Reviewing Cold Therapy for Longevity
The health benefits of the cold therapy have long been touted by mankind, including Hippocrates claiming it cured lethargy and Thomas Jefferson bathing his feet in cold water every morning for decades to maintain good health . This view is still prevalent in modern times, including cold morning showers, swimming in the open water, ice baths in athletic training rooms and cold mineral water spa treatments.
But are these claims supported by science? Is cold therapy just good for sprained ankles, or might it be able to impact aging itself?
Cold therapy induced hormesis for health
Hormesis is a concept that applies to many biological processes, wherein a stressor that is typically considered toxic can provide health benefits at low doses due to an organism’s adaptive response. For example, oxidative stress is a key player in aging and causes mitochondrial and DNA damage. However, in small doses, such as regular exercise, the body adapts to better handle oxidative stress, and these adaptations provide a variety health benefits.
Similar patterns have been noted for a number of other stressors, including, but not limited to, alcohol, caloric restriction, carbon monoxide, methylmercury, heat stress, and hypoxia. [2-6] Cold therapy is relatively less-studied but has shown similar benefits and biomolecular pathways to these other stressors .
The progression of cold exposure
The body’s response to the cold is relatively uniform across people. Light exposure may result in goosebumps, tightening muscles, and attempts to reduce the exposed surface area. Blood begins to be directed away from the exposed area, limbs, and skin, instead moving towards the core. This accelerates if body temperature begins to drop.
Shivering may occur, and brown fat is stimulated to burn calories for body heat. Heart rate, blood pressure, and respiratory rate also increase. Blood glucose rises while insulin secretion decreases .
Mild hypothermia occurs when a body temperature in the range of 32–35°C (89.6–95.0°F) is reached and may be accompanied by mild mental confusion. Eventually, shivering stops, but confusion continues to increase in moderate hypothermia with a core body temperature of 28–32°C (82.4–89.6°F). Reflexes are also delayed, and fine motor skills are blunted at this stage.
In severe hypothermia, different organ systems begin to fail. Blood pressure, respiration, and heart rate fall well below normal levels. In the end, death typically occurs as a result of cardiac arrest .
Cold therapy activates Cold shock proteins
Cold shock proteins were first identified in E. coli in the bacteria’s response to significant decreases in environmental temperature . These proteins are believed to be critical to cellular survival at lower temperatures. Many cold shock proteins initially discovered in E. coli have been particularly well-conserved in yeast, mammals, and humans .
The most well-known include Y-box binding protein-1 (YB-1), DbpA, DbpC, Lin28, CARSHSP1, and CSDE1 . In human cells, cold shock proteins are expressed in response to much smaller temperature drops (25–35°C or 77-95°F). This is likely an adaptation by cells to living in the thermoregulated environment of the human body .
Cold shock proteins are involved at various points in the protein synthesis process, including transcription, supercoiling of DNA, and initiation of translation . Because of their dramatic changes in expression in response to cold stress, this family of proteins may be involved in the underlying mechanisms by which cold stress might provide health benefits. For example, RBM3 is a cold shock protein that enhances mRNA stability and translation and is expressed at higher levels in anti-aging models, such as the long-lived Ames Dwarf mouse and in calorie-restricted mice .
The discovery of cold shock proteins has followed a very similar path to heat shock proteins at high temperatures. Interestingly, human cells also express heat shock proteins in response to cold exposure . The more well-studied heat shock proteins have been implicated in a number of stress responses and longevity pathways, just as cold shock proteins can be stimulated by factors other than cold stress.
Cold shock proteins have been found to play a role in a number of acute and age-related diseases, including cancer, type 2 diabetes, chronic kidney disease, atherosclerosis, chronic liver disease, neurodegeneration, and asthma . They regulate a number of molecules involved in longevity pathways, including NF-kB (inflammation), p53 (DNA damage, senescence), and TGF-ß (fibrosis) . Proposed anti-aging therapies have also been shown to modulate cold shock proteins, such as fisetin and YB-1 .
Brown adipose tissue
Brown adipose tissue is another mechanism involved in the cold stress response. There are two types of fat tissue in our bodies: brown and white. White fat is primarily used for insulation and energy storage. Brown fat primarily functions in thermogenesis instead, creating heat to raise body temperature by burning energy.
As a result, brown fat is much more vascularized with capillaries and innervated with neurons than white fat. It gets its color through the much higher density of iron-containing, energy-producing mitochondria . In many ways, brown fat is more closely related to muscle than to white fat . Unfortunately, brown fat decreases with age [17, 18]. Brown fat in adult humans was only discovered in 2003, prior to which it was believed to disappear after infancy [18-20].
