They Hibernate; Humans Trudge On

Courtesy of Hannah Carey OUT COLD: The Spermophilus tridecemlineatus or thirteen-lined ground squirrel, assumes a spherical posture when in torpor to reduce its surface to volume ratio and therefore rate of heat loss. Its heart rate will go as low as 3-5 beats per minute and its body temperature to just a degree or so above ambient temperature. In this cold room, that's 3° to 4° C. As days shorten and the cold encroaches, roughly two dozen mammalian species fatten up and settle down for a long winter's nap. Humans, however, continue to trudge through the frigid darkness, and researchers aren't entirely sure why. Total human hibernation is a bit far-fetched, yet many mammals--from bears to shrews--hibernate, and researchers want to know more. "The general feeling is that hibernators have the same collection of genes and proteins that humans do, but express them at different places and times," says Hannah Carey, a professor in the Department of Comparative Biosciences at the University of Wisconsin, Madison School of Veterinary Medicine. She says she's confident that studies will uncover and eventually reveal how to manipulate such pathways. Researchers may never be able to recreate Sleeping Beauty. Nonetheless, hibernators could teach humans some other tricks. Black bears stave off osteoporosis during long periods of lethargy. Ground squirrels suppress stress responses that would normally be harmful, including inflammatory shocks to the system and blood rushing to the brain that rivals the severity of strokes. Organs removed from hibernating animals survive three times longer than organs removed from nonhibernators, a tantalizing feature that has caught the attention of transplantation researchers. THE BIG SLOWDOWN Hibernators only look like they're sleeping. Their bodies rest in a state called torpor, which is characterized by an extremely low metabolic rate. Arctic ground squirrels drop their heart rates to just 3-5 beats per minute, cerebral blood flow is reduced by about 90%, and circulating white blood cells fall by 95%. "They are in a state of almost suspended animation," says Ken Storey, a professor at Carleton University in Ontario. During torpor, animals switch from carbohydrate to fat metabolism, and most have a body temperature only a few degrees above their surroundings. Surpassing descriptive studies has been challenging. Although it was shown in the 1970s that a circulating blood factor could trigger hibernation in squirrels,1 efforts to purify this factor, called the hibernation induction trigger (HIT) have been unsuccessful. Progress is also slow because the research community is small, and most of the animals they use must be caught in the wild. The animals are easily disturbed at certain stages, making it hard, for example, to study entrance into torpor. Perhaps most importantly, molecular tools are lacking for such obscure models as, say, black bears. "We're having a hard time because the antibodies we can get don't cross-react with the molecules we're trying to study," says Seth Donahue, an assistant professor at Michigan Technological University in Houghton, who is trying to determine the molecular mechanisms the bears use to prevent bone loss during hibernation. Nevertheless, the research is moving forward. Donahue's research shows that unlike humans, bears continue to make bone at normal rates during long immobile periods.2 He intends to test the effects of bear serum, taken during both hibernation and active periods, on bone cells in culture. He hopes to work with proteins or perhaps gene arrays to identify molecular differences between the two physiological states. HOT AND COLD Heat shock proteins, oddly enough, play a key role in surviving the big chill. They were originally found to be induced when animals were stressed by heat, but it turns out that HSPs, also known as stress proteins, protect cells from all kinds of stress, including heat, cold, changes in salinity, and perhaps the dramatic cellular changes that can occur in hibernating animals. During actual hibernation the animals are stress-free. "I think of it as nirvana," says Kelly Drew, an assistant professor at the University of Alaska in Fairbanks. For most hibernators, nirvana is periodically interrupted by short, dramatic arousals during which the body temperature rises as much as 30 degrees in a few hours. The purpose of arousal baffles hibernation researchers. The animals typically urinate, sleep, and increase protein translation, but nobody is certain what triggers arousal or which activities are necessary. These bouts of arousal provide a natural model for studying tolerance to stroke, because blood rushes through their organs, including the brain. "They're working so hard. Their heart rate peaks and they're shivering. So physiologically [arousal] is the most stressful time," says Drew. Hibernation researchers theorize that stress proteins would play an important role in the animals' ability to endure repeated cycles of torpor and arousal. "[The proteins] help maintain viability when stressful events occur to a cell. The changes that we see in stress-protein expression ... may be part of the whole suite of adaptations that allows hibernators to go through the very dramatic physiological changes." says Carey. Storey says stress-activated kinases, such as P38, are important for modulating the intracellular environment during hibernation and arousal. "Stress-activated kinases reach out and phosphorylate key