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Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Dean Pomerleau

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Hi Dean:


"Whenever I see someone use the word "surely"........... "


Just to be clear, when I use the term "surely" I mean it to be interpreted as meaning:  "It seems highly probable to me that ..... ".  There are seven keystrokes in "surely " and 36 in the alternative.  So "surely" does seem rather more efficient. 


The Oxford Dictionary's explanation of it: "Used to emphasize the speaker’s firm belief that what they are saying is true and often their surprise that there is any doubt of this" contains over 100 characters.


I had thought that that was the meaning others attached to the word also?  But perhaps not?



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It was quite clear what you meant to convey by your use of the word 'surely'. And it is more efficient than writing out the alternatives, as you point out.


It's just that I've internalized the rule-of-thumb that one of my favorite living philosophers, Dan Dennett has described in his really good book Intuition Pumps and Other Tools for Thinking, namely that one way to spot a weak argument is to look out for the word 'surely'. Quoting Dennett:


When you’re reading or skimming argumentative essays, especially by philosophers, here is a quick trick that may save you much time and effort, especially in this age of simple searching by computer: look for “surely” in the document, and check each occurrence. Not always, not even most of the time, but often the word “surely” is as good as a blinking light locating a weak point in the argument. Why? Because it marks the very edge of what the author is actually sure about and hopes readers will also be sure about. (If the author were really sure all the readers would agree, it wouldn’t be worth mentioning.) Being at the edge, the author has had to make a judgment call about whether or not to attempt to demonstrate the point at issue, or provide evidence for it, and—because life is short—has decided in favor of bald assertion, with the presumably well-grounded anticipation of agreement. Just the sort of place to find an ill-examined “truism” that isn’t true!


It's very much like the signature you were using at the bottom of your posts up until quite recently about "conventional wisdom" often turning out not to be true when thought about critically.



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I've collected a ton of research in both rodents and humans documenting the link between cold exposure, reduced core body temperature and longevity.


Here is a good overview diagram of the multiple mechanisms involved. As I've said, cold exposure is like CR in that it has multiple beneficial effects on metabolism and the aging process.




I'm not sure when I'll be able to pull it all together into a single (or even multiple) posts. But for anyone interested, I've created a web page with all my notes and references on the topic.


A few highlights:

  • Calorie restriction linearly reduces core body temperature. Such reduction may be integral to the longevity benefits of CR. Raising the housing temperature of rodents on CR (and hence core body temperature as well) erases the benefits of CR - as discussed earlier in this thread.
  • Cold exposure upregulates uncoupling proteins (UCPs) in muscles as well as both white and brown adipose tissue (WAT and BAT), reducing reactive oxygen species (ROS) production by mitochondria, decreasing oxidative damage and increasing telomere length.
  • Mutations in the UCP genes are associated with increased human longevity.
  • Cold exposure upregulates expression of FGF21 in both the liver and BAT. FGF21 results in higher insulin sensitivity (via less fat accumulation in muscles), reduced cholesterol, and prevents atherosclerosis in APOE-knockout mice. Thus cold exposure could be especially beneficial for people with the APOE4 allele that increases one's risk for cardiovascular disease and Alzheimer's disease. FGF21 has also been shown to extend lifespan in mice without reducing calories.


It's fascinating stuff and provides pretty convincing evidence of the health and longevity benefits of cold exposure.



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I am fascinated by this.  I checked out your cooling vest links.  From the second one:

"Phase Change Material (PCM) releases long-lasting, temperature-specific 58F (14 degrees C), cooling relief.

*Phase Change Material (PCM) is 30% lighter than water."


Any guesses as to what the PCM is?  I'd like to make my own replacement inserts for continuous cooling experiments (the ones they sell are expensive, and just one vest isn't going to cut it).

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Any guesses as to what the PCM is?


Wikipedia is your friend  :)xyz. The wiki page on phase-change materials has a plethora of information, both on natural PCMs, as well as commercially available PCMs pouches, along with links to their website. Obviously many (all - eventually) material change phase as temperature varies, although only a relatively few do so anywhere near human body temperature. Here is an interesting FAQ about commercial PCMs from one of the manufacturers. This 59degF PCM is made from "agricultural sources" (code name for animal and/or vegetable fats - probably not vegan, FWIW...).


 I'd like to make my own replacement inserts for continuous cooling experiments (the ones they sell are expensive, and just one vest isn't going to cut it).


I'm glad someone else is going to try experiments in deliberate cold exposure. Please me us know your experiences!


From the Wikipedia list, it looks like there are enough common materials that change phase in the neighborhood of 60F that you could make DIY inserts.

But you could also buy the packs ready-made. Here you can get an 8-pack of 5"x5", 64F melting-point inserts for $20 + $8 shipping. Or you can get strips of 5, slightly smaller, 60degF pads at mycoolingstore, for $10 each plus $5 flat-rate shipping. Please let me know what you decide. I too will be in the market for replacement pads in a couple months when it warms up here in Pennsylvania...


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Techkewl vest arrived today, made it my profile pic, haha.  I already love this thing, its going to be great when the temps warm up.  Seems to hold a very pleasant, steady cool temp but not so cold that its annoying.  I think they use some type of paraffin for the PCM, but I'm wondering if coconut oil would do the job?


This is actually an environmentally friendly, highly efficient way to cool people in general (as opposed to cooling an entire house or building all Summer long).  I've also been experimenting with the house temps for fun when the family is not here.  I'm fine down to about 62F in a t-shirt, but any lower gets irritating.  And even the low 60's disrupted my sleep when I tried sleeping with only light cover (I woke up numerous times feeling like I wanted to grab a heavy blanket.  Just wanted to determine my lower limits, I'm not crazy enough keep myself annoyingly cold all the time.  I actually like cooler temps in general, I find it pleasant.

