Can cold thermogenesis reduce risk of dementia?
Summary
Insulin resistance protects mitochondria from high blood sugars, but also contributes to formation of plaques (i.e., sclerosis).
Insulin resistance interferes with metabolism of the brain, resulting in cognitive decline that can eventually manifest as Alzheimer's dementia.
Cold acclimation recruits brown fat that increases insulin sensitivity & improves thermogenesis, preventing formation of irreversible brain neurofibrillary tangles.
When activated, brown fat produces neuroprotective hormones.
A regular practice of deliberate cold exposure may promote long-term brain health, although research has yet to confirm this hypothesis in humans.
Cholesterol is not my Mother's problem
I've written about my Mother's advanced dementia in several other articles, published elsewhere. Almost five years ago, when she suffered from fits of rage that endangered her and her caregivers, her doctor told us she might not live more than another six months.
My sisters and I decided to discontinue all of her medications, including her statins, because she didn't like swallowing pills and it was a major point of conflict between her and her nurses.
Why would a woman with six months to live bother to care about her cholesterol, anyway?
She began to improve immediately, and she's still alive today.
I visited her a month ago.
Her Alzheimer's is so advanced that she can't speak. She has almost no motor control -- just unsteady use of her dominant hand.
She has no idea who I am.
Metabolic consequences of carbohydrates - insulin
My Mother's diet has been a problem as long as I've known her. Despite being a champion High School swimmer, she struggled with her fitness and her weight all her life.
Ever since she read Diet for a Small Planet (Lappé & Hahn 1971) my Mother was convinced that the solution to negative feelings about her body would be to eat more plants, less meat, less fat, more processed foods, fewer eggs, and to attempt a diet of strict calorie control.
She was wrong.
It seemed like she got fatter and sicker every year, without stopping to wonder if maybe the diet she adopted to satisfy her environmental ideology was really hurting her health.
She raised me and my sisters on breakfasts of Lucky Charms and Trix cereal, with white bread toast and corn oil margarine. At the dinner table, she lectured us about "complete proteins" that could hypothetically be achieved by mixing canned sweet corn with canned beans, and she scolded me for eating too many eggs.
To please my Mother, I ate everything she fed me, and I got fatter and fatter.
What most people don't realize is that my Mother's diet is exactly the type that elevated her risk of Alzheimer's disease. Concentrated carbohydrates, like sugary cereals, flood the bloodstream with glucose, requiring the islet cells in the pancreas to produce more insulin.
Ironically, the extra carbohydrate load causes a phenomenon called insulin resistance, which is a precursor to Type 2 diabetes.
One of the strangest characteristic of our bodies is that glucose cannot cross the cell membranes into muscles, fat, skeletal, or brain cells without the aid of insulin. In Ice Bath for Fast Keto, I wrote about my son's diagnosis with Type 1 diabetes at the age of six. He no longer has any islet cells. They were destroyed by some disorder of his own immune system, rendering him dependent on insulin shots to metabolize blood glucose.
However, in Type 2 diabetes, the islet cells produce plenty of insulin. The problem is that insulin resistance makes it more difficult to shuttle glucose from the blood stream, across the cell membrane, into the cells where it can be metabolized or stored.
Without insulin injections, my son would not be able to metabolize glucose at all. He would exist in a chronic state of ketosis, which is healthy for people who do produce insulin, but could lead to deadly ketoacidosis in him. Moreover, his inability to clear glucose from his bloodstream would result in chronically high blood sugars that eventually rupture his capillaries and could lead to blindness and circulatory disorders requiring amputation of his extremities.
High blood sugars are dangerous over long periods of time.
Mitochondria
Given the deleterious effects of high blood sugar, why should our cell membranes (which are made of fat molecules) have this strange feature that allows ketones, triglycerides, and other fats to pass through unaided, but require insulin for glucose?
The key is mitochondria.
Inside every cell (except red blood cells) are thousands of organelles called mitochondria that are the site of energy conversion that powers movement, growth, and produces heat.
Mitochondria have their own DNA that exist outside the cell nucleus, so they can synthesize the enzymes necessary for oxidation right at the site of energy conversion, without waiting for the DNA in the nucleus to respond to energy demands. You inherit your mitochondrial DNA exclusively from your Mother, and perhaps because of these two unique features, mitochondrial DNA are ten times more susceptible to damage and more difficult for you body to repair than nucleic DNA.
When too much glucose enters your cells, they can cause intense energetic conversion reactions at your mitochondria, generating free radicals and heat that damage mitochondrial DNA. That's one of the reasons that we experience fatigue during intense exercises -- to slow down the rate of energy conversion in the mitochondria, and protect them from thermal and oxidative damage. So one way to think of insulin resistance is that it is one of the body's mechanisms for protecting the mitochondria inside our cells from damage from glucose overload.
