COLD EXPOSURE PREVENTION OF NEURODEGENERATION INFLAMMATION CONTROL RESEARCH BASED BENEFITS

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1 COLD EXPOSURE RESEARCH BASED BENEFITS Short-term cold exposure is a positive stressor which triggers cellular responses in the body. These cellular responses result in abundant potential benefits. Whole Body Cryotherapy is a form of short term (no more than three minutes) cold exposure in which the body is exposed to cryogenic temperatures as cold as -160 C in an open-top cryogenic sauna. PREVENTION OF NEURODEGENERATION Synapses, nerve cell junctions which are responsible for facilitating communication between nerve cells and play a role in forming memories, are lost with normal brain aging and accelerated in neurodegenerative diseases such as Alzheimer s and Parkinson s and after traumatic brain injury. HOW DOES COLD EXPOSURE ASSIST THE SYNAPSES? Lowering core temperature by exposure to the extreme cold triggers the release of cold shock proteins; notably RNA binding motif 3 (RBM3). RBM3 facilitates the regeneration of synapses that are lost to neurodegenerative diseases and normal brain aging. It plays a vital role in this synapse regeneration by binding to RNA to increase protein synthesis at the dendrites, which are a part of the nerve cell that communicates with synapses. The research surrounding cold shock protein is still very new, however, the ability to lower core temperature significantly to activate RBM3 may have HUGE implications for preventing neurodegenerative disease and brain aging in general. Lowering the core temperature by less than 1 C is enough to induce cold shock proteins in brain cells. This core temperature drop is pretty achievable with just three minutes or less of Whole Body Cryotherapy at 110 C. In addition to the loss of communication between nerve cells, the development of neurodegenerative disease has been attributed to changes in blood vessels, oxidative stress and an increase of inflammation. The anti-inflammatory and anti-oxidative effects of cold exposure may provide additional benefits in preventing neurodegenerative disease. INFLAMMATION CONTROL Inflammation, an immune-mediated response to cell injury, is a necessary and beneficial process in the body it responds to cell injury, clears out dead cells and damaged tissues from the original injury and initiates tissue repair. However, sometimes the immune system triggers an inflammatory response in the absence of a biological threat, causing damage to the body s own tissue. This can be triggered by chronic stress, smoking and sedentary lifestyle, among other factors. In autoimmune conditions, such as rheumatoid arthritis, the immune system targets the body s normal cells as if they were foreign invaders. In addition, inflammation has been associated with numerous age-related diseases and has been identified as a key driver of the

2 aging process. In fact, a study investigating people from the ages of 85 to over 110 years old, found that low inflammation was the ONLY biomarker that predicted survival and mental ability across all age groups¹. HOW DOES COLD EXPOSURE DECREASE INFLAMMATION? Norepinephrine is both a hormone and a neurotransmitter that is released into the brain and the bloodstream in response to cold exposure. Regular cryostimulation at -110 C for just two minutes is sufficient to increase the release of norepinephrine into the blood by up to 300%². Norepinephrine decreases a very powerful inflammation-inducing molecule (TNFalpha), which in turn inhibits the inflammatory pathway and decreases inflammation. Excess levels of TNF-alpha have been implicated in almost every human disease, including type 2 diabetes, inflammatory bowel disease and cancer. Macrophage inflammatory protein-1α, another inflammation-inducing molecule, which, in excess, plays a role in rheumatoid arthritis, is also decreased with cold exposure. IMPROVED IMMUNITY Although immune cells activate inflammation, which, as previously discussed, can wreak havoc on the body, having a large number of various types of immune cells is actually a good thing, as long as they aren t unnecessarily active. HOW DOES THE COLD AFFECT OUR IMMUNE CELL STOCK? Various studies have showed increased (inactive) immune cell numbers with prolonged cold exposure, particularly: white blood cells, which protect the body against infectious disease and foreign invaders, cytotoxic T lymphocytes, a type of specialized white blood cells that fight cancer cells, and natural killer T cells, which kill viruses and tumor cells. A significant store of immune cells is suggested to increase susceptibility to infection by allowing the immune system to rapidly respond to foreign invaders should the need arise. One study demonstrated the association between winter swimming and a 40% decreased incidence of respiratory tract infections³. WEIGHT LOSS FACILITATION Thermogenesis is a response to the cold in which the body produces heat to warm itself up and, in the process, burns fat. HOW DOES EXPOSURE TO THE COLD FACILITATE WEIGHT LOSS? Cold exposure induces muscle contraction to increase energy metabolism and produces heat as a byproduct. Norepinephrine comes into play in this process by increasing the expression of a protein known as uncoupling protein 1 (UCP1), which ultimately produces more mitochondria (cell energy sources) in adipose (fatty) tissue. Brown adipose tissue, in which each fat cell has more mitochondria per cell than white adipose tissue, is more metabolically active than white adipose tissue. This means, the more brown adipose tissue your body has, the more fat your body will burn. Repeated intermittent exposure to extreme cold has been shown to increase brown adipose tissue in humans. INCREASED ANTIOXIDANT ACTIVITY Reactive oxygen species are chemically reactive chemical species which contain oxygen and cause damage to the components of tissues and cells, including DNA. By contributing to the damage of DNA, reactive oxygen species also play a role in the process of aging, mitochondrial dysfunction and diseases such as cancer. The production of reactive oxygen species is a normal response to increased energy metabolism, hence it is important for the body to react to and alleviate