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Techkewl vest arrived today, made it my profile pic, haha. 


Great picture of you and your cooling vest. Thanks for sharing it! I look forward to getting my own when it becomes necessary here in Pennsylvania. It looks like a good fit.


How big are you, and what size did you get? The M/L version I presume?


How long does the cooling effect last before a recharge is required and how long does it take to recharge the inserts in the freezer?


I think they use some type of paraffin for the PCM, but I'm wondering if coconut oil would do the job?

I suspect coconut oil (with a melting point of 77F) would work, perhaps mixed with olive (21F) or peanut oil (37F) to bring down the melting point, and the price!
Here is what I might do, if I decide I don't want to spring for a second set of OEM inserts from Techkewl, or from one of the other makers of inserts linked to above:
  • Put the right volume of a mixture of oils into ziplock sandwich bags.
  • Put the sandwich bags flat in the freezer to get them to solidify into the right shape.
  • Once solidified, remove the slugs of solid oil from the sandwich bags and vacuum seal them into durable freezer storage bags of the right size.

The freezer bags that come with vacuum sealer machines are quite rugged, and the vacuum seal is permanent (unlike sandwich bags), so I wouldn't worry (as much) about them leaking, especially after many freeze/thaw cycles.


I actually like cooler temps in general, I find it pleasant.


Interestingly, I too am experiencing a growing preference for cold conditions. Yesterday I went on my weekly excursion from my house (to grocery shop and get the tube replaced on my stationary bike). It was a unseasonably mild day in PA, about 55F. Driving along in the enclosed car seemed too warm (even with the heat off) so I opened the windows while I drove. It felt very refreshing and invigorating. I suspect it may be a sign of cold adaptation via the synthesis of brown (or beige) adipose tissue via the combination of cold exposure [1] and exercise [2][3].


I'm no Wim Hof (aka the Iceman) yet, but I may be getting there.  :)xyz





[1] Diabetes. 2014 Nov;63(11):3686-98. doi: 10.2337/db14-0513. Epub 2014 Jun 22.


Temperature-acclimated brown adipose tissue modulates insulin sensitivity in
Lee P(1), Smith S(1), Linderman J(1), Courville AB(2), Brychta RJ(1), Dieckmann
W(3), Werner CD(1), Chen KY(1), Celi FS(4).
In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced
thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it
impacts on energy metabolism have not been investigated in humans. We examined
the effects of temperature acclimation on BAT, energy balance, and substrate
metabolism in a prospective crossover study of 4-month duration, consisting of
four consecutive blocks of 1-month overnight temperature acclimation (24 °C
[month 1] → 19 °C [month 2] → 24 °C [month 3] → 27 °C [month 4]) of five healthy 
men in a temperature-controlled research facility. Sequential monthly acclimation
modulated BAT reversibly, boosting and suppressing its abundance and activity in 
mild cold and warm conditions (P < 0.05), respectively, independent of seasonal
fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by
DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05),
evident only after cold acclimation. Circulating and adipose tissue, but not
skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal
changes concordant with cold-acclimated insulin sensitization. These results
suggest regulatory links between BAT thermal plasticity and glucose metabolism in
humans, opening avenues to harnessing BAT for metabolic benefits.
PMCID: PMC4207391
PMID: 24954193

[2] Diabetes. 2015 Jul;64(7):2361-8. doi: 10.2337/db15-0227. Epub 2015 Jun 7.

Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations.
Stanford KI(1), Middelbeek RJ(2), Goodyear LJ(3).
Author information: 
(1)Section on Integrative Physiology and Metabolism, Joslin Diabetes Center,
Boston, MA Department of Medicine, Brigham and Women's Hospital, Harvard Medical 
School, Boston, MA. (2)Section on Integrative Physiology and Metabolism, Joslin
Diabetes Center, Boston, MA Department of Medicine, Brigham and Women's Hospital,
Harvard Medical School, Boston, MA Division of Endocrinology, Diabetes and
Metabolism, Beth Israel Deaconess Medical Center, Boston, MA. (3)Section on
Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School,
Boston, MA laurie.goodyear@joslin.harvard.edu.
Erratum in
    Diabetes. 2015 Sep;64(9):3334.
Regular physical activity and exercise training have long been known to cause
adaptations to white adipose tissue (WAT), including decreases in cell size and
lipid content and increases in mitochondrial proteins. In this article, we
discuss recent studies that have investigated the effects of exercise training on
mitochondrial function, the "beiging" of WAT, regulation of adipokines, metabolic
effects of trained adipose tissue on systemic metabolism, and depot-specific
responses to exercise training. The major WAT depots in the body are found in the
visceral cavity (vWAT) and subcutaneously (scWAT). In rodent models, exercise
training increases mitochondrial biogenesis and activity in both these adipose
tissue depots. Exercise training also increases expression of the brown adipocyte
marker uncoupling protein 1 (UCP1) in both adipose tissue depots, although these 
effects are much more pronounced in scWAT. Consistent with the increase in UCP1, 
exercise training increases the presence of brown-like adipocytes in scWAT, also 
known as browning or beiging. Training results in changes in the gene expression 
of thousands of scWAT genes and an altered adipokine profile in both scWAT and
vWAT. Transplantation of trained scWAT in sedentary recipient mice results in
striking improvements in skeletal muscle glucose uptake and whole-body metabolic 
homeostasis. Human and rodent exercise studies have indicated that exercise
training can alter circulating adipokine concentration as well as adipokine
expression in adipose tissue. Thus, the profound changes to WAT in response to
exercise training may be part of the mechanism by which exercise improves
whole-body metabolic health.
© 2015 by the American Diabetes Association. Readers may use this article as long
as the work is properly cited, the use is educational and not for profit, and the
work is not altered.
PMCID: PMC4477356 [Available on 2016-07-01]
PMID: 26050668
[3] Ann Nutr Metab. 2015;67(1):21-32. doi: 10.1159/000437173. Epub 2015 Jul 25.

