Hidden Dangers of Cold Thermogenesis
Induction of thermogenesis via exposure to cold is becoming an increasingly popular trend in the anti-aging community, not only for weight loss but also for everything from control of inflammation to regulation of blood sugar and pain management. It has been heralded a panacea and, in certain circles, lauded as the greatest health intervention of the 21st century. I do not wish to discourage those that might adopt this practice as a tool to shape their health outcomes. I do, however, feel obligated to share some of the insights I have gathered over the years from both self-experimentation and my work with others. Hopefully, this will shed a small amount of light on what can only be described as an extremely complex topic.
Table of Contents
- Hidden Dangers of Cold Thermogenesis
- The Mechanics of Cold Thermogenesis
- Consequences of Long-Term Cold Exposure
The Mechanics of Cold Thermogenesis
Let’s start by talking about the mechanics of cold thermogenesis (CT). Just to be clear, we are referring to the non-shivering variety that people are using to convert white adipose tissue (WAT) to brown adipose tissue (BAT). In doing so, they are able to leverage the unique ability of BAT to uncouple protons from ATP synthesis as they move down their mitochondrial gradient. This allows the dissipation of energy as heat instead of being stored for use elsewhere in the body. This is, perhaps, the most important concept for us to understand. CT is making a tradeoff to mobilize fatty acids for heat energy by sacrificing, to a degree, ATP generation.
CT, first and foremost, is a stress response triggered by environmental challenge. All of its effects are mediated by an adaptation to some form of environmental shock. Cold stimuli are relayed through the peripheral nervous system to the hypothalamus which in turn signals the adrenal medulla, via the sympathetic nervous system, to release both norepinephrine and epinephrine into the blood stream. These stimulatory neurotransmitters, in turn, stimulate adrenergic receptors on brown or beige adipocytes which increases adenylate cyclase and cAMP levels. cAMP then provokes protein kinase A (PRKACA) to enter the nucleus, modulating the expression of various genes that eventually leads to the activation of UCP1, or mitochondrial uncoupling protein 1.
But let’s step back a few paces and examine the effects of CT in both chronically ill and healthy people.
Problem #1: Hypothyroidism
If, for whatever reason, you have limited ability to convert thyroxine (T4) to triiodothyronine (T3) from hypothyroidism, autoimmune Hashimoto’s, or some other form of thyroid disorder, the acute thermogenic response of BAT to cold will be signficantly diminished. Many of the people I have encountered with thyroid problems continue to abuse themselves with CT because they have been falsely told that it will stimulate the hypothalamus to upregulate secretion of thyrotropin-stimulating hormone (TRH) and reverse their hypothyroidism. This most certainly does not happen. Meanwhile, they are torturing themselves, unable to generate heat, and waiting endlessly for their thyroid to “come back online”. In rare cases, cold stimulation can lower pro-inflammatory cytokine signaling in the brain and reduce hypothalamic inflammation, thus leading to improved neuroendocrine signaling, but this will not happen if there are other underlying issues such as autoimmunity or, worse, polymorphisms in genes governing adenylate cyclase — a problem that is more common than many would suspect.
Problem #2: Catecholamine Deficit
The second problem I frequently see here is a limited ability to produce norepinephrine and, downstream, epinephrine (adrenaline). There are a myriad of reasons this could happen and we won’t go into them here. The most common situation is genetic blocks in dopamine beta-hydroxylase (DBH) which mediates the conversion of L-DOPA to norepinephrine. It is a copper dependent enzymatic reaction, so low copper status could exacerbate the problem. Take this a step further, and there may also be issues in beta-adrenergic receptor expression or, in some cases, antibodies against those receptors, leading to varying degrees of orthostatic hypotension. Jumping into an ice bath for such individuals is not only ill-advised but decidedly dangerous and could severely complicate their health issues.
Effects in Healthy Individuals
So what if the hypothalamus-pituitary-adrenal-thyroid (HPAT)-axis and relevant adenylate cylase genes are all in order? Would that give a person carte blanche to jump into CT with full force? Let’s examine the process more deeply. Initially, if you are, to one degree or another, overweight, upregulation of UCP1 will release heat in adipocytes. There may be an initial period of weight loss, but this eventually plateaus as BAT concentrations reach homeostasis. This is where the trouble may potentially begin. You see, as this practice is engaged chronically, PRKACA is not only entering the nucleus to affect UCP1 expression, but it also begins to affect the MAPK signaling pathway as well. The MAPK (mitogen-activated protein kinase) cascade is a delicate system that mediates a wide variety of cellular functions, including cell proliferation, differentiation, and migration. Each MAPK kinase (MAPKK or activators), however, can be triggered by more than one MAPKK kinase (or MAPKKK), increasing the complexity and diversity of MAPK signaling. I will tell you now that few proponents of CT truly understand this cascade. I have been studying it for over a decade, and there are subtleties that are yet elusive.
