Bear Physiology and
Human Health

The brown bear as a translational model in medical research

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The brown bear is a remarkable animal, exhibiting unique physiological adaptations that allow it to survive in a wide variety of environments. These adaptations are particularly evident during hibernation, a period when the bear undergoes significant changes in metabolism, cardiovascular function, and other physiological processes. Interestingly, despite the drastic physiological changes and the challenges of prolonged inactivity and fasting, the bear emerges from hibernation in a healthy state each spring. This ability to withstand physiological extremes has led researchers to propose using the brown bear as a translational model for understanding human health and disease. Even though they are not closely related, brown bears may be more physiologically similar and therefore relevant to humans than mice and rats, the conventional model animals in medical research. Unlike typical hibernators that lower their body temperature to near-ambient levels, brown bears maintain a moderate hibernation temperature between 33 and 35°C (1). This feature positions them as an interesting translational model for medical research.

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One of the most intriguing aspects of bear physiology is their ability to tolerate obesity and a 'sedentary lifestyle' during hibernation and emerge from the den metabolically healthy in spring. This circular metabolic plasticity is in stark contrast to the linear path to worsening health seen in humans with ‘metabolic syndrome’, a condition characterized by a cluster of conditions that increase the risk of heart disease, stroke, and type 2 diabetes. Understanding the mechanisms underlying the bear's metabolic plasticity could provide valuable insights into the prevention and treatment of metabolic syndrome and other lifestyle-related diseases in humans (2).

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The impact of hibernation on cardiovascular health

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Heart failure: When brown bears hibernate, their cardiac function undergoes significant changes. Using small implantable biologgers, we have been able to monitor heart rate, respiratory rate, and body temperature in bears (3). We observed markedly low winter heart rate in bears, dropping to as few as 10 beats per minute, along with extremely slow blood flow (observed via ultrasound). These findings raise intriguing questions about their ability to evade blood clot formation when they are immobile and provides insights into potential applications for understanding human cardiac conditions like heart failure (the inability of the heart to efficiently pump blood around the body).

 

Behind the scenes: By comparing cardiac structural and functional measures in hibernating and active bears using cardiac ultrasound, we found that during hibernation, bears exhibit a lower heart rate and decreased left ventricular systolic and diastolic measures, including ejection fraction and global longitudinal strain. These findings suggest that hibernating bears undergo cardiac adaptation characterized by reduced myocardial velocities (4, 5).

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Heart attacks: In humans, myocardial infarctions, or heart attacks, usually occur when a coronary artery becomes occluded or obstructed, resulting in a loss of blood supply to the heart. Even after reopening the artery in the hospital using balloon angioplasty, the reestablishment of blood flow can cause additional damage to the heart, known as reperfusion injury. Interestingly, our research suggest that blood serum from brown bears may offer a solution and may serve as a promising new avenue for the development of therapies to treat myocardial infarction.

 

Behind the scenes: When mouse cardiomyocytes (cells responsible for contracting the heart) were treated with winter bear blood serum  (as opposed to summer blood serum ), there was a significant reduction in cell death compared to controls (6).  In another cross-species experiment, we investigated the effects of bear blood serum on human adipose-derived mesenchymal stem cells (ADSCs). We found that ADSCs from patients with ischemic heart disease (coronary heart disease) treated with hibernating bear blood serum showed downregulation of genes linked to inflammation and upregulation of genes associated with cardiovascular development. Blood serum from both hibernating and active bears led to the downregulation of certain genes related to cell growth and differentiation. This suggests that plasma from hibernating bears has the potential to suppress inflammation and promote cardiovascular development in human ADSCs, offering possible therapeutic applications (7).

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Blood clotting – a first breakthrough: Platelets are small, colorless cell fragments in the blood that play a crucial role in blood clotting and wound healing. Brown bears show a notable decrease in platelet aggregation, or clotting, when they hibernate compared to when they are up and active. This reduction in platelet aggregation may serve as a protective mechanism to prevent the formation of blood clots (thrombi) during the periods of reduced blood flow, which are common during hibernation (8). Humans that experience illnesses or injuries that leave them immobile for short periods of time have increased risk of venous thromboembolism (VTE). VTE is characterized by the formation of blood clots in the deep veins of the legs (deep vein thrombosis) that can travel to the lungs (pulmonary embolism) which can be life threatening. Interestingly, both hibernating brown bears, which remain immobile for months, and humans with paralyzed spinal cord injuries are protected from VTE. This has important implications for the prevention and treatment of thrombotic diseases in humans such as deep vein thrombosis and pulmonary embolism.