Role of Exercise in the Activation of Brown Adipose Tissue.

Sanchez-Delgado G(1), Martinez-Tellez B, Olza J, Aguilera CM, Gil Á, Ruiz JR.

Author information:
(1)PROFITH 'PROmoting FITness and Health Through Physical Activity' Research
Group, Department of Physical Education and Sport, Faculty of Sport Sciences,
University of Granada, Granada, Spain.

BACKGROUND: The energy-burning capacity of brown adipose tissue (BAT) makes it an
attractive target for use in anti-obesity therapies. Moreover, due to its ability
to oxidize glucose and lipids, BAT activation has been considered a potential
therapy to combat type 2 diabetes and atherogenesis.
SUMMARY: BAT is mainly regulated by the sympathetic nervous system (SNS); yet,
recent findings have shown a group of novel activators that act independently of
the stimulation of the SNS such as cardiac natriuretic peptides, irisin,
interleukin-6, β-aminoisobutyric acid and fibroblast growth factor 21 that could
influence BAT metabolism. Several strategies are being examined to activate and
recruit BAT with no side effects. In this review, we postulate that exercise
might activate and recruit human BAT through the activation of SNS, heart and
skeletal muscle.
KEY MESSAGES: Epidemiological and well-designed exercise-based randomized
controlled studies are needed to clarify if exercise is able to activate BAT in

© 2015 S. Karger AG, Basel.

PMID: 26227180

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Science News from research organizations

Brown fat responsible for heart disease-related deaths in cold winter months

Date: July 2, 2013




More people die from heart-disease during the winter months, and according to a new study, the increase in mortality is possibly due to the accelerated growth of atherosclerotic plaque in the blood vessels caused by the activation of brown fat by the cold.




More people die from heart-disease during the winter months, and according to a new study published in the journal Cell Metabolism, the increase in mortality is possibly due to the accelerated growth of atherosclerotic plaque in the blood vessels caused by the activation of brown fat by the cold.


It has long been known that the number of deaths from cardiovascular diseases increases during the winter. It has been speculated that this might be the result of over-exertion while shovelling snow and a general decrease in physical activity, although the underlying mechanisms have been unclear. The present study, which has been conducted by researchers at Karolinska Institutet, and Linköping University in Sweden, and three universities in China, demonstrates a new principle by which the cold increases the risk of atherosclerosis.


The researchers conducted their study on a strain of mice genetically modified with a propensity for atherosclerosis. Mice, like humans, have both white and brown body fat. Normal rolls of fat consist mainly of white fat, which is a repository of surplus calories; brown adipose tissue, on the other hand, can convert fat into heat. This heat-generation process is activated by cold temperatures and has been considered beneficial to the health since it can reduce the amount of unnecessary white adipose tissue in the body.


"At first, we thought that the cold activation of brown fat would only make the mice thinner and healthier," says Yihao Cao at the Department of Microbiology, Tumour and Cell Biology at Karolinska Institutet, and the Department of Medicine and Health at Linköping University. "Instead, we found that they ended up having more fat stored in the blood vessels. This came as a surprise and was the opposite of what we thought would happen."


It turned out that exposure to low temperatures accelerated the formation of atherosclerotic plaque in the mice, which can cause myocardial infarction and brain haemorrhaging. Moreover, the cold made the plaque less stable, and if such plaque ruptures, stored fat can leak into the blood, blocking vessels in the heart and brain. The cold-activated breakdown of fatty acids in the mice's brown fat led to the accumulation of low-density lipoproteins (LDL) in the blood and an increase in fat storage in the plaque.


"If this is also true for humans, it might be wise to recommend that people who suffer from cardiovascular disease should avoid exposure to the cold and to put on warm clothes when they are outside during the winter," says Professor Yihai Cao.


The researchers hope to be able to extend their work on mice to studies on humans.


"It would be an extremely important discovery if we found this to be the case in humans too," says Professor Yihai Cao. "Brown adipose tissue is affected not only by the cold -- its activation can also be blocked by several existing drugs, something that we would like to study further."


It was long believed that people only have white fat tissue, and that brown fat was only found in certain mammals, such as rodents; as it is, research has shown that the human body contains two types of brown adipose tissue. Recently, researchers from Sweden and elsewhere has revealed that infants at least have the typical brown, heat generating fat tissue, a discovery that raised hopes about finding new means by which to treat obesity. The present study, however, suggests that activating brown fat to reduce bodyweight can be risky in combination with some form of cardiovascular disease.


Story Source:


The above post is reprinted from materials provided by Karolinska Institutet. Note: Materials may be edited for content and length.


Journal Reference:


Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis.

Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, Zhang C, Seki T, Hosaka K, Wahlberg E, Yang J, Zhang L, Länne T, Sun B, Li X, Liu Y, Zhang Y, Cao Y.

Cell Metab. 2013 Jul 2;18(1):118-29. doi: 10.1016/j.cmet.2013.06.003.

PMID: 23823482 Free PMC Article




Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E(-/-) [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.


