Perspective

Hypothermia for Longevity: A Thermodynamic Perspective on Aging and Life Extension

Authors

Eve Bakaleinikova^1,*

¹Western Governors University, Salt Lake City, UT, USA

^*Corresponding author: ebakal2@wgu.edu

DOI:https://doi.org/10.59368/agingbio.20250041

Received: 3/20/2025, Revised: 5/25/2025, Accepted: 7/25/2025, Published: 8/21/2025

Full Article |  PDF |  Supplementary 

Abstract

Aging arises from a complex interplay of molecular and systemic factors, including oxidative stress, DNA damage, inflammation, and impaired proteostasis. These mechanisms are intimately linked with thermodynamic processes, suggesting that thermoregulation may influence aging trajectories. This article explores mild induced hypothermia as a potential antiaging intervention. By examining the physiological, molecular, and clinical dimensions of hypothermia, its role in mitigating key mechanisms of aging is explored. Synthesizing findings from thermodynamic aging theory, mechanistic studies on metabolic regulation, oxidative stress, DNA repair, and proteostasis, and clinical evidence from the application of therapeutic hypothermia (TH) in conditions such as cardiac arrest, traumatic brain injury, ischemic stroke, and neonatal hypoxic-ischemic encephalopathy. Mild hypothermia attenuates metabolic strain, enhances mitochondrial efficiency, reduces oxidative damage, activates longevity-associated transcription factors (e.g., FOXO), and stabilizes genomic integrity. It also promotes protein quality control via proteasome activation and reduces systemic inflammation through cold-shock proteins like RBM3. However, adverse cardiovascular, neurological, and metabolic effects at lower temperatures highlight the need for precise regulation. TH is already used clinically in critical care and shows promise in broader applications, including neuroprotection and potentially antiaging. A pharmacologically controlled “hypothermia pill” targeting thermoregulation is proposed as a future avenue. Individualized approaches, real-time biomonitoring, and rigorous clinical trials are essential to safely translate mild hypothermia into a viable longevity strategy.

Introduction

The biology of aging encompasses a wide array of hypotheses, each attempting to clarify why organisms deteriorate over time. Since the mid-twentieth century, hypotheses such as the free radical theory¹, immunological decline² , telomere shortening³, and molecular cross-links⁴ have vied to explain the molecular and physiological underpinnings of aging. By the late twentieth century, the number of such theories had grown into the hundreds⁵, prompting efforts to classify them into two major types: error theories, which emphasize the accumulation of damage, and program hypotheses, which posit that aging follows a regulated biological timetable. More contemporary frameworks often blend these views, suggesting aging results from a combination of genetic regulation, maintenance system decline, environmental stress, and stochastic events⁶. Despite ongoing debate, most gerontologists now agree that aging is multifactorial, with no single cause likely accounting for the entire process across species.

One emerging perspective reframes life itself as a system optimized for entropy production. The thermodynamic approach to life was first proposed by Schrödinger, who described organisms as open systems that maintain their structure by exporting entropy⁷. According to this hypothesis, life arose and evolved not in defiance of but due to the second law of thermodynamics⁸. Organisms transform ordered energy (sunlight, chemical compounds) into thermal radiation, thereby increasing the entropy of their surroundings⁹, and evolution drives the formation of organisms that maximize the transition of energy into heat¹⁰. Such a viewpoint has significant implications for our understanding of aging, suggesting it may arise as a consequence of continuous metabolic strain. Within this framework, thermoregulation, particularly core body temperature, emerges as an important variable. The hypothesis that mild, controlled reductions in body temperature may mitigate metabolic wear introduces a novel pathway for exploring antiaging strategies centered on the physiological and pharmacological induction of mild hypothermia.

Aging as a Result of Entropic Wear and Tear

Multiple aging theories intersect with thermodynamic principles. The predominant oxidative stress theory postulates that the accumulation of reactive oxygen species (ROS) induces damage to multiple molecule types, including DNA and proteins¹¹. The DNA damage hypothesis suggests that the accumulation of genetic damage over time causes genomic instability and contributes to cellular aging¹². The protein homeostasis theory adds a further dimension, asserting that aging involves a gradual loss of the cell’s ability to properly fold, maintain, and degrade proteins. This leads to the accumulation of misfolded or aggregated proteins, which are toxic to cells and linked to a myriad of diseases, often affecting the nervous system¹³. Another prominent theory is “inflammaging,” which proposes that aging is driven in part by chronic, low-grade inflammation resulting from sustained immune activation and metabolic imbalance. This persistent inflammatory state is closely associated with many age-related diseases and proposed by many as the main driver of unhealthy aging^14,15. Together, these theories provide a foundation for exploring how cold exposure may modulate aging through its influence on inflammation, genomic maintenance, and protein quality control.