As adenylate cyclase is chronically activated by BAT adrenergic receptor stimulation, PRKACA will increase expression of MAP3K5. This leads to several downstream effects, not the least of which is increased activation of p38, another mitogen-activated protein kinase that responds to stimuli from cytokines, UV radiation, heat shock, and osmotic shock. p38 is also involved in the regulation of cell differentiation and, additionally, controls apoptosis and autophagy. The problem here is that abnormal activity of p38 has been implicated in a wide array of pathological events in tissues, including neuronal, bone, lung, cardiac, skeletal muscle, and red blood cells.1
This may be seen on tests as elevated NF-kB, even with daily CT which supposedly “reduces” inflammatory markers. And the cascade doesn’t end here. p38 also enters the nucleus and increases expression of ATF2 (activating transcription factor 2). This results in an increase in fibroblast growth factor, specifically FGF21. FGF21 is involved in cell growth, morphogenesis, tissue repair, tumor growth and invasion.2
The good news here is that FGF21, with repeated stimulation upstream from cAMP and p38, is eventually secreted from the brown or beige adipocyte and has effects on those same cells at both the FGF receptor (FGFR1) and the klotho beta membrane protein. Why is this important? Because it inhibits the mTORC1 complex, regulating lipolysis, autophagy, lipid accumulation and lipotoxicity.3
The general problem I see here is that the clinical studies which have observed the effects of cold exposure on mTOR signaling do not take all of these intermediaries into account. They only look at the end result — mTORC1 / mTORC2 modulation. As I have stated above, chronic stimulation of this signaling cascade can have different effects for different people. For example, CT will have little effect on mTOR regulation if there are changes in the TSC1/2 or Rheb protein structures, which are responsible for downstream inhibition of mTORC1. Have I seen this clinically? Absolutely. And it manifests as a decreased ability to lose weight, regardless of cold exposure.
But inability to lose weight is not the major problem here. The problem is that chronic cold exposure will trigger this cascade not only in adipocytes. Anywhere there are beta adrenergic receptors, there will be the potential for MAPK initiation and mitochondrial uncoupling. And where else do we see these receptors? Adrenoceptor beta 3, the main receptor involved in thermogenesis, is also expressed in the brain, spinal cord, heart, small intestine, liver, lung, ovary, and testis.4
Do you believe that systemic stimulation of the sympathetic nervous system via our skin surfaces can affect these organs? This is a very deep question, and you’re not going to find direct answers in the literature. You have to put the pieces together as I have. This is a very complex issue and there are no “one size fits all answers”. If you are engaging in CT on a regular basis, you need to understand what it is doing to you, specifically. And that means knowing your cAMP, MAPK, mTOR, and OXPHOS genetics up and down. The skeptics will tell you this is not possible because they are still tethered to clinical studies and epidemiological data. While I am not comfortable discussing my approach to this issue in detail in a blog, I will tell you that it is possible to know these pathways without having to depend on such data. I do it every day and have measured biomarkers to prove its efficacy.
Consequences of Long-Term Cold Exposure
In order to understand whether or not CT is the right choice for you, long-term effects must be considered. Let’s take a deeper look at what might be expected from a prolonged, frequent practice of intentional cold exposure.
The Thermogenesis / ATP Tradeoff
Many believe that more BAT enhances metabolism’s flexibility, and I would tend to agree. However, the tradeoff resulting from repeated, chronic overexposure to cold stimuli must be thoroughly analyzed. This demands a greater understanding of where the threshold lies that delineates positive modulatory effects from the other extreme: metabolic chaos.
This is a very important point.
The threshold is very individual and has much to do with the genetics of not only thermogenesis but also cytokine-cytokine receptor signaling and the various other pathways involved in this metabolic milieu such as mTOR, MAPK, endocannabinoid signaling, HIF-1, IGF-1 and more.
Further, the tradeoff between thermogenesis and ATP is not exclusively in the realm of metabolic bottlenecks. There are a wide variety of scenarios that would favor systemic mitochondrial uncoupling over ATP generation – outside adipocytes – and these effects would not be expected until the above-mentioned threshold was crossed. There are various factors that could be considered “tipping points”, not the least of which are low adipose concentration and catabolic conditions, inefficient thyroid hormone signaling (as stated above), dysregulation in hypothalamic communication with peripheral neuroendocrine systems, and (perhaps most importantly), mitochondrial heteroplasmy. Not knowing an individual’s genetic expression for each of these biological mechanisms could lead to an ATP deficit and chronic, systemic uncoupling, not exclusive to adipocytes.