"These findings are consistent with the decrease of body weight and body mass index (BMI) due to a high metabolic rate during cold acclimation (Figure S1C). The cold-triggered high metabolic rate and lipolysis are likely to alter blood lipid profiles. Indeed, the level of plasma triglyceride (TG) was significantly decreased (Figure 1H), further validating the cold-induced body weight loss. Conversely, levels of cholesterol, LDL cholesterol, and glycerol were increased by 2- to 3-fold".

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Thanks Al,


I noticed the mouse study that is referenced in the article you posted (PMID 23823482) and linked to it at the bottom of my brain dump on cold exposure research, as the one potential negative side effect of cold exposure I've come across.


But I think it's worth noting that the observed increased risk of unstable atherosclerotic plaque formation was in genetically messed up mice which are unusually prone to CVD as a result of knocking out the gene for APoE (which processes cholesterol) or knocking out the gene for the LDL receptor itself, plus they were fed a high fat diet to make sure to induce high cholesterol and obesity prior to, and during, the cold exposure. From the study's visual abstract:




it is apparent that cold exposure results in increased burning of fat, i.e. converting it into free fatty acids and glycerol, an effect that is by now so well established that even the Weather Channel recognizes it :)xyz.


In genetically aberrant animals (or probably people!) who are naturally inclined towards a high levels of serum LDL cholesterol when they burn fat, cold exposure may result in an increase in LDL cholesterol, and increased plaque formation.


But it doesn't appear like it's the "fault" of cold exposure per se, but simply a result of burning more fat. And it appears to be mediated by elevated serum cholesterol, so those of us who have good (or in Saul's case 'stellar'  :)xyz) cholesterol levels, this potential downside of cold exposure shouldn't be an issue.


But it will be worth monitoring cholesterol level during cold exposure to make sure it doesn't go up dramatically. I'm donating blood in a couple weeks, and will get a (free) serum cholesterol test as a perk. I'll see where my LDL is at that time.



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Thanks, Dean.  They were messed up subjects but there would be no results, not even negative ones, using healthy ones.  Wild type subjects fed good diets would have no chance of seeing if there was an effect.  Did you also note that the subjects were "stabbed in the back" so to say by the involvement of your good guy, UCP1?

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Not for the first time I find you language rather cryptic. I'll try to decipher. Correct me if I've misinterpreted your meaning.


They were messed up subjects but there would be no results, not even negative ones, using healthy ones.  Wild type subjects fed good diets would have no chance of seeing if there was an effect.


If you mean no results in terms of elevated LDL and plaque formation if the mouse subjects had normal genes, were eating a good diet and weren't obese, I concur. That was what I was trying to express in my post above. During weight loss via burning fat, a person's (or a mouse's) cholesterol can rise as the fat is broken down and circulated around the body. If one is susceptible to elevated LDL and plaque formation, as these mice were, plaques can & will form.


Did you also note that the subjects were "stabbed in the back" so to say by the involvement of your good guy, UCP1?


What I'm suggesting is that rather than "stabbing them in the back", UPC1 helped the mice to burn the excess fat they were carrying. It was their mutant cholesterol processing genes combined with a diet high in saturated fat that "stabbed them in the back", resulted in elevated LDL cholesterol and plaque formation during the cold-induced weight loss.


By analogy - exercise can help people burn fat & lose weight. But it can also over-stress their cardiovascular system by raising blood pressure, heart rate, etc if they are out of shape, possibly resulting in a heart attack. You wouldn't blame the exercise per se for the heart attack.


But again, as I said in the previous post - if someone is experimenting with cold exposure, it's worth keeping an eye on your cholesterol level.



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Great picture of you and your cooling vest. Thanks for sharing it! I look forward to getting my own when it becomes necessary here in Pennsylvania. It looks like a good fit.


How big are you, and what size did you get? The M/L version I presume?


How long does the cooling effect last before a recharge is required and how long does it take to recharge the inserts in the freezer?

I'm 6' and 148 lbs.  Yes, bought the M/L version.  I would say the panels and vest themselves are sized right, but the adjustment straps are definitely NOT made for CRONies like us, the problem is that they are velcro and you run out of "loops" for your "hooks" if you try to adjust it tight on a skinny body.  I will have to modify the adjustment straps so that I can make it fit snugly.
The panels can recharge in a freezer in 45 minutes, however I suspect to get to the point of maximum cold storage (thermal capacity?) it needs at least 2 hours. I'll do some more experiments on that, haven't had time to do much testing yet.  I also haven't had time to properly test how long it can cool for under various conditions.  Many user reports in Amazon reviews say it can cool for hours.  When mine was delivered it was left outside all day in 40 degree temps, so when I opened it, it was already "charged" but maybe not "supercharged" - the cooling packs were solid and white, I wore it for about an hour and at that point they were 90% liquid, so maybe with a proper charge you might get 2 hours of cooling but I'm guessing maybe not even that much.  Still you could probably get by with just 2 sets of cooling packs.


I think they use some type of paraffin for the PCM, but I'm wondering if coconut oil would do the job?

I suspect coconut oil (with a melting point of 77F) would work, perhaps mixed with olive (21F) or peanut oil (37F) to bring down the melting point, and the price!


Techkewl's MSDS is here:



I found a huge 56oz jar of coconut oil at BJs for just $8.49, I'll be experimenting with that.



Note: I'm not very concerned about elevating my LDL through cold exposure, but I will definitely monitor that.  My LDL was 50 in my most recent test.

Edited by Gordo
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Thanks for the additional details. It's too bad they don't make the vest a little smaller, but I guess we'll have to make due. Regarding the 2-hour charge - that is a little disappointing, but I guess not surprising, since paraffin and oils have only about half the specific heat of water - meaning it only takes half as much energy to raise their temperature.


