ANRV334-ME59-12 ARI 16 December 2007 14:50 Is Human Hibernation Possible? Cheng Chi Lee Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030; email: [email protected] Annu. Rev. Med. 2008. 59:177–86 Key Words The Annual Review of Medicine is online at hypothermia, 5-AMP, torpor, hypometabolism http://med.annualreviews.org This article’s doi: Abstract 10.1146/annurev.med.59.061506.110403 The induction of hypometabolism in cells and organs to reduce is- Copyright c 2008 by Annual Reviews. chemia damage holds enormous clinical promise in diverse fields, in- All rights reserved cluding treatment of stroke and heart attack. However, the thought 0066-4219/08/0218-0177$20.00 that humans can undergo a severe hypometabolic state analogous to hibernation borders on science fiction. Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state. To date, the underlying mecha- nism for hibernation or similar behaviors remains an enigma. The beneficial effect of hypothermia, which reduces cellular metabolic demands, has many well-established clinical applications. However, severe hypothermia induced by clinical drugs is extremely difficult and is associated with dramatically increased rates of cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5-AMP, which allows nonhibernating mammals to rapidly and safely enter severe hypothermia could remove this impediment and enable the wide adoption of hypothermia as a routine clinical tool. 177 ANRV334-ME59-12 ARI 16 December 2007 14:50 INTRODUCTION ing mammals. Whether chemically induced hypometabolism has any connection with the The word hibernation is often associated with natural process is not critical; observations bears taking a long winter rest. However, from these studies can be drawn upon to re- some investigators would argue that bears do veal the underlying biochemical and molecu- not really hibernate but rather enter a state lar processes of hypometabolic behaviors. of torpor. In mammals, the term torpor is of- Clinically, only mild hypothermia of 32– ten used when body temperature drops below ◦ ◦ 34 C can be induced safely by a cocktail of 31 C. Hibernation is often described as deep paralytic drugs and anesthesia (2, 3). Severe torpor. Although both words are widely used hypothermia (28◦C or lower) induced by such in the scientific literature to reflect different drug cocktails results in a high cardiac ar- degrees of a hypometabolic state, their physi- rest rate in nonhibernating mammals (4). To ological definitions are not clear. In addition, date, three classes of molecules will result some reptiles and amphibians can undergo in reversible severe hypothermia when ad- a hypometabolic process known as estivation ministered to small mammals such as mice to survive challenging environmental condi- and hamsters. Two of these are metabolic in- tions. As articulated by Heldmaier et al. (1), hibitors: 2-deoxyglucose and hydrogen sulfide “The physiological properties of daily torpor, (H2S). The third, recently identified in my hibernation and estivation are very similar. laboratory, is the end metabolite 5-adenosine The classification of hibernation, daily torpor monophosphate (5-AMP). It is the first nat- or estivation simply represents gradual differ- ural biomolecule to have this effect (5). ence in the timing, the duration and the ampli- tude of physiological inhibition.” In essence, these are hypometabolic behaviors used by an- 2-DEOXYGLUCOSE AND imals for energy conservation. On the basis HYDROGEN SULFIDE of oxygen consumption measurements, it was Hamsters are known to undergo daily tor- demonstrated that the biochemical and phys- por to conserve energy upon prolonged ex- iological events that inhibit endogenous ther- posure to low environmental temperature moregulation occur rapidly prior to the onset and short photoperiod, which mimic seasonal of hypothermia (1). In contrast, hypothermia changes (6). This torpor behavior of ham- is driven by heat loss from the body to the sters is circadian-driven. This was demon- environment. This process depends on sev- strated by experiments in which ablation eral parameters including surface/volume ra- of the suprachiamastic nucleus (SCN), the tio, the amount of fur and fat insulation, and central circadian structure, disrupts the an- the temperature gradient between the body imal’s temporal rhythm (7). After receiving and the environment. The molecular and bio- the glycolytic inhibitor 2-deoxyglucose, ham- chemical mechanisms underlying the natu- sters readily undergo torpor even when kept ral shutdown of metabolic activities remain in long photoperiod (8). In contrast, inhibi- largely unknown. tion of fatty acid metabolism by