Building upon these foundational theories, it becomes evident that several hallmarks of aging may be responsive to environmental modulation, prompting a high interest in gerotherapeutic interventions¹⁶. One such intervention is mild induced hypothermia, which offers a unique thermodynamic influence on the biological systems implicated in aging. Through targeted cooling, hypothermia has been shown to attenuate oxidative damage, stabilize genomic integrity, enhance protein homeostasis, and suppress chronic inflammation. What follows is an exploration of how this physiological state intersects with and potentially mitigates each of the aforementioned aging mechanisms.

The Mechanisms behind Hypothermia’s Beneficial Effects

Although severe hypothermia is detrimental, mild hypothermia (around 35 °C), which does not produce severe adverse effects, is emerging as a potential longevity-enhancing intervention. This transition from harmful to beneficial outcomes relies on a thermodynamic understanding of aging, proposing that the continuous energetic activity and associated metabolic stress drive the aging process.

Metabolic regulation

A primary beneficial effect of hypothermia on pathologic aging is its impact on metabolic regulation. Mildly reducing core body temperature effectively slows metabolic rate^17,18, potentially minimizing cumulative cellular damage over time and thereby promoting longevity. Lowering body temperature also activates brown adipose tissue (BAT), which boosts energy expenditure and enhances insulin sensitivity. This metabolic shift improves lipid and glucose metabolism and contributes to reducing inflammation commonly associated with metabolic disorders^19,20. Hypothermia has also been implicated in lactate clearance and preventing acidosis, both of which support normal metabolism function^21,22, as well as in enhancing autophagy in BAT and in vivo, helping cells eliminate misfolded proteins and nonfunctional organelles^23,24.

Oxidative stress reduction

Hypothermia also affects oxidative stress, a key driver of cellular aging under the free radical theory. There’s a plethora of mechanisms through which this occurs, all of which lead to multiple organ systems being protected from oxidative stress-induced damage²⁵. By enhancing antioxidant defenses via improving the respiratory control ratio in oxygenated mitochondria, enhancing antioxidative enzyme activity, and reducing ROS production, mild hypothermia helps mitigate molecular and cellular damage, thereby potentially slowing aging processes^26–29.

Protection of DNA integrity

Recent emerging evidence suggests that mild induced hypothermia may also protect DNA integrity. This includes telomere preservation, which safeguards chromosome ends from degradation. The prospective mechanism could be CIRP upregulation, which has a positive effect on telomerase activity and shows heightened expression levels during the winter in hibernating mammals³⁰. Another notable mechanism that could contribute to DNA preservation during hypothermia is the activation of FOXO transcription factors, notably FOXO1 and FOXO3, which are closely linked to longevity³¹. FOXO transcription factors regulate genes involved in oxidative stress resistance, DNA repair, metabolism, and autophagy. These are all avenues through which the FOXO family is linked to extreme longevity in humans³².

Promoting proteostasis

Another mechanism of hypothermia’s role in promoting healthy longevity is the enhancement of protein homeostasis. Hypothermia can stimulate trypsin-like proteasome activity through the PA28γ/PSME3 pathway, enhancing the degradation of misfolded or aggregated proteins. This reduces toxic protein accumulation, which is an important factor in neurodegenerative disease prevention. This phenomenon has been observed in both human cells exposed to moderate cold temperature and in Caenorhabditis elegans, implying a highly evolutionarily conserved mechanism across both poikilotherms and homeotherms and exhibiting potential for multi-disease prevention³³.

Suppressing inflammation

In addition, mild induced hypothermia has been shown to suppress chronic inflammation, a phenomenon referred to as “inflammaging”¹⁴. Hypothermia downregulates pro-inflammatory cytokines and modulates immune responses, which helps reduce systemic inflammation and the risk of age-related diseases such as cardiovascular disorders, diabetes, and neurodegeneration^34–37. There are multiple mechanisms through which this effect takes place, some of which have been unveiled in recent years. Notably, the hypothermia-induced cold-shock protein RBM3 suppresses the activation of inflammation in the lungs, in part through the CysLT1R pathway³⁸. RBM3 also possesses a remarkable neuroprotective effect, as it promotes synaptic regeneration, protects against neuronal loss, enhances memory function, and markedly extends disease-free survival in murine models of neurodegenerative disorders³⁹. Conversely, the neuroprotective effects of hypothermia are potentially mediated by a plethora of mechanisms ranging from the previously discussed metabolic slowing and free radical suppression to lipoprotein membrane fluidity protection and oxygen demand and intracellular acidosis reduction to excitatory neurotransmitter biosynthesis and release suppression⁴⁰.

Pathophysiology of Hypothermia

Despite all of the listed potential benefits, the long-term implications remain complex. While short-term induced hypothermia appears protective, populations in chronically cold environments exhibit higher mortality and cardiovascular risk⁴¹. This highlights the need for deeper research to understand the optimal application and duration of hypothermia for aging interventions, as well as to emphasize the potentially seriously adverse effects of hypothermia should it not be precisely monitored and regulated (Table 1).

Table 1.

Temperature-dependent pathophysiological effects.