Keeping the glucose in the bloodstream is very damaging to our circulatory system in the long run, but allowing it into our cells to damage our mitochondria can be even worse. Thus, Type 2 diabetes (in contrast to Type 1) is a condition in which the islet cells of the pancreas are intact and producing insulin, but the fatty molecules in our cell membranes become resistant to insulin to prevent transport of too much glucose into the cell where it damages mitochondrial DNA.
The problem in Alzheimer's is that brain cells call also become insulin resistant, and when they do, deficits in brain function begin to appear -- even prior to onset of full-blown dementia.
Metabolic deficits such as decreased brain glucose metabolism and central insulin resistance are now considered intrinsic characteristics of Alzheimer's Disease (AD) and consequently, several investigators suggest that AD is a form of “type 3 diabetes.” - Tournissac et al. (2021).
The brain is the single most energetically demanding organ in the body. During the earliest stages of cognitive impairment, PET scanning typically identifies impaired glucose metabolism in the brain, which is consistent with the common co-incidence of Type 2 diabetes and Alzheimer's disease. That is, when metabolism in the rest of the body is dysregulated, the metabolism of the brain is, too. Moreover, insulin resistance is linked to the formation of plaques in blood vessels, and plaque in the brain is a physiological characteristic marker of Alzheimer's.
Metabolic therapy for reversal of Alzheimer's dementia
Considering the metabolic origins of Alzheimer's it would make sense that correcting metabolic disorders might effect improvements in presentation of the disease. In fact, a remarkable summary of ten case studies published by a researcher at the University of California Los Angeles (UCLA) suggests exactly this. Nine of the ten patients suffering from cognitive deficits showed improvement when placed on a protocol that included low carbohydrate or ketogenic diets, intermittent fasting, yoga/meditation, and nutritional supplements (including magnesium threonate) for mitochondrial support and brain health.
In one case, a 55-year old attorney in the early stages of cognitive decline discovered she was leaving the stove on at home, resorted to recording conversations she could no longer remember, and became unable to perform her job. Nonetheless, "after five months on the therapeutic program, she noted that she no longer needed her iPad to record conversations. She was able to work once again, was able to learn Spanish, and began to learn a new legal specialty. Her children noted that she no longer became lost in mid-sentence, no longer thought she had asked them to do something that she had not asked, and answered their questions with normal rapidity and memory" (Bredesen 2014).
Results from these 10 patients suggest that memory loss in patients with subjective cognitive impairment, mild cognitive impairment, and at least the early phase of Alzheimer's disease, may be reversed, and improvement sustained, with the therapeutic program described here. - Bredesen (2014).
The only patient who did not improve was a woman who, like my Mother, was in the late stages of Alzheimer's dementia -- a finding that is consistent with a subsequent study that expanded the patient population and found other instances of reversal amomg patients in early stages (Bedersen et al. 2018). Nonetheless, Bredesen noted that "the program is not easy to follow, and none of the patients followed the entire protocol."
Brown Fat for Your Brain?
One of the best ways to correct your metabolism and increase your insulin sensitivity is a regular practice of deliberate cold exposure. The cold will activate your brown fat to commence non-shivering cold thermogenesis, clear glucose and triglycerides from your bloodstream, and recruit more brown fat cells to strengthen your body's thermoregulatory system. Thus, a little bit of cold exposure might go a long way towards reducing the risk of Alzheimer's, but the metabolic benefits alone might not make up for the kind of concentrated carbohydrate diet my Mother is accustomed to. It turns out that there are two additional mechanisms by which brown fat promotes brain health: 1) thermoregulation to avoid irreversible formation of the neurofibrillary tangles, and 2) secretion of the neuroprotecive hormone, FGF21.
Thermoregulatory protection against tangles
Brown fat declines with age, from infancy into adulthood, into old age. That means elderly often suffer from compromised thermoregulatory capacity, because they lack the brown fat necessary for non-shivering thermogenesis. Ironically, one of the best ways to maintain brown fat (or reverse loss) is a regular practice of deliberate cold exposure. That is, people who feel cold all the time, or complain that they hate the cold, will typically avoid cold temperatures. As a consequence, their thermoregulatory capacity will further deteriorate, making them even less comfortable in the cold, causing them to avoid it further as the cycle further into decline.
