Cold Thermogenesis and The Brain

July 14, 2020

OVERVIEW OF COLD THERMOGENESIS

What does swimming in the freezing ocean, taking a cold shower and drinking cold water all have in common? They are all examples of cold thermogenesis, or cold exposure. In recent years, exposing yourself to cold temperatures has gained serious popularity due to its association with a number of health benefits including neuroprotective benefits, reducing inflammation, regulating body fat levels and fighting off potential diseases.

What is Cold Thermogenesis?

The term ‘thermogenesis’ comes from the Greek word ‘thermos’ which means ‘heat’ and the word ‘genesis’ which means the beginning or production of something. Together they are the production of heat.

Cold thermogenesis (CT) is intentionally exposing the body to the cold for short periods of time to produce adaptive, beneficial hormetic responses (Vosselman, 2014). Thermogenesis is a way to produce heat to keep the body warm. Cold thermogenesis kicks this process into overdrive.

When exposed to colder environments, the body works harder to maintain homeostasis (the body wants to always stay at 98.6F degrees or 37C degrees) and its core temperature. In order to do this, it produces more energy to stay warm, burning calories to produce heat. This in turn stimulates and increases metabolism. Cold thermogenesis becomes a fat burning aid by activating the body’s built in stores of brown fat.

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Cold Thermogenesis Methods

  • Cold showers

  • Splashing cold water on your face

  • Wearing body-cooling gear

  • Ice baths

  • Sleeping in a cold room

  • Keeping your house chilly

  • Sitting in cryotherapy chambers

Cryotherapy is incredibly popular in the athletic and wellness population. It consists of getting into a tank filled with liquid nitrogen that makes it -200 to -250F degrees (-120C - -150C degrees). Once in the chamber, blood beings to pull away from outer extremities and towards internal organs such as the heart and lungs, which stimulates the rate of tissue repair and reduce circulating levels of inflammation (Lombardi, 2017).

PHYSIOLOGICAL REPONSE TO COLD STRESS

When exposed to temperatures below the thermal comfort level, heat loss must equal internal heat production (thermogenesis) in order to achieve homeostasis (maintenance of body temperature). Exposure to the cold may cause physiologic reactions such as a decrease in local metabolic function, local inflammation, nerve conduction velocity, muscle spasm and an increase in local anaesthetic effects (Mooventhan, 2014).

Humans have three mechanisms to defend against cold:

  • Vasocontraction: Constriction of blood vessels (become narrow) allows less blood to flow through the skin and which conserves core body temperature and protects vital organs.

  • Shivering: Muscular Involuntary Contractions: Contraction, or twitching of muscles in cold, known as shivering, produces internal heat as a form of metabolic work. When the body can no longer maintain core temperature by constricting blood vessels, it shivers to increase heat production.

  • Non-shivering thermogenesis: Cold thermogenesis is a non-shivering mechanism. This involves the body burning energy (brown fat) and producing heat without contraction of skeletal muscles (Marlatt, 2017). There is an increase in energy expenditure up to 3-5-fold above the resting energy expenditure in order to counterbalance heat lost (Brychta, 2017).

MECHANISM INVOLVED IN COLD STRESS

Brown Fat Activation – Staying Warm Without Shivering

The bodies contain two types of fat: white fat (WAT) and brown fat (BAT).

White Adipose Tissue (WAT)

  • WAT is principally a storage tissue

  • Think love handles, belly fat, the fat everyone wants to get rid of

  • WAT has a lower rate of metabolism

  • Too much WAT leads to obesity (Longo, 2019).

Brown Adipose Tissue (BAT)

  • Brown fat is a unique highly metabolic active tissue that keeps individuals lean and healthy.

  • It is commonly found in babies and animals who are hibernating that burn brown fat to stay warm

  • It is primary found in the sternum, neck and upper back.

  • It is rich in mitochondria - mitochondria are often called the ‘power plants’ of the cell and are involved in producing ATP for energy.

  • Brown fat burns up regular stored white fat, by releasing heat to warm the body (Keil, 2015).

  • Frequent cold exposures might be an acceptable economical complementary approach to address the current obesity epidemic (Van Der Lans, 2013).

How is Brown Fat Activated?