Body Temperature (°C)	Metabolic Effects	Neurological Effects	Cardiovascular Effects	Hematological Effects
36–35 °C (Mild hypothermia)	Initial increase in basal metabolic rate (BMR), mild insulin resistance	Impaired judgment, fine motor coordination deficits	Peripheral vasoconstriction, increased heart rate	Normal coagulation, mild platelet aggregation
34–32 °C (Moderate hypothermia)	Suppressed gluconeogenesis, glycogen depletion	Slowed nerve conduction, confusion, lethargy	Bradycardia, initial atrial fibrillation, hypovolemia	Hypercoagulability, increased blood viscosity
32–30 °C (Severe hypothermia)	Metabolic acidosis, mitochondrial dysfunction	Stupor, diminished reflexes, cerebellar ataxia	Profound bradycardia, junctional rhythms, high arrhythmia risk	Risk of disseminated intravascular coagulation (DIC)
<30 °C (Profound hypothermia)	Cellular metabolic failure, multiorgan dysfunction	Coma, areflexia, brainstem suppression	Ventricular fibrillation, asystole, extreme hypotension	DIC, microvascular collapse, organ failure
Modified from http://www.ncbi.nlm.nih.gov/books/NBK545239/.

Metabolic dysfunction

Hypothermia induces significant disruptions in metabolic pathways, primarily through the suppression of signal systems⁴². To counteract heat loss, the body initiates energy conservation mechanisms, prominently through shivering, which elevates the metabolic rate up to four- or fivefold⁴³ until core temperature drops to around 32 °C. Beyond this threshold, neuromuscular function deteriorates, and muscular activity is impaired⁴⁴. In addition, a shift toward anaerobic metabolism occurs during severe hypothermia, resulting in elevated lactic acid levels and metabolic acidosis, characterized by a significant drop in blood pH⁴⁵.

Neurological effects

Even though mild hypothermia has long since been established as beneficial and therapeutic for brain injury, hypothermia can profoundly negatively impact brain function and even decrease survival in brain injury patients⁴⁶. Synaptic transmission notably decreases in severe hypothermia, attributed to diminished neurotransmitter release⁴⁷. This reduction leads to slowed cognitive processes. Furthermore, cerebral vasoconstriction intensifies at core temperatures below 31 °C⁴⁸, significantly lowering cerebral perfusion and increasing the risk of brain hypoxia and ischemic injury.

Cardiovascular impact

The cardiovascular system responds to hypothermia by inducing hypertension, predominantly due to sympathetic nervous system activation starting at approximately 34 °C and causing vasoconstriction through catecholamine release. Cardiac workload is increased due to this hypertension, which forms a vicious loop with the renal system through the renin-angiotensin pathway, where angiotensin II levels are increased, and it, in turn, further heightens hypertension^49,50. This often progresses to bradycardia and potentially severe arrhythmias⁵¹.

State of the Art and Future Perspectives

Despite its potential adverse effects, the cumulative evidence supporting the beneficial mechanisms of hypothermia suggests that, when carefully controlled and precisely monitored, it holds promise as a viable strategy in antiaging interventions. To illustrate its clinical potential, several therapeutic scenarios where hypothermia is already being effectively employed in human medicine today are highlighted.

Current use of therapeutic hypothermia

Therapeutic hypothermia (TH) refers to the intentional and controlled reduction of core body temperature to a range between 32 and 35 °C, typically maintained for 24–48 hours⁵². Historically, its application dates back to the early 1800s, when its use in managing fever and febrile illnesses was first documented⁵³.

TH has been extensively studied across a range of medical conditions, particularly as our understanding has deepened regarding the cascade of damaging biochemical and cellular events that occur in the brain following ischemic or traumatic injury. Numerous studies have demonstrated that TH offers neuroprotective benefits in both cardiac and neurological injuries^52,54,55. Consequently, it is now recommended by several international resuscitation organizations for patients experiencing out-of-hospital cardiac arrest (OHCA). Evidence also supports its positive impact on neurological outcomes following cardiac arrest and traumatic brain injury (TBI). Three principal cooling techniques have been developed over the last 50 y: (1) surface cooling via air, (2) surface cooling via fluids, and (3) core cooling using methods such as intravenous catheters, peritoneal lavage, or infusion of iced fluids. To mitigate potential side effects during TH, it is commonly administered alongside sedatives, anesthetics, opioids, magnesium, and neuromuscular blockers.

Recently, TH has been applied pervasively across a spectrum of critical care-associated diseases, which includes TBI, OHCA, ischemic strokes, and perioperative cardiothoracic care. The American Heart Association and Brain Trauma Foundation recommend the use of TH in both OHCA and TBI^56,57. More recently, its potential has also been investigated in the context of cancer therapy, especially its efficient against a subset of tumors with p53 mutations^58,59 . An additional and increasingly important application of TH is in the management of hypoxic-ischemic encephalopathy (HIE) in neonates, a serious condition resulting from oxygen deprivation around the time of birth. HIE leads to acute brain injury and remains a major contributor to long-term neurodevelopmental disorders, including cerebral palsy, epilepsy, and cognitive impairments. In recent years, TH has become the standard of care for infants with moderate to severe HIE, supported by substantial clinical evidence demonstrating its ability to mitigate brain injury and enhance survival with reduced neurological consequences^60,61. Despite these advances, ongoing challenges persist, particularly concerning the optimization of patient selection, timing of intervention, and efficacy in vulnerable populations such as preterm infants and those in low-resource settings⁶².

