection (i.e., primary prevention) from insult as well as secondary prevention of injury progression. At a simplified level, all cells in a living organism require a constant supply of oxygen and nutrients to maintain their baseline function. If this supply is interrupted or demand otherwise outstrips it, a “cascade of destructive events begins at the cellular level in…minutes to hours” (88). It follows that, by decreasing demand in anticipation of a temporarily reduced supply, this destructive cascade is avoided. It is well-established that hypothermia in humans lowers oxygen consumption. In resting tissues, for each degree Celsius below normal, oxygen consumption decreases by 6% in body tissues and 10% in the brain, such that by 32°C, cerebral metabolic processes are reduced to 50% of baseline (88, 122). As hypothermia progresses, the rate of metabolic suppression declines; cerebral oxygen consumption remains 17% of normal at 15°C (77). Hypothermia also interrupts the cascade of destructive processes that constitute post-resuscitation disease following an ischemia-reperfusion event. Secondary prevention occurs by dampening proteolysis, mitochondrial dysfunction, accumulation of excitatory neurotransmitters, free-radical production, vascular permeability, cellular membrane disruption, and pro-inflammatory and pro-thrombotic cascade activation (2, 6, 59, 88).
The mechanisms underlying primary versus secondary prevention guide current treatment of and with hypothermia in medicine, giving promise for expanded applications such as long-range space exploration. Utilized protectively, hypothermia treatment is “initiated before the insult, which leads to preservation” (93). Following the same principles under which the technique was developed in the mid-20th century, as described above, deep hypothermic circulatory arrest in conjunction with cardiopulmonary bypass is employed today for open surgeries on the brain, heart, aortic arch, and great vessels. As described in its name, patients are cooled to profound levels (14–20°C), with a 30- to 40-min period of total circulatory standstill to achieve a static, bloodless field while operating on these central structures (108). Cases of cardiac arrest from accidental hypothermia also illustrate the protective mechanism. This cohort correlates well to a potential space traveler in that many of them are young and healthy at baseline. The lowest recorded temperature in a case of accidental hypothermia with prolonged (6 h and 52 min) cardiac arrest and good neurological outcome was 13.7°C. These patients’ survival does not correlate directly with a shorter duration of circulatory arrest before native or assisted (as in extra corporeal membrane oxygenation) circulation, in contrast to cardiac arrest that is not preceded by hypothermia (56).
Use of hypothermia for secondary prevention of injury, or “resuscitative hypothermia,” has been applied to a variety of medical pathologies. Randomized controlled trials of targeted temperature management (TTM) at mild-moderate levels (32–36°C) for 24–48 h have demonstrated improved survival and neurological outcome among adults after out-of-hospital cardiac arrest (9, 59). Moderate hypothermia (33.5°C) for 72 h is also well supported as standard of care among term infants with hypoxic-ischemic encephalopathy (98). A handful of case-control trials demonstrated decreased intracranial pressures with TTM between 35 and 37°C among patients with traumatic brain injury or spontaneous intracranial hemorrhage but have yet to show improvement in patient-centered outcomes such as survival and neurological function (21).
Although medical practice of hypothermia provides background knowledge to inform future uses, its external validity is currently limited due to the fact that all profound or prolonged applications of hypothermia occur in a critical care setting, requiring a high level of human and material resources to support survival. From an engineering standpoint, deep hypothermia, as in the cases of protective and accidental hypothermia, is desirable for its feature of extreme metabolic depression: little energy is required to sustain life, and little waste is generated. At these temperatures, no sedation, analgesia, or shivering suppression is required, but over one in three patients will develop ventricular fibrillation cardiac arrest, which is universally fatal if untreated or unsupported (70). Even with cardiopulmonary bypass, which is invasive and intensive, studies of aortic arch surgery show that durations of deep hypothermic circulatory arrest for a median of 31 min is associated with a 7% rate of stroke and a 10% rate of mortality, with durations exceeding 45 min, increasing the risk of these outcomes (47). Additionally, duration of cardiopulmonary bypass is an independent predictor of morbidity relating to severe hemorrhage, an event that occurs in up to 25% of aortic arch surgery patients (49). Although moderate hypothermia as used in targeted temperature management for adults is tolerated for up to 48 h, durations of >24 h are associated with increased complications (67, 75). These durations fall far short of the times required for travel to Mars and beyond.