The prime activator of brown fat is cold exposure (Fenzl, 2014). Brown fat ‘turns on’ and begins to burn calories from either glucose or fat to create heat and maintain body temperature. When fully activated, just 100g of brown fat can burn 3,400 calories a day – significantly higher than most people’s daily food intake (University of Cambridge, 2018).

brown adipose tissue

How long does it take to build up BAT?

Long term mild cold exposure can stimulate brown fat growth and activity in humans and potentially benefit glucose and energy metabolism (Silva, 2019).

One study showed an increase in brown fat after only 10 short days when subjects sat in a 60F degrees (15.5C degrees) room for 6 hours a day (Van Der Lans, 2013). Similarly, individuals with obesity or type 2 diabetes experienced an increase in brown fat activity and improved whole-body insulin sensitivity (43%) after 10 days of cold acclimation (57-60F degrees/14-15C degrees) (Hanssen, 2015).

A study conducted by Maastrict University Medical Centre discovered a decrease in body fat after people spent 2 hours per day at 62.6 degrees F (17C degrees) for 6 weeks. Furthermore, after six hours a day in the cold for a period of 10 days, participants increased their levels of brown fat (Van Der Lichtenbelt, 2014).

Researchers in Australia discovered after a month of exposure to 66 degrees F room for 10 hours each night, participants had a 42% increase in brown fat volume and a 10% increase fat metabolic activity. This was accompanied by improved insulin sensitivity and changes to hormones, leptin and adiponectin (Lee, 2014).

Adiponectin Activation: Hormonal response to cold thermogenesis

Adiponectin is a hormone that is produced in and released from fat cells. It combats inflammation and boosts metabolism (Stern, 2017). Low levels of adiponectin are associated with obesity (Gariballa, 2019).

It has been reported that cold exposure increases adiponectin levels (Jankovic, 2013). This breaks down fat and shuttles glucose (blood sugar) into muscles, helping reduce blood sugar levels. In mouse models, researchers discovered that adiponectin treatment improves insulin sensitivity, suggesting it may be a promising candidate for prevention and treatment of metabolic syndrome and insulin resistance (Wei, 2017).

Norepinephrine: Neuroendocrine Response

Norepinephrine is a neurotransmitter and a hormone. It is released when the body’s fight or flight response is activated (e.g. exposure to cold or being chased by a lion). The role that norepinephrine plays in the human body is essential to how the body responds to cold temperatures: by increasing norepinephrine in the blood, it can cause vasoconstriction (narrowing of blood vessels), and retention of bodily heat (Morrison, 2016).

Presence of norepinephrine in the blood stream have profound effects on attention span, mood and vigilance, while the absence of norepinephrine results in inattention, poor mood and decreased energy (Ranjbar-Slamloo, 2020). Additionally, cold exposure responses may even be a viable option for treatment of depression and mood disorders (Shevchuk, 2008).

How cold does it need to be to activate norepinephrine?

Cold water immersion at 68F degrees for one hour does not appear to activate norepinephrine release, however one hour at 57F degrees increases norepinephrine levels by 530% and dopamine levels by 250% (Sramek, 2000). It may seem like the longer time spent in the cold, the better. However, a long-term study conducted showed that this is not necessarily the case. One group of people who sat in cold water at 40F degrees for 20 seconds and another group who participated in whole body cryotherapy at -166 degrees F for 2 minutes both did treatments three times a week for 12 weeks, and in each case, plasma norepinephrine increase by 200-300% (Leppaluoto, 2009).

norepinephrine

Cold Shock Proteins: RBM3

If neurons are damaged or lost, they are unable to grow back, however synapses can. Synapses are gaps between neurons in the brain and they are responsible for normal brain function, cell communication and forming memories. The brain has the ability to create new pathways and modify its connections or rewire itself. This is called neuroplasticity.

The progressive breakdown of synapses is greatly increased by disease (e.g. Alzheimer’s Disease) and environmental factors (e.g. food intake, exercise). Individuals who suffer a traumatic brain injury (TBI) such as concussion will experience synaptic loss (Park, 2013). Synapse loss may significantly contribute to functional impairments and neurological disorders following TBI (Xiong, 2019). Synapse numbers after TBI begins to recover at approximate 10-14 post injury (Semchenko et al. 2006).