Future perspectives: Hypothermia as an antiaging intervention

The translation of mild hypothermia into an antiaging intervention involves several key considerations and innovative strategies.

Precise temperature control

Therapeutic mild hypothermia (around 35 °C) must be carefully and consistently maintained to avoid negative physiological effects associated with lower body temperatures. At approximately 35 °C, metabolic processes slow, potentially reducing metabolic stress and age-associated cellular damage without triggering severe systemic disruptions observed at lower temperatures for prolonged time periods.

Pharmacological temperature regulation (hypothermia pill)

Future antiaging strategies could involve the development of pharmacological interventions—a “hypothermia pill”—capable of safely lowering human core body temperature to approximately 35 °C, without adverse effects caused by cold exposure. Such medication might function through modulation of hypothalamic temperature-regulatory centers. Achieving temperature reduction through a pharmaceutical approach would allow for continuous, precisely controlled mild hypothermia, potentially enhancing longevity outcomes while minimizing the risks associated with external cooling methods. However, this approach requires extensive preclinical and clinical validation to ensure efficacy and safety.

A potential drug could target the hypothalamus, the brain region responsible for thermoregulation, altering its internal “settings” to maintain a lower baseline body temperature. Since the hypothalamus governs body temperature regulation, precise modulation of its neuronal activity could theoretically decrease the body’s temperature set point safely. Specifically, transient receptor potential (TRP) channels, such as TRPM8 and TRPV1, are known to play a central role in thermosensation and hypothalamic temperature regulation⁶³. Pharmacological modulation of these receptors could, in theory, shift the thermoregulatory set point of the hypothalamus toward a lower baseline temperature.

In addition, serotonergic and dopaminergic neurotransmitter systems are involved in central thermoregulation and energy balance. For example, serotonin receptors in the preoptic area of the hypothalamus influence heat production and dissipation, and dopaminergic signaling has been linked to adaptive thermogenesis^63,64. A hypothetical drug could modulate these pathways to induce a controlled and sustained reduction in core body temperature without triggering the adverse effects typically associated with hypothermia.

Another strategy would involve using compounds that affect metabolism and thermogenesis. For example, a drug could regulate the activity of uncoupling proteins (UCPs) in BAT or alter basal metabolic rate directly. Bruno Conti’s experiments with transgenic mice illustrate this approach: by increasing the activity of UCPs, these mice maintained a body temperature 0.3–0.5 °C lower than normal and achieved a significantly extended lifespan—12% longer in males and 20% longer in females—without caloric restriction, directly linking mild hypothermia to enhanced longevity⁶⁵.

As of today, no pharmaceutical pill exists that safely reduces and maintains human core body temperature at around 35 °C over extended periods. However, theoretically, such a drug could be developed and would be of considerable interest in gerontology and longevity research. Developing this treatment would require extensive clinical trials and rigorous long-term safety assessments.

Individualized approaches

Interventions must account for individual health profiles and biological variability, as tolerance to mild hypothermia and responses to temperature reduction can significantly vary based on age, sex, genetic predisposition, metabolic health, body composition, and preexisting medical conditions⁶⁶. Personalized protocols and dosage adjustments would be essential to maximize beneficial outcomes and prevent adverse effects.

Biological markers and monitoring

Implementing comprehensive biological monitoring systems, including but not limited to markers of inflammation, metabolic rate, and oxidative stress levels, is critical. Longitudinal monitoring would allow for real-time tracking of the beneficial effects associated with mild hypothermia and ensure prompt detection and mitigation of any negative physiological impacts.

Research integration and validation

Ongoing rigorous scientific research is essential for translating mild hypothermia into a viable and widely applicable antiaging strategy. Future investigations should include controlled clinical trials, longitudinal epidemiological studies, detailed mechanistic analyses, and robust validation studies to confirm the safety, feasibility, and effectiveness of temperature modulation protocols and pharmacological interventions designed to safely lower core body temperature.

Limitations

While this perspective presents a compelling case for the role of pharmacologically induced mild hypothermia in promoting longevity, several limitations must be acknowledged. First, there is a lack of direct empirical evidence in humans demonstrating that long-term reductions in core body temperature lead to increased lifespan. Most current data are derived from animal models or cross-species comparisons, which may not fully translate to human physiology. Second, ethical and practical challenges complicate the design of clinical trials to assess prolonged hypothermia in healthy individuals, particularly given the risks associated with thermoregulation. These factors highlight the need for cautious interpretation and emphasize the importance of rigorous, multidisciplinary research before translating this approach into clinical practice.