Nonetheless, these problems are not typically seen when following a normal diet and not overdoing cold exposure (i.e. ½ hour of cold water immersion a day or less). Nonetheless, some individuals are not capable of enduring even minor stresses, and it is with these types of people that I primarily work.
Mechanisms of Heat Preservation
The heat generation process is not absolutely confined to a stress-mediated thermogenic response to cold exposure. In addition to a gradual adaptation to cold stressors and the increased ability to induce expression of UCP1, there is also the question of cardiovascular tone. This is one area in which there is wild genetic variability.
The pathway for vascular smooth muscle contraction is a microcosm in and of itself, and it includes many inputs including (but not limited to) norepinephrine, angiotensin II, ADH, and endothelin as vasoconstrictive triggers and adenosine, calcitonin, prostaglandin I2, and adrenomedullin as vasodilators. Each of these ligands has their own receptor, and polymorphisms in receptor expression can cause an extremely wide variety of effects downstream. This will directly effect an individual’s ability to maintain heat preservation through cardiovascular tone.
There are many other factors mediating vascular tone such as natriuretic peptides, their receptors, or dysregulation in eNOS and related nitric oxide deficits. We could discuss this particular topic in great depth, and it would necessarily include a thorough treatment of arachidonic acid (AA) metabolism and calcium signaling, which can have very relevant effects on vascular contraction (via mysoin), especially in those that are AA deficient from over-consumption of EPA / DHA-containing foods. I do not wish to go off on a tangent here, because my point is simple: individual variability in smooth muscle contraction may strongly determine vascular tone, in general. Poor vascular tone will also have a direct effect on the ability to enter and maintain thermogenesis.
One approach, in particular, called the “Wim Hoff Method” (named after its founder), involves hyperventilation and prolonged holding of breath to mitigate drops in skin temperature. This reveals yet another aspect of temperature regulation: HIF-1 signaling. HIF-1 expression is triggered by hypoxia, and this has multiple downstream effects, including upregulated erythropoiesis, iron metabolism, angiogenesis and – yes – vascular tone, mediated by eNOS and HMOX, among others.
HIF isoforms are expressed in the skin and regulate systemic arterial pressure. If there are polymorphisms in any of the genes governing this pathway, there will be varying degrees of oxygen-deprivation and hypo-vasodiolation in the presence of stressors. As a matter of fact, I see this all the time in people with poor tolerance for cold. And, of course, this ties intimately into the considerations for oxidative stress.
So while some people are able to exercise their cardiovascular adaptation for heat preservation using short cold exposures, this adaptation is very individual. Measuring the personal “threshold” is a significant clinical challenge that has not yet been effectively implemented, as far as I know. Identifying this threshold will be of utmost importance in quantifying the therapeutic (and longevity promoting) utility of any form of cold adaptation.
It could be said that BAT% is expected to increase only in longer, milder cold exposures but, again, the process by which BAT is formed and stimulated to produce heat, via uncoupling, can be dysfunctional to varying degrees. Add to this variations in cardiovascular tone, endocannabinoid and HIF-1 signaling, and eNOS, and we have a very complex case demanding individual attention, indeed.
In any case – daily, prolonged exposures are contra-indicated for human longevity, due to the the overall negative effects they are expected to have on immunological response.
Immune System Dysregulation
Clearly, variations in vascular tone play a role in hypothermic responses regardless of cold exposure duration, but there are also polymorphisms in the pathway for retrograde endocannabinoid signaling. You see, cannabinoids have a very tenuous relationship with TRP channels. TRPM8, specifically, is inhibited by activation of CB1 receptors. Anandamide and NADA have been shown to antagonize TRPM8 at submicromolar concentrations.5
The CB1 receptor plays an interesting role in mitochondria, regulating neuronal energy metabolism. Endocannabinoid 2-AG and anandamide agonization of CB1R inhibit expression of adenylate cyclase and reduce neuronal ATP production. Why is this important? Again, because TRPM8 activation (by cold) attenuates systemic inflammation and TRP channels also act as ionotropic cannabinoid receptors. Any dysregulation in retrograde endocannabinoid signaling can cause malfunction of this system in the presence of consistent cold stressors.