 

Behind the scenes: Our recent research suggests the mechanism behind this is the downregulation, or decreased production, of a certain heat shock protein (HSP) called HSP47. HSPs are proteins that are produced in higher quantities when the body is exposed to stressful conditions. Downregulation, or decreased production, of HSP47 decreases immune cell activation as well as something called ‘neutrophil extracellular trap formation’. The result is that the downregulation of HSP47 offers protection from thrombosis and VTE for both hibernating bears and paralyzed humans. This appears to be an evolutionarily conserved mechanism that protects hibernating bears from thrombosis while not elevating the risk of bleeding. Importantly, this sets it apart from most conventional anticoagulants used for clot prevention in humans (9). Following a recent major research grant, we are now investigating the role of HSP47 in patients with VTE and other types of blood clots with the hope of developing a new type of anticoagulant.

 

Maintaining oxygen supply: Bears sustain efficient oxygen delivery to the tissues in their body during hibernation without elevating their metabolic rate, a phenomenon that could have applications in human metabolic and respiratory medicine.

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Behind the scenes: Oxygen consumption and blood oxygen affinity, two crucial aspects of respiratory function, also change in brown bears during hibernation. Hibernating bears exhibit a significant reduction in basal oxygen consumption rate (about 25% of that compared to during the active time of year) and a moderate decrease in body temperature. This suggests a temperature-independent aspect of their metabolic depression. Interestingly, despite the decrease in oxygen consumption, hibernating bears exhibit higher blood oxygen affinity, attributed to lower levels of a certain red blood cell (Hb-cofactor 2,3-diphosphoglycerate, or DPG) during hibernation. This decrease in DPG is crucial for maintaining tissue oxygen tension during hibernation without significant upregulation of glycolysis, the metabolic pathway that converts glucose into pyruvate and generates energy (10).

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Hibernation and lipid metabolism, diabetes, and atherosclerosis

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Avoidance of diabetes - lipids and the gut: Fatty acid metabolism is another area where bears exhibit unique adaptations during hibernation. We investigated how free-ranging brown bears manage to gain weight before hibernation without developing issues like insulin resistance. Insulin resistance is an impaired response to insulin by the body that results in elevated levels of blood sugar (glucose), which is a key component of type 2 diabetes and often a problem related to human obesity. We also explored whether gut microbiota (the microorganisms that live in the digestive tract) help bears adapt to hibernation. Our results suggest that gut microbiota play an important role in bear metabolic adaptations and cardiovascular health. This information could potentially offer insights into novel treatments for lifestyle diseases like chronic kidney disease, which is often associated with cardiovascular disease (11).

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Behind the scenes: The first example study focused on the expression of proteins associated with lipid (fat) breakdown, or lipolysis, in the bears' adipose tissue (body fat). This study found that while the expression of Adipose Triglyceride Lipase (ATGL) remained constant across seasons, there was a significant increase in the expression of proteins that inhibit the breakdown of lipids, or fats, during the summer. This suggests that bears naturally regulate the breakdown of fat in a way that preserves insulin sensitivity even as they gain weight, potentially offering options for human therapies (12).

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Both brown bears and garden dormice show consistent changes in fatty acid profiles between hibernation and summer, including reduced levels of certain fatty acids (alpha-linolenic acid and eicosapentaenoic acid), and increased levels of others (docosapentaenoic acid which is an omega-3 fatty acid). Interestingly, dietary differences affect these profiles, with high intake of linoleic acid, an omega-6 fatty acid, unexpectedly boosting the transformation of omega-3 fatty acids. These findings suggest a link between fatty acid patterns and the hibernation phenotype, highlighting the complex connections between diet, fatty acid metabolism, and hibernation (13).

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In a study of gut microbiota of brown bears, we explored how they maintain metabolic health despite seasonal obesity. We found distinct changes in the microbial composition and diversity of gut microbes between active and hibernating states, accompanied by shifts in lipid metabolism markers like cholesterol and triglycerides. When these gut microbes were transplanted into germ-free mice, the bear microbiota induced some of these seasonal metabolic changes. Mice transplanted with summer microbiota became obese, whereas those with winter microbiota remained lean; notably, both groups evaded insulin resistance - a prominent characteristic of obesity and a precursor to diabetes (14). These findings imply a functional role for gut microbiota in the bear's metabolic adaptations.