Conclusion

The application of mild hypothermia (approximately 35 °C) as an antiaging intervention presents a promising yet largely unexplored area of biogerontology. By modulating metabolism, oxidative stress, genomic stability, inflammation, and proteostasis, it addresses several of the most prominent aging theories from a thermodynamic perspective. While TH is already validated in acute medical contexts, its translation to antiaging medicine demands cautious optimism.

Considering the severe health risks associated with deeper hypothermia, the strategic translation into safe human application requires scientific validation and careful therapeutic protocol design. Promising avenues include precise monitoring of biomarkers, personalized intervention strategies, and innovative pharmacological approaches, such as developing a “hypothermia pill” capable of safely maintaining mildly reduced core temperatures.

Ultimately, comprehensive and carefully controlled clinical studies are essential to validate the feasibility, effectiveness, and safety of mild hypothermia as a longevity-enhancing intervention. The concept of a pharmacologically induced, temperature-modulating therapy represents a visionary yet plausible path forward in longevity science—one that bridges foundational aging biology with precision thermal regulation.

Acknowledgments

I am grateful to Dr. Ana Cindric for her editorial support during the preparation of this article.

References

1. Harman D. (1993). Free radical involvement in aging. Drugs Aging 3(1), 60–80. PMID: 8453186; doi: 10.2165/00002512-199303010-00006.

2. Effros R.B. (2005). Roy Walford and the immunologic theory of aging. Immun. Ageing 2(1), 7. PMID: 15850487; doi: 10.1186/1742-4933-2-7.

3. Kruk P.A., Rampino N.J., & Bohr V.A. (1995). DNA damage and repair in telomeres: relation to aging. Proc. National Acad. Sci. 92(1), 258–262. PMID: 7816828; doi: 10.1073/pnas.92.1.258.

4. Bjorksten J. (1968). The crosslinkage theory of aging. J. Am. Geriatrics Soc. 16(4), 408–427. PMID: 4868749; doi: 10.1111/j.1532-5415.1968.tb02821.x.

5. Medvedev Z.A. (1990). An attempt at a rational classification of theories of ageing. Biol. Rev. 65(3), 375–398. PMID: 2205304; doi: 10.1111/j.1469-185X.1990.tb01428.x.

6. da Costa J.P., Vitorino R., Silva G.M., Vogel C., Duarte A.C., & Rocha-Santos T. (2016). A synopsis on aging—Theories, mechanisms and future prospects. Ageing Res. Rev. 29, 90–112. PMID: 27353257; doi: 10.1016/j.arr.2016.06.005.

7. Schrödinger E. (1974). What is Life? & Mind and Matter: The Physical Aspect of the Living Cell. Cambridge, UK: Cambridge University Press.

8. England J.L. (2013). Statistical physics of self-replication. J. Chem. Phys. 139(12), 121923. PMID: 24089735; doi: 10.1063/1.4818538.

9. Schneider E.D., & Kay J.J. (1994). Life as a manifestation of the second law of thermodynamics. Math. Comput. Modell. 19(6), 25–48. doi: 10.1016/0895-7177(94)90188-0.

10. Cushman S.A. (2023). Entropy, ecology and evolution: toward a unified philosophy of biology. Entropy (Basel) 25(3), 405. PMID: 36981294; doi: 10.3390/e25030405.

11. Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D., … Abete P. (2018). Oxidative stress, aging, and diseases. Clin. Interv. Aging. 13, 757–772. PMID: 29731617; doi: 10.2147/CIA.S158513.

12. Schumacher B., Pothof J., Vijg J., & Hoeijmakers J.H.J. (2021). The central role of DNA damage in the ageing process. Nature 592(7856), 695–703. PMID: 33911272; doi: 10.1038/s41586-021-03307-7.

13. Chen X.-Q., Shen T., Fang S.-J., Sun X.-M., Li G.-Y., & Li Y.-F. (2023). Protein homeostasis in aging and cancer. Front. Cell Dev. Biol. 11, 1143532. PMID: 36875752; doi: 10.3389/fcell.2023.1143532.

14. Franceschi C., Bonafè M., Valensin S., Olivieri F., De Luca M., Ottaviani E., … De Benedictis G. (2000). Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908(1), 244–254. PMID: 10911963; doi: 10.1111/j.1749-6632.2000.tb06651.x.

15. Franceschi C., Garagnani P., Morsiani C., Conte M., Santoro A., Grignolio A., … Salvioli S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. Front Med (Lausanne) 5, 61. PMID: 29662881; doi: 10.3389/fmed.2018.00061.

16. Kroemer G., Maier A.B., Cuervo A.M., Gladyshev V.N., Ferrucci L., Gorbunova V., … López-Otín C. (2025). From geroscience to precision geromedicine: understanding and managing aging. Cell 188(8), 2043–2062. PMID: 40250404; doi: 10.1016/j.cell.2025.03.011.

17. Erecinska M., Thoresen M., & Silver I.A. (2003). Effects of hypothermia on energy metabolism in mammalian central nervous system. J. Cereb. Blood Flow Metab. 23(5), 513–530. PMID: 12771566; doi: 10.1097/01.WCB.0000066287.21705.21.