Additional challenges of inducing and maintaining moderate hypothermia—and their associated complications—abound in nearly every aspect and organ system (FIGURE 2). Although hypothermia was historically achieved by external cooling, endovascular cooling is currently recommended for TTM since it achieves target temperature faster, affords better control of temperature, especially during induction and rewarming phases, is associated with fewer temperature-related complications (88), and has lower rates of shivering (75). This approach, however, requires central venous access, which comes with its own adverse outcomes. In the U.S., there are approximately three central venous catheter-related bloodstream infections for every 1,000 catheter-days, with an associated mortality of 0.4–0.75 per 1,000 catheter-days (74). In one study, the compound rate of adverse mechanical complications, including arterial injury, hematoma, and pneumothorax, was two events per 1,000 catheter-days, and the rate of symptomatic deep vein thrombosis was 1.7 per 1,000 catheter-days (74). In the cardiovascular system, bradycardia and hypotension are expected, and arrhythmias are common (21). Continuous monitoring of rhythm by telemetry is standard. When they do occur, arrhythmias are generally less responsive to medical and electrical management than in normothermia (122). In a study of patients undergoing TTM after out-of-hospital cardiac arrest (OHCA), 36% experienced a clinically significant arrhythmia, with a relative risk of 1.25 compared with OHCA patients not undergoing TTM (120). Accurate monitoring of blood pressure is required. In the intensive care unit (ICU), this is done by an intra-arterial line, which carries the potential for hematoma, aneurysm, and fistula formation, in addition to limb ischemia.
FIGURE 2.Features and concerns regarding targeted temperature management as currently practiced
Figure depicts issues central to the care of critically ill patients undergoing targeted temperature management. Type colors indicate the following: black, needs (N) and/or complications (C); blue, what is required; red, adverse effects, for each organ system. *Central line complications, including infection, arterial injury, hematoma, occlusion, thrombosis, and pneumothorax. **Adverse effects associated with TPN include breakdown of the endogenous gut barrier, decreased mesenteric blood flow, suppressed local systemic immune function, electrolyte derangements, hepatic steatosis, cholestasis, bowel sepsis, impaired oxygenation, and a generalized pro-inflammatory state. ***Although deeper hypothermia may confer benefits, in humans, it leads to myocardial irritability, arrhythmogenicity, circulatory collapse, hypoventilation, electrolyte derangements, immunosuppression, and coagulopathy. Little is known about outcomes of deep hypothermia in the absence of cardiopulmonary bypass or for prolonged periods of time.
Hypothermia leads to immune-related dysfunction (17, 75): 39% of ICU patients undergoing TTM after cardiac arrest experience pneumonia, with a relative risk of 1.18 compared with normothermic controls. Six percent of the same population developed sepsis (120). Effects of TTM in the dermatological system include skin breakdown and pressure ulcers; subsequent systemic infection with cutaneous flora is common with TTM in the ICU setting (88). Skin breakdown, at least, is likely to be less problematic in a zero-gravity environment. In the renal and genitourinary systems, hypothermia induces diuresis, requiring volume expansion with intravenous fluids (75) as well as a waste management system. Indwelling urinary catheters are associated with a high incidence of urinary infection at baseline (1.5 per 1,000 catheter-days), with bacteruria developing at a rate of 3–10% per day of catheterization (36) and even greater rates among TTM patients (88). Long-term transurethral catheters can also cause local pressure necrosis and tissue breakdown.