RNA-binding protein 3 (RBM3) is a specific protein found in your brain, heart, liver and skeletal muscle. Cold exposure and hypothermia stimulate the activity of cold shock proteins, especially RBM3, which takes part in neural plasticity and suppresses synapse loss (Zhu, 2016).

HEALTH BENEFITS ASSOCIATED WITH COLD THERMOGENESIS

Norepinephrine: Decreased Inflammation

Inflammation is part of the body’s defence mechanism. It is the body’s process of removing the cause of cell injury, eliminating dead cells before the healing process begins. Inflammatory diseases are the most significant cause of death in the world (Pahwa, 2020).

Norepinephrine acts both as a neurotransmitter and hormone and is released in the body when exposed to cold temperatures. Norepinephrine has anti-inflammatory properties at high concentrations (Pongratz, 2014). The norepinephrine signalling pathway also plays an extremely important role in the regulation of hippocampal function, which is important for memory and learning (Kim, 2019).

O’Neill et. al (2018) suggests that the increase of norepinephrine in the body may:

  • Provide neuroprotection in CNS disorders where inflammation is present

  • Supress microglia and astrocyte activation (both are major players of neuroinflammation and is linked to the progression of Alzheimer’s Disease, Multiple Sclerosis and Parkinson’s Disease)

  • Inhibit production of inflammatory mediators (a messenger that promotes an inflammatory response)

Antioxidant Activity

Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) (e.g. free radicals) and the ability to counteract or detoxify their harmful effects through neutralization by antioxidants. In other words, ROS are molecules that can damage body’s cells and antioxidants help fight ROS.

Improving levels of antioxidants can be extremely important to staying healthy by preventing and repairing damage (Kurutas, 2016). Oxidative stress can cause chronic inflammation and may contribute to several neurodegenerative conditions such as Alzheimer’s Disease and Chronic Traumatic Encephalopathy (CTE) (Cruz-Haces, 2017).

How can oxidative stress be reduced?

Cold exposure has been shown to activate antioxidizing systems (Saltykova, 2019). A study showed that cryotherapy treatment may inhibit generating free radicals and reduce oxidative stress (Miller, 2010), while another study found the effects of cryotherapy helped reduce oxidative stress following an injury (Siqueira, 2017).

Superoxide dismutase is important for cleaning up damage that is produced in the mitochondria. Glutathione is responsible for alleviating oxidative stress. Both antioxidants increased in activity from 43-68% following daily cold exposure up to 20 days (Lubkowska, 2012).

A recent study in mice found that it plays a critical role in mediating synaptic repair processes essential for neuroprotection of neurodegenerative disease (Bastide, 2017). In humans, it appears that a 2F degrees (-15C degrees) reduction in core body temperature is enough to induce cold shock proteins, including RMB3, in human astrocytes (a type of brain cell) (Jackson, 2015). Therapeutic cold exposure could be a breakthrough in neurogenerative disorder treatment, however, the precise mechanism on how this protein acts on the brain is still not fully understood.

oxidative stress

Enhanced Immune System

Cryotherapy has been proven to enhance the immune system, primarily by increasing levels of immune cells that help fight disease and infection. Research suggested that cryotherapy can increase the amount of white blood cells, (the solider cells that fight infection) cytotoxic T-lymphocytes and other beneficial immune cells (Lubkowska, 2010).

Increase cell longevity

mTOR is a protein which regulates cell growth and survival. mTOR should not be viewed as good or bad – it is one of those things that is good to have cycled. Sometimes it needs to be increased to grow muscle, while the rest of the time low levels are preferred to increase longevity, decrease cancer and reduce inflammation (Saxton, 2017).

In times of stress such as cold temperature exposure or reduced caloric intake, mTOR is inhibited (Zhou, 2010). Cold exposure has a similar effect on mTOR pathways to caloric restriction: it can induce cellular autophagy, which is a process that detoxes and cleans out the junk within cells (Anton, 2018). This in turn leads to longer cell life and overall longevity. In short, it is ideal to keep mTOR levels low most of the time (cold exposure does this) for improved health and longevity.