mercaptoac- The goal of this article is not to reca- etate did not induce torpor in hamsters kept pitulate the physiology of hypometabolism in long photoperiod (6). These observations that occurs naturally, as there are excellent implicate impediment of glucose utilization reviews in the literature (1). Instead, I fo- as a key event for hypometabolism. How- cus on recent attempts to mimic the induc- ever, the biochemical mechanism underlying tion of a hypometabolic state in mammals, 2-deoxyglucose induction of torpor remains which may have potential clinical applica- unclear. tions. I also offer some hypotheses on how Another metabolic inhibitor, H2S, was re- hypometabolism could occur in nonhibernat- cently found to enable mice to enter severe 178 Lee ANRV334-ME59-12 ARI 16 December 2007 14:50 hypothermia or suspended animation at a low the environment will not be adequately con- dosage of 80 ppm (9). Mice given H2S could trolled. This reasoning is consistent with the be cooled down to 15◦C into a state of sus- hypothesis that decreased ATP production or pended animation for up to six hours. Arousal utilization is involved in hibernating behav- was spontaneous, and no apparent detrimen- iors (1, 12). How these biochemical observa- tal outcome was observed after recovery. It has tions can be reconciled with the widely held been thought that a core body temperature dogma that the preoptic area of the hypotha- below 20◦C in nonhibernators will lead to car- lamus controls thermal regulatory response in diac fibrillation (10). Our lowest recording of mammals is not clear (13). core body temperature in mice during torpor induced by fasting was about 26◦C even when the ambient environmental temperature was SEARCH FOR AN ENDOGENOUS maintained at 8◦C ( J. Zhang & C.C. Lee, un- MOLECULE FOR published observations). Thus, the ability to HYPOMETABOLISM drop a nonhibernating mammal’s core body For hibernators to achieve a severe hypother- temperature to 15◦C is a major step forward. mic state, the basic principles of metabolic It suggests that nonhibernators are fully capa- biochemistry must be preserved to ensure en- ble of withstanding extreme hypometabolism. ergy homeostasis (12). This raises the possi- As with 2-deoxyglucose, the mechanism bility that such biochemical processes may be underlying H2S induction of severe hy- retained in all mammals. Mammalian organs pothermia remains unclear. H2S is a specific can be maintained in a hypothermic but highly and reversible inhibitor of cytochrome c ox- hypoxic state for many hours (14), as we see idase, a key component of the mitochondria when donor organs are transported in coolers respiratory complex IV (9). Inhibitors of the for organ transplantation. Upon transplan- mitochondria respiratory chain are toxic to tation, the restoration of blood flow and its mammals because they disrupt ATP produc- rewarming revive the basic functions of the tion by oxidative phosphorylation. Similarly, donor organ. In addition, examples from acci- 2-deoxyglucose inhibits glycolysis, which is dental hypothermia have suggested that under another biochemical process involved in the certain conditions, humans can recover fully generation of ATP and NADH from glucose from prolonged periods in severe hypother- outside of the mitochondria. Thus, the actions mia. Critically, these observations suggest that of both H2S and 2-deoxyglucose affect the nonhibernators’ organs are inherently capa- cellular production of ATP. In turn, the lower ble of withstanding extreme hypoxic stress if ATP level would downregulate biochemical their metabolic demands are reduced. Thus, reactions necessary for thermal regulation de- a project was initiated to probe the possibil- fenses. It has been observed that during hiber- ity of identifying genes from nonhibernating nation, erythrocytes and organs have signifi- mammals that are activated in an environment cantly lower ATP levels (11, 12). In particular, encountered during hibernation. the ATP level of erythrocytes from a hiber- It is widely recognized that mammals en- nating animal is ∼50% of the level observed ter hibernation in an environment of constant in a euthermic state (11). Such a large de- darkness (1). Using liver mRNA, gene expres- crease in ATP level in the erythrocyte would sion in mice exposed to regular 12:12 h cycles significantly compromise its function in regu- of light:dark (LD) was compared to gene ex- lating oxygen/carbon dioxide molecules nec- pression in mice kept in constant darkness or essary for maintaining high metabolic activity dark:dark (DD). From microarray analysis, a of the major organs. Under such conditions, it gene encoding procolipase