 

Gut metabolites (substances produced by the gut microbiota) also play a crucial role in the bear's cardiovascular health during hibernation. In a study comparing the levels of the gut metabolites betaine, choline, and trimethylamine N-oxide (TMAO) in human chronic kidney disease and various animal species, including hibernating brown bears, we found that these metabolites are associated with kidney function in humans. In contrast, free-ranging brown bears exhibit a unique pattern during hibernation, with increased betaine and choline levels but undetectable TMAO (11).

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Atherosclerosis – clogged arteries: Despite the large lipid (fat) fluxes during hibernation, brown bears do not develop atherosclerosis. Atherosclerosis a condition characterized by the buildup of fats, cholesterol, and other substances in and on the artery walls which results in clogged arteries. This is in contrast to humans and non-hibernators, who often develop clogged arteries and related cardiovascular diseases in response to high cholesterol levels and other metabolic problems. Our research suggests that brown bears may serve as a model for studying atherosclerosis resistance and related cardiovascular diseases in humans (15)

 

Behind the scenes: We analyzed lipid profiles and arterial histopathology in free-ranging brown bears during hibernation and active periods. Despite elevated lipid levels during hibernation, bears showed no signs of clogged arteries, suggesting brown bears may serve as a model for studying atherosclerosis resistance (15). Another, contributing mechanism shielding bears from heart attack was found when we studied two antibodies (known as anti-PC and anti-MDA) in brown bears during hibernation and active periods. Elevated levels of certain anti-PC antibodies were found in hibernating bears, potentially serving as a natural defense against heart issues like atherosclerosis (16).

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One of the mechanisms underlying the bear's resistance to clogged arteries is the management of lipid fluxes through changes in the composition of high-density lipoproteins (HDL), the so-called 'good' cholesterol. For instance, bears exhibit higher levels of inflammatory metabolites (such as 7-ketocholesterol and 11ß-prostaglandin F2α) during hibernation, which correlate inversely with cardioprotective HDL proportions and HDL sizes. Additionally, greater plasma antioxidant capacities in hibernating bears prevent excessive lipid-specific oxidative damages in plasma and muscles (17). These findings suggest that modulation of lipid metabolism and antioxidant defenses could be a promising strategy for preventing atherosclerosis and related cardiovascular diseases in humans.

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In another study we examined plasma lipoproteins across winter and summer in 10 bears, focusing on LDL cholesterol (so-called ‘bad cholesterol) binding to arterial proteoglycans and cholesterol efflux capacity (CEC) (18). We found that bear LDL, which is larger and richer in triglycerides, binds less to arterial proteoglycans than human LDL and that bears have higher plasma CEC, particularly in the HDL cholesterol (‘good cholesterol’) fraction. This suggests the bears' resistance to early atherosclerosis may also be due to these unique lipid transport properties in their blood.

Hibernation and muscle and bone

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Muscle preservation and protein regulation: Muscle atrophy, or the wasting away of muscle tissue, is a major health challenge in humans, particularly for people with prolonged immobility or certain diseases. Interestingly, hibernating brown bears are able to resist muscle atrophy despite the prolonged period of inactivity during hibernation. Remarkably, human muscle cells exposed to winter bear blood serum showed reduced protein turnover and inhibited proteolysis, resulting in increased muscle cell protein content (19). Thus, research on hibernating bears has important implications for the prevention of muscle loss in humans with medical conditions that leave them immobile for extended periods of time.

 

Behind the scenes: Halofuginone, a pharmacological agent, activates Activating Transcription Factor 4 (ATF4)-regulated genes associated with muscle atrophy. Interestingly, it also inhibits Transforming Growth Factor-beta (TGF-β) signaling while promoting Bone Morphogenetic Protein (BMP) signaling, leading to reduced muscle atrophy under hindlimb suspension conditions. These regulatory patterns are similar to those observed in the muscles of hibernating brown bears, which are resistant to atrophy. The data suggest that activation of ATF4 does not invariably result in muscle atrophy and that modulation of TGF-β/BMP signaling may present a novel approach for preventing muscle loss (20). Another potential musculo-protective mechanism in bears involves increased expression of cold-inducible proteins and downregulation of components in mitochondrial electron transfer, reducing reactive oxygen species production (21).