Hormone regulation: Metabolism

The thyroid gland plays a crucial role in regulating metabolism. It releases two hormones Thyroxine (T4) and Triiodothyronine (T3). Too little of T3 and T4 released from the thyroid can result in tiredness, forgetfulness and weight gain. Too much can result in a rapid heartbeat, anxiety and sensitivity to heat (Mullur, 2014). Since the thyroid plays a major role in metabolism, dysfunction can affect almost every part of the body, including energy levels and the ability to burn calories.

Cryotherapy can be a potential tool to relieve symptoms of hypothyroidism (not enough T3 and T4) and improving thyroid function. It has been shown to decrease TNF-a and IL-2-pro-inflammtory cytokines (The Journal of Physiological Sciences, 2013). Pro-inflammatory cytokines play a central role in inflammatory diseases. By lowering these cytokines, dysfunction in the thyroid is reduced and normal hormonal secretion T3 and T4 can occur. In addition, cryotherapy also reduces cortisol levels – which have been shown to lower hormonal secretions leading to hypothyroidism (Grasso, 2014).

In another study, young men were immersed up to their necks in cold water of various temperatures for 1 hour – 32C degrees (90F), 20C degrees (68F), 14C degrees (57F). Afterwards, various biomarkers were measured. Under cold conditions, the participants resting metabolism increased by 93% percent in the 20C degree (68F) water and 350% in the 14C degree (57F) water (Sramek, 2000).

Cold Thermogenesis Increases Insulin Sensitivity

Insulin sensitivity refers to how sensitive the body’s cells are in response to insulin. High insulin sensitivity allows the cells of the body to use blood glucose more effectively, reducing blood sugar (Freeman, 2019). When the body stops responding to insulin the way it should, it can run into various problems including diabetes.

Cold thermogenesis increases levels of brown fat. A higher ratio of brown fat can increase sensitivity to insulin (Orava, 2011). A study discovered that participants who spent hours in a cold chamber daily not only experienced an increase in the heat output of brown fat, but also an improvement in the control of glucose (blood sugar) via insulin (Mueez, 2018). Another study on mice, which were exposed to cold temperatures (4C degrees (39F), 2 hours per day and 5 days a week for 14 weeks) showed an improvement in glucose tolerance and enhanced insulin sensitivity (Wang, 2015).

cold therapy and the brain

COLD EXPOSURE AND THE BRAIN

Chronic Traumatic Encephalopathy is a neurodegenerative disease. Although not directly linked to concussion, it is highly associated with repeated trauma to the head and mild traumatic brain injury (mTBI) (e.g. concussion). A traumatic injury to the brain can turn on biochemical pathways that lead to progressive deterioration and loss of function in brain cells.

A recent study by the University of Wisconsin conducted experiments on chilling concussed brain cells in a petri-dish and discovered several key parameters that determined the effectiveness of therapeutic cooling for mitigating damage to the injured cells. In order for the treatment to be a success, there is a cooling sweet spot – not too little, not too much and a window of opportunity following the injury (Scimone, 2020). Future treatments for mTBI could be as simple as just cooling the brain.

TBI damages the blood brain barrier, which protects the brain from pathogens and toxins (Ben-Gurion University, 2019). The permeability (allowing things to pass through) of the blood brain barrier is altered in many central nervous system (CNS) pathologies, including mTBI, Alzheimer’s Diseases and major depression (Malkiewicz, 2019). It becomes more permeable during inflammation (e.g. during a concussion). By keeping this barrier healthy, the brain is able to function in a healthy manner. Cold exposure can keep the blood brain barrier healthy by increasing blood flow and nitric oxide delivery to the brain. Cold exposure increases the blood brain barrier integrity and suppresses blood brain barrier degeneration (Miller et. al, 2010).

HOW TO DO COLD THERMOGENESIS

Even though there are currently no proven protocols on how to adapt to the cold, it is encouraged to slowly build a tolerance and not start by jumping into a freezing cold lake. Cold thermogenesis doesn’t require full body submersion in order to get fat burning and other benefits. Here are some ways to practice CT:

Beginner Cold Thermogenesis

  • Sitting in a 66F (19C) degrees room with minimal clothing

  • Sleeping in a cool room (around 66F/19C degrees) for 4 weeks can be enough to get started

  • A mild increase in calorie burn occurs as the sympathetic nervous system is activated to increase body temperature and there is a slight increase in breathing.