3 the damage effectively. HOW DOES THE COLD PROTECT AGAINST CELL DAMAGING OXIDANTS? Cold exposure activates very potent antioxidant systems. It significantly increases the activity of antioxidant enzymes (molecules which accelerate chemical reactions), specifically glutathione reductase and superoxide dismutase. With repeated cold exposure, one study showed that the activity of these antioxidant enzymes could be doubled. SPORT AND EXERCISE ENHANCEMENT The effect that cold exposure has on sport performance and recovery depends on two important factors: the nature of exercise being done and the timing of cold exposure in relation to the exercise. TIMING OF COLD EXPOSURE PRE WORKOUT. Cryotherapy prior to exercise activity may contribute to a more vigorous and beneficial work out. Since energy metabolism naturally activates reactive oxygen species (see INCREASED ANTIOXIDANT ACTIVITY), cold exposure prior to exercise will give the body a kickstart in responding appropriately and effectively to oxidation induced by exercise. In addition, slight cooling of muscle tissue results in a slower rate of fatigue. POST WORKOUT. As previously mentioned, inflammation is highly beneficial when applied in the right context. Immediately after exercise activity there is an increase in pro-inflammatory cytokines, which activate immune cells and are involved in tissue repair. This inflammatory process is necessary to activate genetic pathways which contribute to creating more mitochondria and play a role in increasing the size of skeletal muscle through a growth in size of its component cells. In response to this immune activation, there is an activation of antiinflammatory cytokines to keep the immune system balanced so as to prevent excessive tissue damage. The anti-inflammatory response peaks one hour after activity, and since some inflammation and immune activation is good, cold exposure at least one hour after exercise would be most beneficial. Levels of inflammation which continue to be elevated after this peak process may result in acute performance deterioration and muscle damage in subsequent training sessions due to residual soreness and muscle function changes. A study performed on elite runners using cryotherapy one hour postexercise showed a great enhancement in muscle recovery as a result of decreased inflammation. NATURE OF EXERCISE Exercise places (good) stress on the body, and, in response, the body activates genes and pathways that build adaptation to that stress. The nature of exercise that is performed determines the characteristics of the adaptation that occurs. ENDURANCE TRAINING. Endurance training, such as running, inflicts predominantly aerobic stress on the body, which places a greater demand on the cells to be able to use oxygen in order to produce energy. Mitochondria are what give us the ability to use oxygen in order to produce cellular energy. The more mitochondria we have, the greater our ability to utilize oxygen and hence, the more adapted we may be to aerobic activity. Highly aerobic activity also requires more muscle fibres that use oxygen and are somewhat resistant to fatigue. These are predominantly type I, also known as slow twitch, muscle fibres, as well as type IIa muscle fibres, a category of fast twitch muscle fibres. HOW DOES COLD EXPOSURE ENHANCE ENDURANCE TRAINING? Cold exposure activates a gene known as PGC-1α which creates more