Although cardiac instability and infectious complications are paramount, hypothermia affects every organ system, and each poses risk to the organism at large. In the pulmonary system, mechanical ventilation is required for airway protection and to maintain respiratory drive in hypothermic patients. This necessitates close monitoring for changes and complications, and frequent pulmonary toilet. Prolonged intubation requires tracheostomy to prevent laryngeal damage, but tracheal stenosis or fistulas can still occur. Positive-pressure mechanical ventilation is associated with a host of dangerous complications, including pneumonia and ventilator-induced lung injury. Over long periods in conjunction with stasis and inflammation, the intrinsic muscles of respiration may become weak and insufficient to resume adequate native respiration (75). Effects of hypothermia in the endocrine system include electrolyte shifts, decreased insulin secretion, and increased insulin resistance (17). Among cardiac-arrest patients undergoing TTM, clinically significant hyperglycemia, hypoglycemia, and hypokalemia occurred in 37%, 6%, and up to 50%, respectively. The relative risk of hypokalemia among cardiac-arrest patients undergoing TTM compared with normothermia was 2.35 (83, 120). Standard monitoring and treatment include regular laboratory testing, electrolyte repletion, and exogenous insulin administration for glucose control. In the gastrointestinal system, hypothermia is associated with decreased gastrointestinal motility, which can lead to ileus, obstruction, perforation, and sepsis. Total enteral nutrition is tolerated in TTM (17) and preferred (versus total parenteral nutrition), since it helps prevent structural breakdown of the endogenous gut barrier, improves mesenteric blood flow, and enhances local systemic immune function. Total parenteral nutrition may help decrease stool output but requires a central venous catheter (with associated complications as listed above) and increases risk of electrolyte derangements, infection, hepatic steatosis, cholestasis, bowel sepsis, impaired oxygenation, and a generalized pro-inflammatory state (75). Fecal management systems decrease general sacral skin breakdown but can also cause anorectal pressure wounds and fissuring. Hypothermia is associated with coagulopathy, whereas stasis is a pro-thrombotic state. It is unclear what cumulative long-term effects these opposing processes would have on the hematological system in a zero-gravity environment. Muscular deconditioning, atrophy, myopathy, and osteopenia are complications faced by both astronauts and ICU patients (31, 37, 69). Stasis while hypothermic in zero gravity may compound these issues. Finally, affecting the central nervous system, mild and moderate hypothermia require sedation, muscle relaxation, and potentially paralysis to prevent discomfort, agitation, and shivering (75). Uncontrolled shivering depletes energy reserves (17), reverses or combats hypothermia, and leads to muscle breakdown and metabolic derangements. Long-term sedative use can lead to withdrawal and delirium (75).
Therapeutic hypothermia as currently practiced is resource intensive and invasive. Many of the complications discussed have overall low absolute risk even among an unhealthy patient population, but the compound risk of any adverse event occurring is inherently higher. Although it is difficult to interpret how the litany of complications described above would manifest—if at all—in a population of young and robust individuals, under the demands of space exploration there is little tolerance for iatrogenic outcomes that diminish function. Moderate hypothermia as currently induced with targeted temperature management cannot be extrapolated to a healthy population preparing for long-duration spaceflight. Healthy human volunteers, however, have demonstrated the ability to achieve and tolerate mild hypothermia (35–36.3°C) for 90 min using intravenous dexmedetomidine and no other form of support or intervention (18), but the effects of deeper and more prolonged hypothermia in this population remain unknown.
In contrast to the multi organ-system battle that ensues in the artificially hypothermic human, when natural hibernators enter torpor in ambient temperatures near or below freezing, their metabolic rate plummets and body temperature drops to
0°C (5), yet the animals are protected from tissue damage and organ dysfunction throughout the body (19, 104). Such hibernators, representing the most extreme examples of metabolic depression known in mammals (62, 114), store fat before the onset of hibernation, which allows them to completely cease eating and drinking for several months (26). During this time, the hibernator preserves organ function and integrity throughout the body while fueling their metabolism with strictly endogenous stores (19, 29). Although these physiological traits of hibernation would be highly desirable for long-duration space exploration and applicable to numerous health challenges encountered routinely on earth (104), the feasibility of a hibernating human is questionable. Unlike natural hibernators, humans generally do not tolerate wide physiological deviations from our accepted homeostatic range. Even if we did, there is much to learn about the mechanisms underlying natural hibernation before synthetic torpor can be engineered in humans. Yet, although these obstacles are significant, they may not be as insurmountable as they appear.