Note: I'm not very concerned about elevating my LDL through cold exposure, but I will definitely monitor that.  My LDL was 50 in my most recent test.


You'll have even less reason to worry in about five minutes, when I submit my next post...



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Sorry, Dean, I am cryptic.  The message I was trying to say was that the control mice with the same treatments except cold exposure did not get plaque.  Mice with wild type genes and good diet would never get plaque.


A person who overdoes exercise ignores the advice given to check with your doc first.  If one has the rare heart conditions predisposing sudden death when exercise moderately or excessively, don't exercise that way.  If cold exposure might induce plaque, ...

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Al wrote:

 If cold exposure might induce plaque, ...


I did a little more research on the issue Al raised - the potential for increased LDL cholesterol and cardiovascular disease risk associated with cold-exposure. Good news! The Pubmed gods were smiling on me today. Study [1] addresses exactly the point I was making, and vindicates the perspective I expressed above on the subject. You gotta love it when that happens. :-)


This study used mice as well, but mice that weren't messed up in their APoE or LDL-receptor genes, as the mice were in the study Al reference above (PMID 23823482). As the authors say in [1]:


[This strain of mice is] a well-established model for human-like lipoprotein metabolism that unlike

hyperlipidemic Apoe(-/-) and Ldlr(-/-) mice [i.e. the one's used in Al's study] expresses functional apoE and LDLR [LDL cholesterol receptor].


The authors have a good explanation for the process by which cold exposure leads to increased burning of fat via brown adipose tissue (BAT) activation:


[C]old exposure activates BAT via stimulation of noradrenalin release by sympathetic neurons, which
subsequently binds to b3-adrenergic receptor (b3-AR) on the brown adipocyte membrane (11)...
Activation of the b3-AR on brown adipocytes rapidly induces intracellular lipolysis of triglycerides (TGs)
from lipid droplets, resulting in release of fatty acids (FAs) into the cytoplasm. FAs are directed towards
mitochondria where they either activate the uncoupling protein-1 (UCP1) in the inner membranes of
mitochondria (13) or undergo oxidation. The intracellular TG stores of brown adipocytes are rapidly replenished
mainly by uptake of FA derived from lipolysis of TG-rich lipoproteins (TRLs) in the plasma (14).
In other words, cold exposure activates BAT, which burns free fatty acids, which come from triglycerides. The triglycerides in the BAT cells are replenished by sucking triglycerides out of the bloodstream, which the author's note is a good thing for lowering plasma triglycerides and combatting obesity. But, citing Al's study (Dong et al), the author's acknowledge that the breaking down of triglycerides can result in elevated cholesterol-rich 'remnants' in the blood (e.g. LDL and VLDL cholesterol) that can contribute to atherosclerotic plaques:
However, increased lipolytic processing of plasma TRL naturally accelerates
formation of pro-atherogenic cholesterol-rich remnants as well, which are usually cleared by the liver. Thus, Dong et al.(20)
described that BAT activation by cold exposure aggravates hypercholesterolaemia and atherosclerosis development in
Apoe/ and Ldlr/ mice, which are the most widely used atherosclerosis mouse models.
But, in short, they say what I did above, namely that the genetically messed up mice in Al's study aren't very representative of most humans. To illustrate, study [2] observes that "The [APoE knockout] mutant mice had five times normal plasma cholesterol, and developed foam cell-rich depositions in their proximal aortas by age 3 months." A 3 month-old mouse with serious atherosclerosis is about the equivalent of a 18-year-old human with serious heart disease - not exactly representative of the general population...
The authors then go on to say they've got a better mouse model of CVD:
It is likely to be that the enhanced clearance of plasma TGs on BAT activation may require efficient clearance of
cholesterol-enriched lipoprotein remnants by the liver, a pathway that is considered to be crucially dependent on a
functional apoE-LDLR axis (21)....
The APOE*3-Leiden.CETP (E3L.CETP) [mouse] model is a well established model for hyperlipidaemia and atherosclerosis, which,
unlike Apoe/ and Ldlr/ mice, responds well to the lipid lowering and anti-atherogenic effects of statins, fibrates
and niacin. E3L.CETP mice express a naturally occurring mutant form of human apoE3 that slows down remnant
clearance, but does not completely abrogate the interaction with the LDLR. This results in attenuated hepatic remnant clearance
that is sufficient to induce hyperlipidaemia and atherosclerosis when feeding a Western-type diet (WTD), but, importantly, the
hepatic remnant clearance route is still functional and can be modulated. In addition, E3L.CETP mice are transgenic for human
cholesteryl ester transfer protein (CETP), which transfers cholesteryl esters from HDL to (V)LDL particles and for which
rodents are naturally deficient. Hence, E3L.CETP mice are considered to display a more human-like lipoprotein metabolism.
So they are going to activate BAT in their strain of mice and observe the same markers of lipid metabolism and plaque formation that Al's study measured. But rather than torturing the mice with cold (although they do that too - see below), they are going to short circuit the process of activating BAT by using a pharmacological treatment, namely a b3-adrenergic receptor (B3-AR) agonist, rather than cold exposure:
[T]he cold-stimulated activation of brown adipocytes inducing thermogenesis can be pharmacologically
mimicked by selective b3-AR agonists such as CL316243, one the most selective b3-AR agonists available (11,12).

Specifically what they did was feed their strain of mice an "atherogenic Western Type Diet (WTD)" for 10 weeks, both with a B3-AR agonist to stimulate brown fat (BAT) activity (the treatment group) and without the B3-AR agonist (the control group).


What did they find?