So there are the multiple studies which claim that the primary stress response to cold attenuates proinflammatory response (TNF-a, IL6, and IL8) while promoting anti-inflammatory response (IL10). Obviously, TRP channels and their interactions with cannabinoids play a significant role in the dynamics of this response. But we must also not forget the vascular tone mediators.
One study, in particular, demonstrated a climb in pro-inflammatory IL6 levels in long-term cold stress at 10C for a week. The addition of adrenomedullin, a vasodilator peptide hormone, significantly decreased IL6 levels. Furthermore, RNAi knockdown of IL6 also attenuates cold-induced hypertension, via a vascular superoxide dependent mechanism. What is important to remember here is that many of these studies looking at pro-inflammatory cascades were using “longer exposures”. This is specifically what I am calling “chronic CT”, and crossing the threshold into pathological effects may be, to some degree, explained by variations in the pathways discussed thus far.67
But there are also the “hidden effects” that have not been the subject of rigorous clinical study; effects that I have observed only by virtue of repeated clinical testing in myself and others. In particular, I am referring to alterations in NF-kappa beta signaling. NF-kB is the master regulator of DNA governing cytokine production. It responds primarily to stress, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. It has been noted to transiently rise with repeated cold exposure in studies looking at antioxidative defense and mitochondrial thermogenic response in BAT.8
The key here is that NF-kB transiently rises, followed by attenuation. Clearly, biofeedback is at play in order to maintain homeostasis. So why the elevated NF-kB in individuals that “chronically” expose themselves long-term to cold? I hinted at an answer above, but let’s explore this in more detail.
With repeated, prolonged (i.e. non-hormetic) cold exposures, there is repeated stimulation of both PKA and PKG, both of which lead to up-regulation of p38 in order to send directives to the nucleus to increase expression of UCP1. We have already discussed how PKA is stimulated by increased adenylate cyclase / cAMP, downstream from catecholaminergic activation of adrenergic receptors. But there is also another trigger as well: natriuretic peptides. Via their receptor, such peptides stimulate the increase of cGMP (and PKG), which in turn raises nitric oxide levels, increases vasodilation and activates p38. This is not a problem in brief, intermittent exposures.
But when you are consistently crossing the “threshold” I have implied above, there are consequences across over 50 pathways in organs throughout the body, including (but not limited to) cellular senescence, pluripotency of stem cells, Toll and NOD-like receptor signaling, Th1 / Th2 immune cell differentiation, and even neurogenesis. We will go into more detail on this subject in future articles. For now, suffice it to say that consistent activation of p38 is not necessarily a problem in an “optimally healthy” human being, but should there be any downstream metabolic blocks (especially those that are not measurable with biomarkers, such as reduced TP53 expression), constantly stressing the body with cold is, quite simply, flirting with disaster. And one of the consequences can be a loss in biofeedback regulatory mechanisms telling p38 to “stand down”.
This is a problem with devastating implications for individuals with Fc-epsilon RI signaling dysregulation – read that, “mast cell activation disorder”. Upregulating expression of p38 will simultaneously trigger gene transcription for cytokines such as IL3, 4, 5, and 13. This leads to a stimulation and amplification of Th2 (allergic profile) cell response. There will also be an increase in eosinophil production and activation. Do we see elevated eosinophils and mast-cell mediated histamine responses in people with this problem taking baths in ice water? Yes, of course.
PKA and PKG-mediated expression of p38, even transiently, will promote the maturation of mast cells. And those that suffer cold-induced urticaria will be pleased to know the vascular changes in this reaction are also mediated by mast cells. It is important to note here that urticaria need not be present for there to be mast cell degranulation elsewhere in the body, as anyone with MCAD that has immersed themselves in cold water will tell you.910
Is it possible to safely embrace CT?
Chronic cold exposure, regardless of source, produces a stress response via the mechanisms described above. And while uncoupling mitochondria to generate heat may bring down the net reactive oxygen species concentration (which is higher in ATP-productive processes), there is still a measurable cascade of oxidative stress occurring in tissues systemically. This is not a problem if your genetic expression for superoxide dismutase, catalase, BAX, BAD, etc. are in perfectly good working order. But many people I see do not have this luxury. And measuring their 8-OHdG and lipid peroxide levels before and after prolonged CT has been very revealing. That said, do you know what it is doing to you, in your own particular case? Regardless of what you think, measure your cytokines, oxidative stress markers, and yes — telomeres. You may be surprised at what you find. And know your genetics. They matter, regardless of what the “experts” out there are saying, all the while grossly oversimplifying biology for their own ends.1112
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