Hibernation lies at the extreme end of a continuum of depressed activity states that begins with slow-wave sleep (FIGURE 3A) (7, 78, 114). Because humans typically spend a significant proportion of every night in slow-wave sleep with lowered metabolic rate and reduced body temperature (39, 53, 65, 66), we can conclude that the physiological mechanisms needed to orchestrate depressed metabolism and permit a decline of core body temperature are innately present. Hibernators enter torpor from slow-wave sleep (51, 117). Thus one potentially viable approach to achieve synthetic torpor in humans is to learn to deepen and elaborate these more subtle mechanisms of metabolic depression during sleep.
Metabolic flexibility is in our DNA. Species that use daily torpor, hibernation, or estivation—all patterns that include periods of depressed metabolism—are widely distributed among mammals (92). Controlled metabolic depression appears on all three of the main mammalian lineages: monotremes, marsupials, and placentals. Within placentals, species exploiting metabolic depression are interspersed with species that do not in all four of the main branches, including the one leading to primates (FIGURE 3B). Daily torpor or hibernation is also used by several species of birds (78). This broad distribution of endotherms with metabolic flexibility implies that the common mammalian ancestor was either capable of torpor or that only relatively simple modification of the genetic hardware found in all mammals is required to orchestrate and survive torpor (103). Either scenario suggests it should be feasible to exploit preexisting genetic and biochemical pathways to achieve controlled, reversible metabolic suppression in humans.
FIGURE 3.Features of natural hibernation
A: continuum of sleep, torpor, and hibernation. B: Phylogenetic tree of mammals (see Ref. 38), branches with at least one species using torpor or hibernation are indicated (+). C and D: body temperature dynamics during hibernation in an arctic ground squirrel (C), or a fat-tailed dwarf lemur in either a well-insulated (top) or a poorly insulated (bottom) tree hole (D). Note that the increase in metabolic rate (D) follows tree hole temperature passively, and no additional metabolic rate elevation is required. Lines represent temperatures of tree hole (black), outside ambient (red), and lemur body (blue); green symbols show metabolic rate. Orange and white regions of bar across the top of graphs in D represent dark and light cycles, or subjective night and day, respectively. Graphs in C and D were modified from Refs. 27, 114, with permission from Springer.
Examples of hypometabolism in humans range from mild and naturally reversible to extreme with survival dependent on invasive medical intervention as described above. On the natural end, metabolic flexibility in Australian aborigines demonstrates tolerance of cold as measured by a lack of shivering, low metabolic rates, and ability to sleep through the night. This tolerance contrasts to unacclimated Scandinavian researchers tested under the same conditions, who were unable to achieve normal sleep patterns due to shivering, discomfort, and elevated metabolic rates (96). Hypometabolism is observed in controlled relaxed states such as meditation (107, 118), where parasympathetic responses dominate over sympathetic responses, analogous to what has been reported for entrance into and maintenance of torpor (50, 124). The human dive reflex, which initiates when the face is submerged in water that is at a cooler temperature than ambient air, also exhibits several physiological parallels to torpor, including reduced heart and metabolic rates (95). On the extreme end, humans have recovered full function after prolonged apnea and cardiac arrest from accidental hypothermia with body temperatures below 18°C, albeit only after aggressive, invasive procedures, as described above (43, 91). Nevertheless, these examples illustrate that humans have an innate ability to survive, and to some extent orchestrate, metabolic depression beyond the
32% (65) achieved for 8 h each night during sleep.