 

MicroRNAs and the endocannabinoid system in muscle atrophy resistance: Our research suggests that microRNAs (small non-coding RNAs that regulate gene expression) also play a crucial role in the bear's resistance to muscle atrophy during hibernation.

 

Behind the scenes: A study using quantitative reverse transcription PCR (RT-qPCR) found that several microRNAs associated with skeletal muscle development, metabolism, and regeneration are upregulated in the vastus lateralis, a muscle in the thigh, of hibernating brown bears. These include miR-1 and miR-206, which are controlled by the transcription factor MEF2A and promote muscle maintenance by downregulating the genes pax7 and id2. Additionally, several metabolic microRNAs, including miR-27, miR-29, and miR-33, are increased during hibernation, suggesting metabolic suppression (22). These findings highlight the complex interplay between microRNAs and other regulatory molecules in the bear's resistance to muscle atrophy during hibernation.

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The endocannabinoid system (ECS), a complex cell-signaling system that plays a crucial role in regulating a wide range of physiological processes. During hibernation in brown bears, the ECS undergoes marked changes, such as decreased concentrations of 2-arachidonoylglycerol in adipose and muscle tissues and reduced mRNA levels for CB1 and CB2 receptors. These alterations facilitate fatty acid mobilization and carbohydrate metabolism in muscle, likely playing a pivotal role in sustaining hibernation. Elevated levels of the endocannabinoid-like compound N-oleoylethanolamide may support lipolysis and fatty acid oxidation, while also conserving anorexigenic signals (23).

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Bone health and vitamin D metabolism: Bone health is another area where bears exhibit unique adaptations during hibernation. In addition to muscle loss, humans also experience bone loss during prolonged periods of immobility or inactivity. However, bears do not lose bone mass during hibernation. Understanding the mechanisms underlying the bear's preservation of bone health during hibernation could provide valuable insights into the prevention and treatment of osteoporosis and other bone diseases in humans (24).

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Behind the scenes: We examined 25-hydroxy-vitamin D (25OHD) levels and bone markers in hibernating and active bears found that levels of 25OHD, a measure of vitamin D status, are higher in summer than in winter. Despite this seasonal variation in 25OHD levels, bears do not lose bone mass during hibernation (24).

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Hormonal changes and their impact on metabolism during hibernation

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Hypothyroidism: Hibernating bears are hypothyroid, meaning the thyroid gland is making less thyroid hormone when bears are hibernating compared to active. This hypothyroid state is associated with several physiological features that are also seen in hypothyroid humans, including decreased basal metabolic rate, bradycardia (slow heart rate), hypothermia (low body temperature), and fatigue (25). Further research on bear thyroid function could offer insights into human endocrine and metabolic disorders.

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Behind the scenes: Hibernating bears have levels of thyroid hormones thyroxine (T4) and triiodothyronine (T3) reduced to less than 44% and 36%, respectively, of those measured during their active period.

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The role of steroid hormones: Shifts in hormones may contribute to the bear's ability to survive the prolonged period of inactivity and fasting during hibernation. This presents another interesting avenue for research linking bear physiology to human medicine.

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Behind the scenes: In brown bears during hibernation, total plasma protein concentrations increase, even though most individual plasma proteins decrease. Notably, there is a striking 45-fold increase in Sex Hormone-Binding Globulin (SHBG) (26, 27). This increase in SHBG could potentially dampen the activity of reproductive hormones, thereby contributing to the bear's ability to survive the prolonged period of inactivity and fasting during hibernation (28). The protein adaptations are likely facilitated through three key mechanisms: dehydration, which augments protein concentration without new synthesis; reduced protein degradation, due to a moderate drop in body temperature and lowered protease activity; and strategic de novo synthesis of select vital proteins.

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Conclusion

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Brown bear physiology serves as a novel translational model for advancing our understanding of human metabolic and cardiovascular disorders. The bear's distinctive anti-thrombotic mechanisms hold significant promise, offering insights that could lead to the development of safer and more effective anticoagulant therapies. The unique metabolic adaptations observed in hibernating bears could guide the creation of novel interventions for human conditions such as insulin resistance and obesity. Moreover, bears display intriguing cardio-protective and anti-inflammatory properties, suggesting new therapeutic possibilities for managing ischemic heart disease. Collectively, our findings have the potential to transform both the prevention and treatment of a wide array of human diseases.