calcium channels that regulate how cells deal with blood," he says. Without these stress-activated kinases that are upregulated during hibernation, sodium and potassium would leak out of cells, and calcium would rush in, ensuring cellular disaster. "[These] kinases that are turned on in hibernation keep cells from leaking or pumping to death," says Storey. In new, unpublished work, Carey and her collaborators discovered other stress proteins that may be important in hibernation. Hibernating ground squirrels have significantly increased gut levels of glucose-regulated protein 75 (GRP75), which is known from other studies to help chaperone mitochondrial proteins and keep them in the proper folded state during stress. Carey and Sandra Martin at the University of Colorado Health Sciences Center in Denver say they also discovered that the livers in hibernating squirrels have an excess of the chaperone GRP78, which has been implicated in ischemic preconditioning in the brain. GRP78 could help the liver better tolerate reperfusion during arousal. Other researchers also have found increased expression of both GRP75 and GRP78 in brains of bats arousing from hibernation.3 Further, Carey's group found that hibernating squirrels, when compared to rats, have the well-characterized chaperone, HSP70, at levels five to 10 times higher in a variety of organs. They did not see a difference between summer and winter squirrels, but rather a consistently high level of HSP70. The results support an emerging hypothesis that hibernators may have overall higher levels of stress proteins to precondition them for the stress associated with entrance into or arousal from torpor. Drew has similar, unpublished results showing that during their active phase, Arctic ground squirrels are experiencing chronic stress: Mild hypoxia (as demonstrated by low PaO2 levels) continually activates molecules in stress-activated kinase pathways such as c-Jun N-terminal kinase (JNK) and p38. "I think it prepares them for the transition out of hibernation," she says. Cells might be preconditioned to better tolerate the intermittent bouts of arousal, where Drew's group has noticed that despite apparent physical stress, stress-activated protein kinase activity is attenuated. "So at the physiological level they are stressed, but at the cellular level they are protected. Some of these processes associated with hibernation are keeping these [stress] processes in check during arousal, allowing them to tolerate the whole thing," she says. Drew emphasizes that the squirrels suppress inflammation during arousal and that understanding how this happens may be important for stroke research. "[In humans] when blood starts to flow after stroke, inflammation plays a key role in progressive deterioration of the brain.... These squirrels are dramatically immunosuppressed," she says. Courtesy of Hannah Carey AWAKENINGS: An active squirrel will have a body temperature 36° to 37°C, and a heart rate of 200-300 beats per minute. ORGANS ON ICE The adaptations that seem to allow hibernators to endure the dramatic changes of the hibernation cycle also may provide clues for prolonged storage of organs. For example, kidneys transplanted from animals in deep hibernation could withstand 72 hours on ice, whereas those from nonhibernating animals lasted only 24 hours. Livers also can withstand cold storage for much longer periods when the donor is a hibernator. At the physiological level, the livers appear to last longer because a subset of endothelial cells lasts longer. These cells support microcirculation in the liver, and they break down quickly in organs from nonhibernators. Researchers think that increased levels of stress proteins and antioxidants may prolong the liver's shelf life. "There seems to be less oxidative stress to cold-stored livers in the hibernators," says Carey, whose research is funded by the US Military's Defense Advanced Research Projects Agency. The military would like to slow down tissue and organ damage on the battlefield, allowing more time for soldiers to reach medical facilities. "[Hibernators] undergo major changes of metabolism, body temperature, respiration, heart rate, and other physiological events as they enter torpor, and then everything is rapidly reversed during arousal," says Carey. "If we understand at the tissue and cellular level the protective mechanisms hibernators use to withstand such extreme changes, we are in a better position to translate hibernation biology into new ways to improve trauma care in other species, including humans." Mignon Fogarty (mignon@welltopia.com) is a freelance writer in Santa Cruz, Calif. References 1. A.R. Dawe et al., "Summer hibernation induced by cryogenically preserved blood 'trigger,'" Science, 168:497-8, 1970. 2. E. Russo, "Bear bones research," The Scientist, 17[8]:27, April 21, 2003. 3. M. Lee et al., "Activation of stress signaling molecules in bat brain during arousal from hibernation," J Neurochem, 82:867-73, 2002. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

They Hibernate; Humans Trudge On

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Courtesy of Hannah Carey
OUT COLD: The Spermophilus tridecemlineatus or thirteen-lined ground squirrel, assumes a spherical posture when in torpor to reduce its surface to volume ratio and therefore rate of heat loss. Its heart rate will go as low as 3-5 beats per minute and its body temperature to just a degree or so above ambient temperature. In this cold room, that's 3° to 4° C.