The next key step to engineering human torpor for long-duration spaceflight is to demystify the mechanisms underlying natural hibernation. Our understanding of this process is still fragmentary, and many questions remain. Here, we highlight several recent discoveries about natural torpor and hibernation that are particularly relevant to the application of engineering a comparable phenotype in humans. A more comprehensive view of this field, however, is provided by several review articles and references therein (19, 20, 62, 84, 104).
Understanding thermoregulation is critical to decoding the processes that drive natural hibernation and torpor. As noted above, humans have a strong homeostatic drive to maintain body temperature at the 37°C setpoint, and this must be overcome to induce therapeutic hypothermia. In a functioning brain, this generally requires a combination of sedative and analgesic agents and neuromuscular blockade to suppress shivering, during which respiratory drive is compromised in the absence of artificial support by means of mechanical ventilation. In contrast, when hibernators enter torpor, they gradually lower their homeostatic setpoint such that thermogenic mechanisms are not invoked, and body temperature is allowed to fall slowly (52). Adenosine signaling through A1 receptors in the brain appears to be important for this decline in body temperature during entrance into torpor. In 2011, Jinka et al. (64) showed that central inhibition of adenosine A1 receptors activates metabolic heat production, reversing the fall in body temperature as arctic ground squirrels enter torpor. A decline in body temperature can be induced in these animals by central administration of an adenosine A1 receptor agonist, but only during the season of hibernation, indicating that there is a shift in adenosine A1 receptor distribution or sensitivity when the animals are in hibernation mode versus the half-year when they are not (64). Subsequently, central stimulation of adenosine A1 receptors using the same agonist, N6-cyclohexyladenosine, was shown to lower metabolism and induce hypothermia in a non-hibernator (rat) by inhibiting both shivering and non-shivering thermogenesis (113). This finding supports the existence of a shared mammalian thermoregulatory circuitry (79, 80, 100, 106, 123), but, although central activation of adenosine receptors is necessary (60), it is not sufficient (116) to recapitulate daily torpor in mice. Because skin receptors play a key role in sensing and signaling the need for thermogenic adjustments by stimulating thermogenesis in cold ambient conditions (79), this system must be altered when animals enter torpor such that metabolic heat production is suppressed despite skin cooling. This effect, termed thermoregulatory inversion, is observed when thermogenesis is suppressed by central activation of adenosine A1 receptors in rats (112). The transient receptor potential melastatin-8 (TRPM8) channel is found on primary sensory neurons in the skin that are activated by cold and affect heat generation and conservation mechanisms. Hence, TRPM8-containing neurons appear to be the key afferent signaling pathway in the thermoregulatory system (1). Species-specific amino acid substitutions in TRPM8 in two hibernators, 13-lined ground squirrels and hamsters, cause decreased cold sensitivity on a cellular level and increased cold tolerance on an organismal level compared with rats (76). Additional research is needed to elucidate the role of these genetic modifications in TRMP8 and the resultant influence on thermoregulatory dynamics of hibernation and torpor.
Metabolic depression is just one side of natural hibernation. Although hibernation persists for months, in most species, the animals are not consistently torpid (but see below). Torpor is periodically interrupted by brief arousals, during which metabolic, heart, and respiratory rates, as well as body temperature, are fully restored to euthermic conditions, typically for <1 day (FIGURE 3C). Arousals are fueled solely by endogenous mechanisms and require intense, albeit short, periods of metabolic heat production. Tissue demand for oxygen and body temperature rise rapidly as the torpid hibernator rewarms (in striking contrast to the slow rewarming rates used clinically to reverse moderate hypothermia in targeted temperature management), providing a metabolic milieu that threatens ischemia-reperfusion injury. Survival likely depends on resistance to ischemia-reperfusion injury; such resistance has been demonstrated in multiple organ systems among hibernators (14, 40, 41, 68, 71). The protected phenotype of hibernation in some cases appears to be genetically hardwired, such that the hibernator demonstrates its resistance year round (10), or it may be seasonally expressed (68, 71). Although in most cases the mechanisms underlying resistance are unknown, a recent study demonstrated that the 13-lined ground squirrel is genetically resistant to cold-induced mitochondrial stress caused by reactive oxygen species that lead to catastrophic microtubule depolymerization in neurons and other cell types (85).