First, mice in the treatment group (labelled 'CL316243' - the name of the B3-AR agonist) with activated BAT gained dramatically less fat mass (b), without reduced lean mass (c) or food intake (d), relative to control mice (labelled 'Vehicle') when both were fed a crappy Western diet:



They observe the treatment group avoided getting fat because of their increase in BAT-mediated thermogenesis, rather than increased physical activity:


The b3-AR-mediated prevention of body fat gain was probably
the consequence of increased adaptive thermogenesis, as total EE
was markedly increased on the day of treatment (+17%; Fig. 2a)
without differences in activity levels (Fig. 2b). The increase in EE
was confined to increased FA oxidation (+67%; Fig. 2c) rather
than carbohydrate oxidation


Here is the graph of fatty acid oxidation - as you can see it was markedly elevated in the mice treated with B3-AR to simulate cold exposure, but only on the treatment days:




So the mice were burning more fat, and avoiding getting fat as a result of simulated cold exposure. But what about their cholesterol? Did it shoot up like it did in the Al's study mice?


Nope - it went down - dramatically.


In particular, triglycerides when down by an average of -54% (a), total cholesterol went down by -23% (c), LDL and VLDL cholesterol went down by -27% (d,e), without negatively impacting the level of "good" HDL cholesterol - if anything it slightly raised it relative to controls (e):





So did this improvement in cholesterol translate into better cardiovascular health - i.e. fewer plaques?  As you might guess by now - yes, by nearly 50% as illustrated in this graph:




Alright you might say - that looks all well and good. But is their treatment with this mysterious "CL316243" b3-adrenergic receptor agonist really equivalent to exposing the mice to cold in terms of its impact on cholesterol and heart disease?


Apparently yes. They did a further experiment, exposing a bunch of mice from their strain to cold (39degF for 7 days - ouch!) and found: 


This lipid-lowering effect of CL316243-mediated brown fat activation
did not differ from cold-induced effects, as cold exposure
reduced hyperlipidaemia in E3L.CETP mice as well (Fig. 5a,b),
despite a marked increase in dietary cholesterol intake in the cold (Fig. 5c).


Basically, the cold-exposed mice ate almost 100% more food (c) and hence consumed almost 100% more dietary cholesterol (from the crappy western diet they were fed) than controls, but nonetheless had dramatically lower levels of triglycerides (a) and total cholesterol (b) in their blood than controls (note: the y-axis in Figure b is mislabelled 'Plasma TG' rather than 'Plasma TC'):




They go on to show through a series of additional histological tests that all these positive effects of cold exposure and its pharmacologically-induced equivalent are indeed mediated by activation of brown adipose tissue (BAT), and that an intact liver for processing the cholesterol remnants released from this fat oxidation is important (and why Al's study mice didn't benefit).


In short, these researchers showed that cold exposure (and its pharmacologically-induced equivalent) dramatically reduces cholesterol levels and arterial plaque formation in their more accurate mouse model of human cholesterol processing and cardiovascular diseases. They conclude:


[A]ctivation of BAT is a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from atherosclerosis.


So it looks like unless you've got some sort of freakish, familial hypercholesterolemia due to unfortunate genetics which prevents your liver from processing cholesterol, cold exposure is likely to be beneficial when it comes to cardiovascular disease risk.





[1] Nat Commun. 2015 Mar 10;6:6356. doi: 10.1038/ncomms7356.

Brown fat activation reduces hypercholesterolaemia and protects from
atherosclerosis development.

Berbée JF(1), Boon MR(1), Khedoe PP(2), Bartelt A(3), Schlein C(4), Worthmann
A(4), Kooijman S(1), Hoeke G(1), Mol IM(1), John C(4), Jung C(5), Vazirpanah
N(1), Brouwers LP(1), Gordts PL(6), Esko JD(6), Hiemstra PS(7), Havekes LM(8),
Scheja L(4), Heeren J(4), Rensen PC(1).


Full text: http://www.nature.com.sci-hub.io/ncomms/2015/150310/ncomms7356/full/ncomms7356.html

Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering
plasma triglyceride levels and reducing obesity. However, the precise role of BAT
in plasma cholesterol metabolism and atherosclerosis development remains unclear.
Here we show that BAT activation by β3-adrenergic receptor stimulation protects
from atherosclerosis in hyperlipidemic APOE*3-Leiden.CETP mice, a
well-established model for human-like lipoprotein metabolism that unlike
hyperlipidemic Apoe(-/-) and Ldlr(-/-) mice expresses functional apoE and LDLR.
BAT activation increases energy expenditure and decreases plasma triglyceride and
cholesterol levels. Mechanistically, we demonstrate that BAT activation enhances
the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT,
subsequently accelerating the hepatic clearance of the cholesterol-enriched
remnants. These effects depend on a functional hepatic apoE-LDLR clearance
pathway as BAT activation in Apoe(-/-) and Ldlr(-/-) mice does not attenuate
hypercholesterolaemia and atherosclerosis. We conclude that activation of BAT is
a powerful therapeutic avenue to ameliorate hyperlipidaemia and protect from

PMCID: PMC4366535
PMID: 25754609



[2] Science  16 Oct 1992: Vol. 258, Issue 5081, pp. 468-471

DOI: 10.1126/science.1411543


Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E

SH Zhang, RL Reddick, JA Piedrahita, N Maeda
Apolipoprotein E (apoE) is a ligand for receptors that clear remnants of chylomicrons and very low density lipoproteins. Lack of apoE is, therefore, expected to cause accumulation in plasma of cholesterol-rich remnants whose prolonged circulation should be atherogenic. ApoE-deficient mice generated by gene targeting were used to test this hypothesis and to make a mouse model for spontaneous atherosclerosis. The mutant mice had five times normal plasma cholesterol, and developed foam cell-rich depositions in their proximal aortas by age 3 months. These spontaneous lesions progressed and caused severe occlusion of the coronary artery ostium by 8 months. The severe yet viable phenotype of the mutants should make them valuable for investigating genetic and environmental factors that modify the atherogenic process.
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A few items came to my mind, Dean.