4 mitochondria in the muscle. More mitochondria per muscle cell equal a greater aerobic capacity. The anti-inflammatory effects of cold exposure one hour post-exercise (see TIMING OF COLD EXPOSURE) also play a role in enhancing endurance training by accelerating the rate of recovery, hence reducing the risk of injury and facilitating a quicker return to training. The below table identifies the results observed in a few studies following post training cold exposure: STUDY POPULATION COLD EXPOSURE TIME RESULTS Elite runners 1 hour, 24 hours and 48 hours post hill sprint running 20% increase in speed and power up to two days later Enhanced muscle recovery Elite tennis players Twice/ day morning and eveninmg while training in the afternoon for five days 2.5 fold decrease in pro-inflammatories 23% increase in anti-inflammatories Elite cyclists 30 minutes post training 4 times per week for 39 days 4.4% increase in average sprint power 3% enhancement in repeat cycling performance 2.7% increased power RESISTANCE TRAINING. It is important to allow the natural oxidant and inflammatory processes to take effect after exercise and before cold exposure, as this play a vital role in muscle hypertrophy. Once the peak anti-inflammatory process has been reached at least one hour post exercise, cold exposure may be beneficial. Following cold exposure one hour after plyometric exercise (squat jumps and leg curls), one study showed improvements in power at the start of the squat jump and squat jump workout, as well as a decrease in pain. The pain measure was improved both at rest and at the next squat jumping session. cold exposure show a lot of promise. Cold exposure has been shown to potentially prevent neurodegeneration, control inflammation, improve immunity, facilitate weight loss, increase antioxidant activity and enhance sport and exercise performance. This document is intended for informational purposes only and not medical advice. Although Whole Body Cryotherapy has not resulted in adverse effects where the necessary precautions are taken, it is important to consult a physician before beginning a new treatment regime, especially where there are preexisting conditions. A BRIEF SUMMARY Although much of the literature regarding cold exposure is fairly new and many of the benefits anecdotal, the science based mechanisms behind

5 REFERENCES ADAPTED FROM Cold Shocking the Body: Exploring Cryotherapy, Cold-Water Immersion, and Cold Stress by Rhonda Perciavalle Patrick, Ph. D. PREVENTION OF NEURODEGENERATION Peretti, D. et al RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature 518 (7538): Jackson, T.C. et al Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons. Neuroscience 305: Misiak, B. and Kiejna, A Translating whole-body cryotherapy into geriatric psychiatry A proposed strategy for the prevention of Alzheimer s disease. Medical Hypotheses 79 (2012): INFLAMMATION CONTROL ¹ Arai, Y. et al Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians. EBioMedicine 2(10): ² Leppäluoto, J. et al Effects of long term whole body cold exposures on plasma concentrations of ACTH, betaendorphin, cortisol, catecholamines and cytokines in healthy females. Scandinavian Journal of Clinical and Laboratory Investigation 68(2): Hirvonen, H.E. et al Effectiveness of different cryotherapies on pain and disease activity in active rheumatoid arthritis: A randomised single blinded controlled trial. Clin Exp Rheumatology 24(3): IMPROVED IMMUNITY ³ Kolettis, T. M. and Kolettis, M. T Winter swimming: healthy or hazardous?: Evidence and hypotheses.medical Hypotheses 61(5-6): Jansky, L. et al Immune system of cold-exposed and cold-adapted humans. Eur J Appl Physiol Occup Physiol 72(5-6): Brenner, I. K. M. et al Immune changes in humans during cold exposure: effects of prior heating and exercise. Applied Physiology 87(2): brown adipose tissue in healthy men. NEJM 360(18): van der Lans, A.A.J.J. et al Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. The Journal of Clinical Investigation 123(8): INCREASED ANTIOXIDANT ACTIVITY Lubkowska, A., Dolegowska, B. and Szygula, Z Whole-Body Cryostimulation - Potential Beneficial Treatment for Improving Antioxidant Capacity in Healthy Men - Significance of the Number of Sessions. PLoS ONE 7(10): Wozniak, A. et al The effect of whole-body cryostimulation on the prooxidant antioxidant balance in blood of elite kayakers after training. European Journal of Applied Physiology 101(5): SPORT AND EXERCISE ENCHANCEMENT Ihsan, M. et al Postexercise muscle cooling enhances gene expression of PGC-1α. Med Sci Sports Exerc. 46(10): Pournot, H. et al Time-Course of Changes in Inflammatory Response after Whole-Body Cryotherapy Multi Exposures following Severe Exercise. PloS ONE 6(11): Hausswarth, C. et al Effects of Whole-Body Cryotherapy vs. Far-Infrared vs. Passive Modalities on Recovery from Exercise-Induced Muscle Damage in Highly- Trained Runners. PloS ONE 6(12): Ziemann, E. et al Five-Day Whole-Body Cryostimulation, Blood Inflammatory Markers, and Performance in High-Ranking Professional Tennis Players. Journal of Athletic Training 47(6): Halson, S.L. et al Does hydrotherapy help or hinder adaptation to training in competitive cyclists? Med Sci Sports Exerc. 46(8): Fonda, B. and Sarabon, N Effects of whole-body cryotherapy on recovery after hamstring damaging exercise: A crossover study. Scandinavian Journal of Medicine and Science in Sports 23(5): WEIGHT LOSS FACILITATION van Marken Lichtenbelt, W.B. et al Cold-activated