Although adenosine plays a central role in the thermoregulatory aspects of torpor, other metabolites are also implicated in natural hibernation. Hydrogen sulfide (H2S) showed initial promise in inducing a hibernation-like state of metabolic depression (11), although the original results were obtained in mice, which naturally use torpor when food-deprived (72). A hypometabolic effect of H2S was not reproduced in other mammals (30, 105), and the hypothermia seen in the original mouse model now appears to have been a consequence of hypoxia rather than H2S (54). H2S is an endogenous gasotransmitter with a myriad of effects in multiple physiological systems (119), including playing a protective role in ischemia-reperfusion injury (33, 58, 86, 99, 121). Results from a plasma metabolomics screen using carefully timed samples from hibernating 13-lined ground squirrels supports a role for H2S in resistance to reperfusion damage during hibernation by depressing the activity of complex IV in the mitochondrial electron transport chain to reduce ROS accumulation during arousal (25). This and other metabolomics data sets underscore a pattern whereby arousals restore levels of metabolites that either deplete or accumulate during torpor (34). Metabolomic, proteomic and transcriptome data sets highlight a shift away from glucose toward fatty acids as the primary fuel during hibernation (3, 44, 45, 73, 81, 82, 97, 115), which may itself be protective against ischemia-reperfusion damage (13). Elevated beta-hydroxybutyrate, typical of hibernation, is also protective in a hemorrhagic shock model (87). Peripheral glutamate receptor activation is required for maintenance of torpor (63). The loss of glutamate signaling, perhaps caused by transamination and conversion to glutamine to protect against toxic nitrogen accumulation (34), results in arousal from torpor (63).
Hibernation has been best studied in small animals that undergo dramatic, periodic cycles between torpor and arousal (FIGURE 3C), but these interruptions of torpor are not an absolute requirement for hibernation. For long-duration space travel, it would be ideal to engineer a torpor that bypassed the need for periodic arousals. Lemurs provide a striking example of metabolic flexibility in terms of their hibernation behavior, exhibiting distinct patterns depending on the environmental conditions. Specifically, when animals are hibernating in constantly cold ambient conditions, torpor is interrupted every few days using metabolic heat production (FIGURE 3D). However, if the ambient temperature increases daily such that body temperature can passively follow it to at least 30°C, torpor is not interrupted (28). Tenrecs (111) and bears (110) also appear to exhibit torpor over extended periods of time at body temperatures near 30°C without the need for periodic arousals. It would be valuable to know whether any of the classical hibernation models, like ground squirrels, could avoid the need for arousal if they were housed in conditions where environmental temperature rose daily above 30°C. If so, this would provide a powerful handle with which to isolate and identify the key regulatory components of the torpor-arousal switch without invasive studies of rare and protected species (12).
In summary, numerous obstacles must be overcome to engineer torpor in humans for long-duration space travel. Hypothermia alone, as currently employed in medical practice, cannot sufficiently create an independently operating, safe milieu of synthetic torpor. Just as basic research on mechanisms underlying thermoregulation inform strategies for achieving induced hypothermia without shivering, so should basic research on the mechanisms underlying natural hibernation torpor help us achieve reversible metabolic depression and tissue protection, bringing us closer to engineering a natural, reversible synthetic torpor in humans. The best chance of success will come from integrating knowledge gleaned from applying modern -omics and quantitative genetics approaches to samples taken from precise time points across the physiological transitions of natural hibernation. Precise sampling should reveal the dynamics of metabolites and gene products, which should illuminate the underlying mechanisms that orchestrate the profound and desirable changes in physiology exhibited by hibernators. Knowledge of the mechanisms responsible for tissue protection and metabolic suppression in the natural hibernator, when applied to engineering synthetic torpor in Homo sapiens, should allow us to push the boundaries of human exploration to the next frontier.