Your paper [1] does not need access via Sci-Hub, which makes things like searching for "plaque", which it did not have, can be readily be search in the freely available full-texts:





The Dong et al paper I introduced can also be seen via its pdf:




[1] fed mice cholesterol, not too good, I thought.  It actually looked at cold exposure effects too, but only treated to cold 7 days, not 8 weeks and in the Dong et al paper.  It looked at total cholesterol after cold exposure, not LDL as Dong et al did, despite [1] making much of the Dong et al paper, and mislabeled total cholesterol as triglyeride in Figure 5b.


The experiments were very different, I grant you that, but the bottom line, I am uncertain about. 


The Dong et al paper also looked at the effects of cold exposure in human subjects, and their LDL levels went up significantly.

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[Dean's paper - PMID 25754609) fed mice cholesterol, not too good, I thought.  


Yes they did feed the mice cholesterol. Here is the diet statement from the Methods section:


Mice were fed a WTD [Western Type Diet] (HopeFarms, Woerden, The Netherlands) supplemented with 0.1% cholesterol...
What's wrong with that? It seems reasonable to simulate a diet containing cholesterol, since that is what most people eat. It would seem to stack the deck towards seeing elevated serum cholesterol - wouldn't you think? Also remember, this strain of mice in my study has cholesterol processing genes similar to humans, unlike the mice from your study. 

 It [Dean's paper] actually looked at cold exposure effects too, but only treated to cold 7 days, not 8 weeks and in the Dong et al paper [Al's paper].


Seems like a minor distinction to me. I'd like to see you try living for 7 days at a constant temperature of 39 degF :-).

It [Dean's paper] looked at total cholesterol after cold exposure, not LDL as Dong et al [Al's paper] did


My paper looked at LDL and VLDL in the main part of the study (where they pharmacologically-induced BAT activity to simulate cold exposure) and both were dramatically reduced in the treated mice relative to controls. They did the cold exposure experiment with their strain of mice simply to validate their model, and show similar results were elicited from actual cold exposure as with pharmacologically-induced simulated cold exposure. Results were similar between the two treatments. 

The Dong et al paper [Al's paper] also looked at the effects of cold exposure in human subjects, and their LDL levels went up significantly.


Did you see that that was an experiment with five human subjects with already high LDL cholesterol conducted over two days with only 2 hours of cold exposure per day at 60degF? The authors don't even appear to have controlled for diet over those two days in the human subjects, at least their diet isn't mentioned. For all we know the cold-exposed men may have gone out for a Double Big Mac meal (or a McDonald's kale salad :-) ) to compensate for the extra calories they burned via thermogenesis. I'd say it's pretty hard to draw conclusions from such a small, biased, short and poorly-controlled pilot study, and your study's authors apparently concur:
We admit the fact that only a small number of human subjects were recruited at this time,
and this pilot study may lack a sufficient statistical power to justify a definite conclusion.
But I'll once again acknowledge (as I have several times in this thread), if you have pathologically high (or even just unusually high) cholesterol despite a good diet and lifestyle, suggesting that your body just doesn't process cholesterol very well (likely due to genetics), than it may be prudent to check your cholesterol level when you start to practice cold exposure - since cold exposure preferentially burns fat, which naturally releases cholesterol remnants which your body will have to clear.
Fortunately there are very few people practicing CR, or eating a plant-based diet and getting sufficient exercise, who have to worry about high cholesterol. You and I certainly don't!
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One other thing I forgot to mention from my paper (PMID 25754609). They tested the same pharmacologically-induced simulated cold exposure in mice that had their APOE gene or their LDL-receptor gene knocked out, just like in your study (PMID 23823482). Unlike their own strain of mice (with an intact, human-like cholesterol processing system), and like the Dong et al (Al's study) mice, these knockout mice did not benefit from BAT activation (i.e. simulated cold exposure) as reflected by either their cholesterol level or plaque formation. The authors of my study explain these results quite clearly in the context of Dong et al:


Our study indicates that the ability of the liver to clear apoE-enriched lipoprotein remnants via the LDLR is a prerequisite for

the anti-atherogenic potential of BAT activation. According to this view, it is not surprising that Dong et al.20 recently observed
that BAT activation by cold exposure in Apoe[-knockout] and Ldlr[-knockout] mice actually increased plasma (V)LDL-C levels and
In fact, they mention something I didn't notice when I read you study Al (my emphasis):
In fact, Dong et al.20 did show that activation of BAT by cold in normolipidemic wild-type C57Bl/6 mice actually decreased
plasma TC and (V)LDL-C levels, which is in full accordance  with a functional hepatic apoE–LDLR clearance route of lipoprotein
remnants in wild-type mice.


In short - the evidence appears pretty strong that cold exposure will improve serum cholesterol level and CVD risk in mice (and probably people), as long as they have intact genes which allow their liver to clear cholesterol remnants.



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In this post earlier in this thread, I cited a study (PMID 9032756) which showed that housing B57BL/6 mice at what for them is a cool temperature was necessary for CR to have lifespan benefits. CR did not extend median lifespan of mice relative to ad lib-fed controls when they both were housed at what for mice is a thermally-neutral temperature. But neither that study, nor the infamous "rats with cold feet" study (PMID 3781978), measured the physiological effects (particularly the activity of brown adipose tissue (BAT)) of cool housing temperature on the mice.