18. Flickinger K.L., Weissman A.J., Guyette F.X., DeMaio R., Jonsson A., Wu V., … Callaway C.W. (2025). Sustained metabolic reduction and hypothermia in humans. PLOS ONE 20(4), e0321117. PMID: 40258026; doi: 10.1371/journal.pone.0321117.

19. Huo C., Song Z., Yin J., Zhu Y., Miao X., Qian H., … Zhou L. (2022). Effect of acute cold exposure on energy metabolism and activity of brown adipose tissue in humans: a systematic review and meta-analysis. Front Physiol. 13, 917084. PMID: 35837014; doi: 10.3389/fphys.2022.917084.

20. Loap S., & Lathe R. (2018). Mechanism underlying tissue cryotherapy to combat obesity/overweight: triggering thermogenesis. J. Obes. 2018, 5789647. PMID: 29854439; doi: 10.1155/2018/5789647.

21. Léon K., Pichavant-Rafini K., Ollivier H., & L’Her E. (2015). Effect of induced mild hypothermia on acid-base balance during experimental acute sepsis in rats. Ther. Hypothermia. Temp. Manag. 5(3), 163–170. PMID: 26083241; doi: 10.1089/ther.2015.0008.

22. Starodub R., Abella B.S., Grossestreuer A.V., Shofer F.S., Perman S.M., Leary M., & Gaieski D.F. (2013). Association of serum lactate and survival outcomes in patients undergoing therapeutic hypothermia after cardiac arrest. Resuscitation 84(8), 1078–1082. PMID: 23402966; doi: 10.1016/j.resuscitation.2013.02.001.

23. King K.E., McCormick J.J., & Kenny G.P. (2024). Temperature-dependent relationship of autophagy and apoptotic signaling during cold-water immersion in young and older males. Adv. Biol. 8(3), 2300560. PMID: 38150671; doi: 10.1002/adbi.202300560.

24. Yau W.W., Wong K.A., Zhou J., Thimmukonda N.K., Wu Y., Bay B.-H., … Yen P.M. (2021). Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue. iScience 24(5), 102434. PMID: 34027318; doi: 10.1016/j.isci.2021.102434.

25. Ostadal P., Mlcek M., Kruger A., Horakova S., Skabradova M., Holy F., … Neuzil P. (2013). Mild therapeutic hypothermia is superior to controlled normothermia for the maintenance of blood pressure and cerebral oxygenation, prevention of organ damage and suppression of oxidative stress after cardiac arrest in a porcine model. J. Transl. Med. 11(1), 124. PMID: 23688243; doi: 10.1186/1479-5876-11-124.

26. Alva N., Palomeque J., & Carbonell T. (2013). Oxidative stress and antioxidant activity in hypothermia and rewarming: can RONS modulate the beneficial effects of therapeutic hypothermia? Oxid. Med. Cell Longev. 2013(1), 957054. PMID: 24363826; doi: 10.1155/2013/957054.

27. Stanek A., Cholewka A., Wielkoszyński T., Romuk E., & Sieroń A. (2018). Whole-body cryotherapy decreases the levels of inflammatory, oxidative stress, and atherosclerosis plaque markers in male patients with active-phase ankylosing spondylitis in the absence of classical cardiovascular risk factors. Mediators Inflamm. 2018(1), 8592532. PMID: 29483842; doi: 10.1155/2018/8592532.

28. Stanek A., Wielkoszyński T., Bartuś S., & Cholewka A. (2020). Whole-body cryostimulation improves inflammatory endothelium parameters and decreases oxidative stress in healthy subjects. Antioxidants (Basel) 9(12), 1308. PMID: 33371392; doi: 10.3390/antiox9121308.

29. Tissier R., Chenoune M., Pons S., Zini R., Darbera L., Lidouren F., … Morin D. (2013). Mild hypothermia reduces per-ischemic reactive oxygen species production and preserves mitochondrial respiratory complexes. Resuscitation 84(2), 249–255. PMID: 22796545; doi: 10.1016/j.resuscitation.2012.06.030.

30. Redon L., Constant T., Smith S., Habold C., & Giroud S. (2024). Understanding seasonal telomere length dynamics in hibernating species. J. Therm. Biol. 123, 103913. PMID: 39002254; doi: 10.1016/j.jtherbio.2024.103913.

31. Zhang X., Ge L., Jin G., Liu Y., Yu Q., Chen W., … Ou J. (2024). Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage. Nat. Commun. 15(1), 2859. PMID: 38570500; doi: 10.1038/s41467-024-47095-w.

32. Santos B.F., Grenho I., Martel P.J., Ferreira B.I., & Link W. (2023). FOXO family isoforms. Cell Death Dis. 14(10), 1–16. PMID: 37891184; doi: 10.1038/s41419-023-06177-1.