The problem with that for the brain is that even small reductions in body temperature (mild hypothermia) have been shown to promote the phosphorylation of tau proteins in the brain, and tau phosphorylation is another of the signature physiological markers of Alzheimer's. In laboratory studies, chronic cold exposure induces tau phosphorylation and impairs memory and learning in rats (Ahmadian-Attar et al. 2014). In healthy subjects, cold-induced tau phosphorylation reverses upon rewarming. However, in subjects with compromised rewarming capacity, the resulting tangle formations can become permanent.
People who are acclimated to cold exposure have increased levels of brown fat, improved thermoregulatory function, and maintain warmer body temperatures during cold exposure. Recent research showed that cold-acclimated mice "were completely resistant to tau hyperphosphorylation in the hippocampus" -- even when subjected to a 24-hour cold challenge (Tournissac et al. 2019). Thus, a regular practice of ice baths that maintains brown fat might protect against Alzheimer's.
Brown fat produces neuroprotective hormone FGF21
Although brown fat is best known for its metabolic properties, it is now clear that it is also a secretory organ, producing hormones that the body depends upon to modulate other functions, including the thyroid and the brain. For example, in The Thyroid Connection to Cold I wrote about how brown fat modulates thyroid function by producing thyroid hormones that can resolve disorders like Hashimoto's thyroiditis. More recently, I've learned about the potential for brown fat to secrete FGF21 -- a hormone with neuroprotective properties. For example, Canadian researchers measured 66% more FGF21 circulating in the blood of cold-acclimated mice, compared to controls (e.g., Tournissac et al. 2019). Their findings are consistent with an earlier cross-over comparison in humans that showed increased levels of FGF21 resulting from mild cold exposure (Lee et al. 2013), but what constitutes proper cold acclimation remains in question. Decreases in FGF21 were recently obtained in human trials using a cooling vest - but only in those subjects who were brown fat positive who started from higher baseline FGF21 values prior to cold exposure (Sun et al. 2020). Nonetheless, separate studies have shown that increases in FGF21 have reversed cognitive deficits in rats, corrected blood-brain barrier disruptions, and protected against neurotoxicity, which suggests that maintenance of brown fat via cold acclimation may help reduce risk of cognitive decline.
Brain Protection Protocols?
I can't say what sort of cold exposure regimen is required to optimize brain benefits. Although it is clear that metabolic and thermoregulatory deficits contribute to Alzheimer's disease, and that deliberate cold exposure can remedy these deficits, researchers caution that "present work does not confirm whether brown adipose (fat) tissue training leads to improved cognitive faculties." As I wrote in Cognition & Cold Exposure, human studies are limited to people managing brain injuries. I'm not aware of any studies that show ice baths will enhance long-term cognition in humans, postpone the onset of cognitive decline, or reverse the progression of Alzheimer's. In any case, I can not imagine subjecting my Mother to an ice bath. Her thermoregulatory capacity is gone, and even brief periods of mild cold may only serve to make things worse.
Nonetheless, with my own brain, I'm not taking any chances. I will keep practicing 2-4 min of ice bath a day at about 34F, and hope I maintain my sharp mind long past the age at which my parents were considered feeble.
UPDATE 13 Nov 2022
Dr. James DiColantonio brought my attention to a study that demonstrated reversal of mild cognitive decline in Alzheimer's patients via metabolic pathways (Wroolie et al. 2017). in this case, the target of the treatment was magnesium levels in the brain. After 8 weeks of supplementing patients with magnesium-l-threonate (MgT) + Vitamins C & D, the patient cohort showed measurable improvement in cognitive function. Moreover, after discontinuing they supplement, patients regressed.
This results of this study reinforce the supposition that Alzheimer's is metabolic in origin, because magnesium deficiency has been demonstrated to impair brain metabolism. Magnesium is essential for mitochondrial function, and is particularly important in activation and maintenance of brown fat, which is dense with thousands of mitochondrial cells per brown fat cell.
One of the best things you can do for you brain and mental health is to ensure you get sufficient magnesium. As I wrote in Magnesium is Critical for Cold Thermogenesis, a diet rich in green, leafy vegetables is unlikely to provide sufficient magnesium to support brain health, because industrialized agricultural practices have depleted soil magnesium levels. However, transdermal absorption and oral supplementation may be sufficient to meet the micronutritional demands of a regular deliberate cold exposure practice.
UPDATE 28 Nov 2022
I got the call from my sister early this morning. Mom passed away in her sleep overnight.
She went peacefully, four days after Thanksgiving and my sister and I are grateful that her soul has passed on to a place it is no longer constrained my her dysfunctional brain.
About the Author
Thomas P Seager, PhD is an Associate Professor in the School of Sustainable Engineering at Arizona State University. Seager co-founded the Morozko Forge ice bath company and is an expert in the use of ice baths for building metabolic and psychological resilience.
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