  • In order to receive more metabolic burning benefits, the intensity needs to be increased

Moderate Cold Thermogenesis

  • Sitting in a 50-60F (10-15.5C) degrees room while wearing minimal clothing

  • This is cold enough to ‘turn on’ the burning of brown fat which burns calories from either glucose or fat

Advanced Cold Thermogenesis

  • This intensity involves shivering, which burns a substantial amount of calories

What temperature and duration are required?

Cold water immersion at 68F (20C) degrees for one hour does not appear to activate norepinephrine release, however one hour at 57F (14C) degrees increases it by 530% (Sramek, 2000).

Taking a cold shower, jump into a cold pool, lake, river, seas for at least 2 to 5 mins a day is a good way to start. This type of cold-water immersion has been shown to be just as effective as cryotherapy for tapping into the many benefits of cold. A long-term study of a group of people who sat in cold water at 40F (4C) degrees for 20 seconds and another group who did whole body cryotherapy at -166F (-110C) degrees for 2 minutes. Both did their treatments three times a week for 12 weeks. In each case, plasma norepinephrine increase by 200-300% (Leppaluoto, 2009).

In addition to 2-5mins a day, 1-2 times a week, incorporating a longer 10-20 minute cold soak or ice bath that brings a state of shivering can be beneficial (or a series of 2-3 rounds of 2-3mins of ice baths). These longer and more intensive colder soaks can significantly enhance the conversion of white fat to brown fat (a key part of how CT helps to burn fat) and can also be used as a quick cognitive boost.

ATHLETES AND COLD EXPOSURE

More athletes are turning to cold exposure to promote recovery and reduce workout-related fatigue. This is because cold immersion results in the nervous system creating vasoconstriction, which narrows the arteries and blood vessels. This reduces blood flow to damaged muscles, in turn reducing inflammation and mitigating the onset of swelling and bruising (Chaudhry, 2020).

However, decreasing inflammation can also be a bad thing. Acute inflammation has a purpose. It is needed to signal ‘damage’ in order for the immune system to clear out old damaged tissue and replace it with new healthy strong tissue. Decreasing inflammation too much will delay tissue healing (Singh, 2017). If the individual consistently uses cold water tanks or cryotherapy chambers after exercise, muscles may not adapt (may not get the strength gains). It may also delay tendon and ligament healing due to delayed collagen synthesis (Hohenauer, 2015).

A study examining cold water immersion vs. active recovery found 10 minutes of cold water immersion twice a week for 12 weeks after resistance training session blunted long term gains in muscle mass and strength (Roberts, 2015). However, in other contexts there may be improvements as well. Cold water immersion has shown to significantly reduce the loss in maximal strength and delayed onset muscle soreness (DOMS) for up to 96 hours post-exercise (Bleakley, 2012). In the same study, a lower rating of perceived fatigue was observed after cold water immersion an exposure of 11-15C degrees over 11-15 mins (Machado et al., 2016).

Summary:

  • Cold thermogenesis is the practice of intentionally exposing parts of the body to cold in order to produce adaptive, beneficial hormetic responses.

  • Practices include cold baths, cold showers, ice soaks, going outside on a cold day, keeping the house cold, or spending time in a cryotherapy chamber

  • Cold exposure increases metabolism in two main ways: shivering thermogenesis and non-shivering thermogenesis.

  • Non shivering thermogenesis is mediated by a unique type of mitochondrial dense fat called brown fat, which converts food to heat and keeps you warm without shivering.

  • Cold temperatures stimulate brown fat activity. Cold signals the nervous system to release norepinephrine, which in turn stimulates brown fat and increases energy expenditure.

  • Cold exposure shuts down inflammation caused by exercise and wounds and activates the sympathetic, fight or flight nervous system, which regulates the mobilization and metabolism of stored fat.

CONCLUSION

When it comes to improving health, many of the simplest strategies can have a significant impact. Regularly exposing yourself to cold temperatures can catalyse a number of potential health benefits and maybe be a potential tool for neurodegeneration diseases, cognitive disorders and obesity treatment. More extensive research in this area needs to be conducted in order to better understand its full potential.

Cold ice bath

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