Since then, numerous health benefits have been found from activating brown fat or in individuals with greater brown fat deposits, including prevention of atherosclerosis, reduced triglycerides and cholesterol levels [21, 22], improved glucose homeostasis and insulin sensitivity [35, 36], and bone health . In rodents and humans, various regimens of cold exposure have been repeatedly shown to increase brown fat activation [18, 23].
Benefits of cold therapy for general health
Fruit flies exposed to cold stress are later able to survive heat, cold, and fungal infection later in life [24, 25]. Cold exposure in mice (4°C air, 1 to 7 days) resulted in increased brown fat deposits in certain areas and facilitated the conversion of a small amount of white fat to behave like brown fat, a phenomenon known as beige fat .
After young and old mice received repeated exposure to 6°C air for one week intervals, both groups improved their thermogenic abilities, although young mice more so than old mice . Pretreating rats with cold water swimming exercises improved their recovery of traumatic brain injury .
In humans, the most well-established health application of cold exposure is to accelerate recovery from injury. When applied superficially, cold therapy locally reduces inflammation, pain, muscle spasms, and metabolic activity .
Winter swimming (4 times per week on average) improved survey scores of tension, fatigue, memory, and mood compared to non-swimmer controls. Improvements in rheumatism, fibromyalgia, and asthma were also self-reported, albeit with a very low number of participants .
It also may prove beneficial for depression . A 1 hour immersion in 14°C water decreased cortisol levels (the stress hormone) in healthy individuals . A 10-week treatment with three cold affusions and two upper-body cold washings per week reduced infection rate and improved well-being of COPD patients .
Benefits of cold therapy for longevity
Among the first evidence that cold therapy could potentially impact longevity was a study in rats that used cold exposure to study the “rate-of-living” theory of aging. Rather than looking at cold exposure directly, the researchers used it to increase energy expenditure. The rats were immersed in 23°C (73.4°F) water for four hours a day, five days per week. Despite consuming more calories and weighing less than control rats (indicating a higher “rate of living”), these mice lived slightly longer. This result appeared largely due to a lower cancer incidence rate. Notably, this differed from previous studies that showed chronic cold exposure to decrease lifespan .
Fruit flies exposed to mild cold stress live longer . Mice increase mitochondrial biogenesis in response to cold stress . Like most hormetic stressors, cold therapy may also impart longevity benefits through the mTOR pathway in a cell-specific manner . Brown fat stimulation has been shown to increase several longevity-associated molecules: adiponectin , SIRT1 , FGF-21 , and irisin .
A recent review concluded with promising, but inconclusive evidence for whole-body cold therapy reducing inflammation and/or improving immune function in humans . After controlling for multiple confounding variables, a study in Belgium found telomere length to have been increased prenatally in fetuses gestated in colder environments .
Winter swimmers have also been found to have a protective antioxidant adaptation . Lastly, it is well-established across multiple organisms that a low basal body temperature results in increased longevity within a species. However, it is unknown whether lower body temperature is a cause or an effect of longevity or if cold exposure is capable of mimicking this phenomenon [41-43].
How can cold therapy be applied?
Part of the difficulty of teasing out the benefits of cold therapy is the multitude of different methods by which it can be applied. Individuals can increase their exposure to colder temperatures simply by living in a colder environment or increasing their outdoor activities during the winter months. Cold water swimming is a dangerous but often sworn-upon technique.
Indoors, many people similarly swear by taking a cold shower every morning to introduce a little cold therapy into their lives. Athletes can be found applying ice packs and submerging themselves in ice baths or cold whirlpools. Many spas also offer various forms of cold therapy, from mineral baths to reverse saunas to topical treatments.
Risks of cold exposure
While potentially beneficial, cold exposure is not without its risks. Many people die or face long-term health deficits from cold exposure each year. Hypothermia and frostbite are rare, but obvious examples and are easily avoided if proper precautions are taken. Drug use, homelessness, the weather, accidents, and/or poor preparation are commonly the main contributors leading up to hypothermia and frostbite.
Additionally, individuals with low fat and muscle tissue are more susceptible to cold temperatures. Older individuals, especially, are poor thermoregulators and die at much higher rates than their younger counterparts .
Cold exposure also likely plays a role in many deaths each year that are attributed to other causes. For example, cardiovascular-related deaths increase during the winter months . Rapid exposure to extreme cold can be shocking, but it can also send individuals into shock, as it’s defined medically, a life-threatening condition of circulatory failure . Heart arrhythmias are also observed more frequently after extreme cold exposure, possibly due to the simultaneous activation of the sympathetic and parasympathetic nervous systems .