33. Lee H.J., Alirzayeva H., Koyuncu S., Rueber A., Noormohammadi A., & Vilchez D. (2023). Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes. Nature Aging 3(5), 546–566. PMID: 37118550; doi: 10.1038/s43587-023-00383-4.

34. Cain T., Brinsley J., Bennett H., Nelson M., Maher C., & Singh B. (2025). Effects of cold-water immersion on health and wellbeing: a systematic review and meta-analysis. PLOS ONE, 20(1), e0317615. PMID: 39879231; doi: 10.1371/journal.pone.0317615.

35. Peake J.M., Roberts L.A., Figueiredo V.C., Egner I., Krog S., Aas S.N., … Raastad T. (2017). The effects of cold water immersion and active recovery on inflammation and cell stress responses in human skeletal muscle after resistance exercise. J. Physiol. 595(3), 695–711. PMID: 27704555; doi: 10.1113/JP272881.

36. Spiljar M., Steinbach K., Rigo D., Suárez-Zamorano N., Wagner I., Hadadi N., … Trajkovski M. (2021). Cold exposure protects from neuroinflammation through immunologic reprogramming. Cell Metab. 33(11), 2231–2246.e8. PMID: 34687652; doi: 10.1016/j.cmet.2021.10.002.

37. Vieira Ramos G., Pinheiro C.M., Messa S.P., Delfino G.B., Marqueti R.deC., Salvini T.deF., & Durigan J.L.Q. (2016). Cryotherapy reduces inflammatory response without altering muscle regeneration process and extracellular matrix remodeling of rat muscle. Sci. Rep. 6(1), 18525. PMID: 26725948; doi: 10.1038/srep18525.

38. Badrani J.H., Strohm A.N., Lacasa L., Civello B., Cavagnero K., Haung Y.-A., … Doherty T.A. (2022). RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R. Nat. Commun. 13(1), 4435. PMID: 35908044; doi: 10.1038/s41467-022-32176-5.

39. Preußner M., Smith H.L., Hughes D., Zhang M., Emmerichs A.-K., Scalzitti S., … Heyd F. (2023). ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo. EMBO Mol. Med. 15(5), e17157. PMID: 36946385; doi: 10.15252/emmm.202217157.

40. The Hypothermia after Cardiac Arrest Study Group. (2002). Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med., 346(8), 549–556. PMID: 11856793; doi: 10.1056/NEJMoa012689.

41. Alahmad B., Khraishah H., Royé D., Vicedo-Cabrera A.M., Guo Y., Papatheodorou S.I., … Koutrakis P. (2023). Associations between extreme temperatures and cardiovascular cause-specific mortality: results from 27 countries. Circulation 147(1), 35–46. PMID: 36503273; doi: 10.1161/CIRCULATIONAHA.122.061832.

42. Han H.S., Park J., Kim J.-H., & Suk K. (2012). Molecular and cellular pathways as a target of therapeutic hypothermia: pharmacological aspect. Curr. Neuropharmacol. 10(1), 80–87. PMID: 22942881; doi: 10.2174/157015912799362751.

43. Jacobs Ira, Marriott B.M., & Carlson S.J. (1996). Muscle metabolism and shivering during cold stress. In Nutritional Needs In Cold And In High-Altitude Environments: Applications for Military Personnel in Field Operations. National Academies Press (US). https://www.ncbi.nlm.nih.gov/books/NBK232868/.

44. Brown D.J.A., Brugger H., Boyd J., & Paal P. (2012). Accidental hypothermia. N. Engl. J. Med., 367(20), 1930–1938. PMID: 23150960; doi: 10.1056/NEJMra1114208.

45. Rosenfeld J.B. (1963). Acid-base and electrolyte disturbances in hypothermia. Am. J. Cardiol. 12(5), 678–682. PMID: 14075998; doi: 10.1016/0002-9149(63)90259-5.

46. McCune R.L., Long B.J., Dengler B.A., Rizzo J.A., Peitz G.W., Moran M.M., … Schauer S.G. (2025). The effect of environmental hypothermia on survival in isolated blunt traumatic brain injury. World Neurosurg. 195, 123736. PMID: 39889956; doi: 10.1016/j.wneu.2025.123736.

47. Hook M.J.V. (2020). Temperature effects on synaptic transmission and neuronal function in the visual thalamus. PLOS ONE 15(4), e0232451. PMID: 32353050; doi: 10.1371/journal.pone.0232451.

48. Castellani J.W., & Young A.J. (2016). Human physiological responses to cold exposure: acute responses and acclimatization to prolonged exposure. Auton. Neurosci. 196, 63–74. PMID: 26924539; doi: 10.1016/j.autneu.2016.02.009.

49. Ikäheimo T.M. (2018). Cardiovascular diseases, cold exposure and exercise. Temperature 5(2), 123–146. PMID: 30377633; doi: 10.1080/23328940.2017.1414014.

50. Sun Z. (2010). Cardiovascular responses to cold exposure. Front. Biosci. (Elite Edition) 2(2), 495–503. PMID: 20036896; doi: 10.2741/e108.