A large number of drowning cases each year are likely also attributable to the cold. Submersion in cold water can result in an involuntary initial gasp for air or hyperventilation, both of which can cause water to enter the lungs. It may also cause temporary muscle paralysis, reducing swimmers’ ability to keep their heads above water .
It is extremely important to consult a physician before beginning any cold exposure routine and to take proper precautions to avoid more disastrous consequences.
As far as longevity strategies go, cold therapy is relatively unproven. The many different modes of applying cold stress, in addition to different temperatures, durations, and frequencies, make it difficult to compare across studies.
Cold water swimming is perhaps the most frequently studied in humans, but it is also the most dangerous route due to the risk of drowning. Additionally, it is not clear if the benefits of cold water swimming are above and beyond those seen from exercise alone in many studies.
Healthspan and lifespan data has been studied in bacteria, yeast, worms, and flies but is lacking in mammals. Some studies that have been done in mice have found small benefits. Others have found detriments to lifespan, but it seems likely that these mice were over-exposed and experienced chronic stress rather than a hormetic dose. More research is likely needed in rodents before even moving on to clinical trials.
Still, it seems likely that various mechanisms brought on by cold stress (brown fat activation, cold shock proteins, mild stress response) form a solid rationale behind how cold stress could feasibly increase longevity. Ultimately, many anti-aging strategies are still unproven but can be enjoyable (sauna use, good sleep, fasting, exercise, eating certain foods, etc).
None are guaranteed to make you live longer, but most are safe if done properly and are enjoyed by different people. In fact, improved mood from cold showers or swimming may be the benefit with the most evidence in humans. Ultimately, whether to incorporate it into one’s life is an extremely individual decision not yet completely refuted or supported by scientific research.
 Tipton, M.J. et al. Cold water immersion: kill or cure? Experimental Physioloy (2017). https://doi.org/10.1113/EP086283
 Ristow, M. and Zarse, K. How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). Experimental Gerontology (2010). https://doi.org/10.1016/j.exger.2010.03.014
 Calabrese, E.J. and Cook, R. The Importance of Hormesis to Public Health. Environmental Health Perspectives (2006). https://doi.org/10.1289/ehp.8606
 Heinz, G.H. et al. Enhanced reproduction in mallards fed a low level of methylmercury: An apparent case of hormesis. Environmental Toxicology and Chemistry (2010). https://doi.org/10.1002/etc.64
 Adjirackor, N.A. et al. Eukaryotic response to hypothermia in relation to integrated stress responses. Cell Stress Chaperones (2020). https://doi.org/10.1007/s12192-020-01135-8
 Brown D.J. et al. Accidental hypothermia. The New England Journal of Medicine (2012). https://doi.org/10.1056/NEJMra1114208
 Wistow, G. Cold shock and DNA binding. Nature (1990). https://doi.org/10.1038/344823c0
 Landsman, D. RNP-1, an RNA-binding motif is conserved in the DNA-binding cold shock domain. Nucleic Acids Research (1992). https://doi.org/10.1093/nar/20.11.2861
 Lindquist, J.A. and Mertens, P.R. Cold shock proteins: from cellular mechanisms to pathophysiology and disease. Cell Commun Signal. (2018). https://doi.org/10.1186/s12964-018-0274-6
 Jones, P.G. and Inouye, M. The cold-shock response–a hot topic. Mol Microbiol. (1994). https://doi.org/10.1111/j.1365-2958.1994.tb00359.x
 Hettinger Z.R. et al. Skeletal muscle RBM3 expression is associated with extended lifespan in Ames Dwarf and calorie restricted mice. Exp Gerontol. (2021). https://doi.org/10.1016/j.exger.2020.111214
 Holland, D.B. et al. Cold shock induces the synthesis of stress proteins in human keratinocytes. J Invest Dermatol (1993). https://doi.org/10.1111/1523-1747.ep12363791
 Khan, M.I. et al. YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget (2014). https://doi.org/10.18632/oncotarget.1790
 Enerbäck, S. The origins of brown adipose tissue. New England Journal of Medicine (2009). https://doi.org/10.1056/NEJMcibr0809610
 Celi, F.S. Brown adipose tissue – when it pays to be inefficient. New England Journal of Medicine (2009). https://doi.org/10.1056/NEJMe0900466
 Graja, A. and Schulz, T.J. Mechanisms of aging-related impairment of brown adipocyte development and function. Gerontology (2015). https://doi.org/10.1159/000366557
 Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes (2009). https://doi.org/10.2337/db09-0530
 Cohade, C. et al. Uptake in supraclavicular area fat (“USA-Fat”): description on 18F-FDG PET/CT. J Nucl Med. (2003). PMID: 12571205
 Yeung, H.W. et al. Patterns of (18)F-FDG uptake in adipose tissue and muscle: a potential source of false-positives for PET. J Nucl Med. (2003). PMID: 14602861
 Berbée, J.F.P. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nature Communications (2015). https://doi.org/10.1038/ncomms7356
 Hoeke, G. et al. Role of Brown fat in lipoprotein metabolism and atherosclerosis. Circ. Res. (2015). https://doi.org/10.1161/CIRCRESAHA.115.306647
 Ravussin, Y. et al.vEffect of intermittent cold exposure on brown fat activation, obesity, and energy homeostasis in mice. PLoS One (2014). https://doi.org/10.1371/journal.pone.0085876
 Le Bourg, E. et al. The NF-?B-like factor DIF could explain some positive effects of a mild stress on longevity, behavioral aging, and resistance to strong stresses in Drosophila melanogaster. Biogerontology (2012). https://doi.org/10.1007/s10522-012-9389-0
 Polesello, C. and Le Bourg, E. A mild cold stress that increases resistance to heat lowers FOXO translocation in Drosophila melanogaster. Biogerontology (2017). https://doi.org/10.1007/s10522-017-9722-8
 Jia, R. Characterization of cold-induced remodelling reveals depot-specific differences across and within brown and white adipose tissues in mice. Acta Physiol (Oxf). (2016). https://doi.org/10.1111/apha.12688
 Shefer, V.I. and Talan, M.I. Change in heat loss as a part of adaptation to repeated cold exposures in adult and aged male C57BL/6J mice. Exp Gerontol. (1997). https://doi.org/10.1016/s0531-5565(96)00131-3
 Zhou, Z-W. et al. Cold water swimming pretreatment reduces cognitive deficits in a rat model of traumatic brain injury. Neural Regen Res. (2017). https://doi.org/10.4103/1673-5374.213553
 Weston, M. et al. Changes in local blood volume during cold gel pack application to traumatized ankles. J Orthop Sports Phys Ther. (1994). https://doi.org/10.2519/jospt.19184.108.40.206
 Huttunen, P. Winter swimming improves general well-being. Int J Circumpolar Health. (2004). https://doi.org/10.3402/ijch.v63i2.17700
 Shevchuk, N.A. Adapted cold shower as a potential treatment for depression. Med Hypotheses. (2008) https://doi.org/10.1016/j.mehy.2007.04.052
 Srámek, P. Human physiological responses to immersion into water of different temperatures. Eur J Appl Physiol. (2000). https://doi.org/10.1007/s004210050065
 Goedsche, K. [Repeated cold water stimulations (hydrotherapy according to Kneipp) in patients with COPD] Forsch Komplementmed. (2007). https://doi.org/10.1159/000101948
 Holloszy, J.O. and Smith, E.K. Longevity of cold-exposed rats: a reevaluation of the “rate-of-living theory” Appl. Physiol. (1986). https://doi.org/10.1152/jappl.19220.127.116.116
 Chung, N. The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue. Journal of Exercise Nutrition & Biochemistry (2017). https://doi.org/10.20463/jenb.2017.0020
 Imbeault, P. et al. Cold exposure increases adiponectin levels in men. Metabolism: Clinical and Experimental (2009). https://doi.org/10.1016/j.metabol.2008.11.017
 Gerhart-Hines, Z. et al. The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD+. Molecular Cell (2011). https://doi.org/10.1016/j.molcel.2011.12.005
 Lee, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metabolism (2014). https://doi.org/10.1016/j.cmet.2013.12.017
 Martens, D.S. et al. Early Biological Aging and Fetal Exposure to High and Low Ambient Temperature: A Birth Cohort Study. Environ Health Perspect. (2019). https://doi.org/10.1289/EHP5153
 Siems, W.G et al. Improved antioxidative protection in winter swimmers. QJM (1999). https://doi.org/10.1093/qjmed/92.4.193
 Carillo, A.E. et al. Caloric restriction and longevity: Effects of reduced body temperature. Aging Research Reviews (2011). https://doi.org/10.1016/j.arr.2010.10.001
 Fluoris, A.D. and Piantoni, C. Links between thermoregulation and aging in endotherms and ectotherms. Temperature (Austin) (2014). https://doi.org/10.4161/23328940.2014.989793
 Conti, B. Considerations on temperature, longevity and aging. Cell Mol Life Sci. (2008). https://doi.org/10.1007/s00018-008-7536-1
 Kloner, R.A. et al. When Throughout the Year Is Coronary Death Most Likely to Occur? A 12-Year Population-Based Analysis of More Than 220,000 Cases. Circulation (1999). https://doi.org/10.1161/01.CIR.100.15.1630