51. Dietrichs E.S., Tveita T., & Smith G. (2019). Hypothermia and cardiac electrophysiology: a systematic review of clinical and experimental data. Cardiovasc. Res. 115(3), 501–509. PMID: 30544147; doi: 10.1093/cvr/cvy305.

52. Arrich J., Holzer M., Havel C., Müllner M., & Herkner H. (2016). Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst. Rev. 2(2), CD004128. PMID: 26878327; doi: 10.1002/14651858.CD004128.pub4.

53. Currie J., Humphreys J., & Benjamin & Thomas Kite (Firm), publisher (with U.S. National Library of Medicine). (1808). Medical Reports, on the Effects of Water, Cold and Warm, as a Remedy in Fever and Other Diseases: Whether Applied to the Surface of the Body, or Used Internally. Philadelphia: Printed for James Humphreys, and for Benjamin and Thomas Kite. http://archive.org/details/2548021R.nlm.nih.gov.

54. Sun Y.-J., Zhang Z.-Y., Fan B., & Li G.-Y. (2019). Neuroprotection by therapeutic hypothermia. Front. Neurosci. 13, 586. PMID: 31244597; doi: 10.3389/fnins.2019.00586.

55. Yenari M.A., & Hemmen T.M. (2010). Therapeutic hypothermia for brain ischemia: where have we come and where do we go? Stroke; A J. Cerebral Circul. 41(10 Suppl), S72–S74. PMID: 40730908; doi: 10.1161/STROKEAHA.110.595371.

56. Carney N., Totten A.M., O’Reilly C., Ullman J.S., Hawryluk G.W.J., Bell M.J., … Ghajar J. (2017). Guidelines for the management of severe traumatic brain injury, Fourth Edition. Neurosurgery 80(1), 6–15. PMID: 27654000; doi: 10.1227/NEU.0000000000001432.

57. Donnino M.W., Andersen L.W., Berg K.M., Reynolds J.C., Nolan J.P., Morley P.T., … ILCOR ALS Task Force. (2016). Temperature management after cardiac arrest: an advisory statement by the advanced life support task force of the international liaison committee on resuscitation and the American heart association emergency cardiovascular care committee and the council on cardiopulmonary, critical care, perioperative and resuscitation. Resuscitation, 98, 97–104. PMID: 26449873; doi: 10.1016/j.resuscitation.2015.09.396.

58. Hu W., & Feng Z. (2021). Hypothermia is a potential new therapy for a subset of tumors with mutant p53. Cancer Res. 81(14), 3762–3763. PMID: 34266914; doi: 10.1158/0008-5472.CAN-21-1025.

59. Lu J., Chen L., Song Z., Das M., & Chen J. (2021). Hypothermia effectively treats tumors with temperature-sensitive p53 mutations. Cancer Res. 81(14), 3905–3915. PMID: 33687951; doi: 10.1158/0008-5472.CAN-21-0033.

60. Aker K., Støen R., Eikenes L., Martinez-Biarge M., Nakken I., Håberg A.K., … Thomas N. (2020). Therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy in India (THIN study): a randomised controlled trial. Arch. Dis. Child Fetal Neonatal Ed. 105(4), 405–411. PMID: 31662328; doi: 10.1136/archdischild-2019-317311.

61. Wassink G., Davidson J.O., Dhillon S.K., Zhou K., Bennet L., Thoresen M., & Gunn A.J. (2019). Therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy. Current Neurol. Neurosci. Rep. 19(2), 2. PMID: 30637551; doi: 10.1007/s11910-019-0916-0.

62. Proietti J., Boylan G.B., & Walsh B.H. (2024). Regional variability in therapeutic hypothermia eligibility criteria for neonatal hypoxic-ischemic encephalopathy. Pediatr. Res. 96(5), 1153–1161. PMID: 38649726; doi: 10.1038/s41390-024-03184-6.

63. Morrison S.F., & Nakamura K. (2019). Central mechanisms for thermoregulation. Ann. Rev. Physiol. 81, 285–308. PMID: 30256726; doi: 10.1146/annurev-physiol-020518-114546.

64. Szelényi Z., & Komoly S. (2018). Thermoregulation: from basic neuroscience to clinical neurology, part 2. Temperature (Austin), 6(1), 7–10. doi: 10.1080/23328940.2018.1541680.

65. Conti B., Sanchez-Alavez M., Winsky-Sommerer R., Morale M.C., Lucero J., Brownell S., … Bartfai T. (2006). Transgenic mice with a reduced core body temperature have an increased life span. Science (New York, N.Y.) 314(5800), 825–828. PMID: 17082459; doi: 10.1126/science.1132191.

66. Haman F., Souza S.C.S., Castellani J.W., Dupuis M.-P., Friedl K.E., Sullivan-Kwantes W., & Kingma B.R.M. (2022). Human vulnerability and variability in the cold: establishing individual risks for cold weather injuries. Temperature (Austin) 9(2), 158–195. PMID: 36106152; doi: 10.1080/23328940.2022.2044740.