This new study [1] fills in that gap. Researchers at Williams College1 subjected the same strain of mice (C57BL/6) as in PMID 9032756 to either thermally-neutral temperature (30°C = 86°F) or typical laboratory temperature (20°C = 68°F), either alone or in group cages, either with or without bedding. When housed alone, either with or without bedding, mice kept at the cool (but typical) temperature showed many overt signs of thermal stress (including elevated heart rate, blood pressure, shivering, lower core body temperature) relative to the mice housed at thermal neutrality. Most interestingly, the cool-housed mice showed a 22-fold increase in activity of the gene which measures brown adipose tissue (BAT) activity relative to warm-housed mice.


They found that living in a group cage blunted this effect, presumably because the mice are able to huddle together in a group cage to stay warm. Adding bedding to the cages of singly-housed mice did not blunt the effects.


In most well-conducted CR rodent experiments, including PMID 9032756 which showed C57BL/6 mice need to be kept cold to benefit from CR, the animals are housed individually and at temperatures well below thermal neutrality, which means they are cold-stressed and have highly activated brown fat, based on the results of [1].


So it's looking more and more like cold exposure (and BAT activation) may be required for anyone hoping to mimic the conditions of CR experiments with rodents, the one group of mammals where CR has been shown to pretty robustly extend lifespan.





1Williams College is my undergraduate alma mater. Weird how the two studies I've posted today come from the two schools (Williams and CMU) that I attended after graduating from high school!



[1] Am J Physiol Regul Integr Comp Physiol. 2015 Jun 15;308(12):R1070-9. doi:

10.1152/ajpregu.00407.2014. Epub 2015 Apr 15.

Group housing and nest building only slightly ameliorate the cold stress of
typical housing in female C57BL/6J mice.

Maher RL(1), Barbash SM(1), Lynch DV(1), Swoap SJ(2).

Author information:
(1)Department of Biology, Williams College, Williamstown, Massachusetts.
(2)Department of Biology, Williams College, Williamstown, Massachusetts

Huddling and nest building are two methods of behavioral thermoregulation used by
mice under cold stress. In the laboratory, mice are typically housed at an
ambient temperature (Ta) of 20°C, well below the lower end of their thermoneutral
zone. We tested the hypothesis that the thermoregulatory benefits of huddling and
nest building at a Ta of 20°C would ameliorate this cold stress compared with
being singly housed at 20°C as assessed by heart rate (HR), blood pressure (BP),
triiodothyronine (T3), brown adipose (BAT) expression of Elovl3 mRNA, and BAT
lipid content. A series of experiments using C57BL/6J female mice exposed to 20°C
in the presence or absence of nesting material and/or cage mates was used to test
this hypothesis. Mice showed large differences in HR, BP, shivering, and core
body temperature (Tb) when comparing singly housed mice at 20°C and 30°C, but
only a modest reduction in HR with the inclusion of cage mates or bedding.
However, group housing and/or nesting at 20°C decreased T3 levels compared with
singly housed mice at 20°C. Singly housed mice at 20°C had a 22-fold higher level
of BAT Elovl3 mRNA expression and a significantly lower triacylglycerol (TAG)
content of BAT compared with singly housed mice at 30°C. Group housing at 20°C
led to blunted changes in both Elovl3 mRNA and TAG levels. These findings suggest
that huddling and nest building have a limited effect to ameliorate the cold
stress associated with housing at 20°C.

Copyright © 2015 the American Physiological Society.

PMID: 25876655

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Translating animal model research: does it matter that our rodents are cold?

Physiology (Bethesda). 2014 Nov;29(6):413-20. doi: 10.1152/physiol.00029.2014.

Maloney SK, Fuller A2, Mitchell D, Gordon C, Overton JM.

PMID: 25362635

Free full text




Does it matter that rodents used as preclinical models of human biology are routinely housed below their thermoneutral zone? We compile evidence showing that such rodents are cold-stressed, hypermetabolic, hypertensive, sleep-deprived, obesity-resistant, fever-resistant, aging-resistant, and tumor-prone compared with mice housed at thermoneutrality. The same genotype of mouse has a very different phenotype and response to physiological or pharmacological intervention when raised below or at thermoneutrality.


"Rodent Longevity


The rodent models that have attracted public attention, perhaps more than any others, are those demonstrating artificially enhanced longevity. Engineering a mouse's hypothalamus to overproduce uncoupling protein 2 results in the local production of heat in the hypothalamus. Because the hypothalamus is the most thermosensitive region in the mammalian body and provides the majority of the input signal for thermoregulation (26), the local heating results in a lower than normal Tb everywhere else in the body. Those engineered mice also live longer than normal (14), providing evidence of an association between Tb, energetics, and longevity (3).


There are other mouse genotypes that live longer than average. These genotypes produce dwarf strains, and their LCTs are higher than those of the average mouse. They tend to have lower Tb than normal mice, even at Ta of 26°C (7). The hypopituitary Ames and Snell strains live for ∼1,150 days compared with 720 days for a normal mouse (8). In dwarf mice, the longevity appears to be related to increased metabolic rate (3). The long-lived growth hormone-resistant (GHR-KO) strain has a metabolic rate higher than that of wild-type mice when housed at 23°C but not when housed at 30°C (3), implying that enhanced longevity would not be evident in the TNZ. That implication is manifested in the C57Black-6 (B6) strain of mouse that lives for ∼785 days (35) when its lifespan is extended by calorie restriction (CR). Placing B6 mice onto a CR diet, where they receive 60% of their normal daily energy requirement, extends their life to ∼1,148 days at 21°C (35). If the B6 mice are fed a CR diet at thermoneutrality, they live for ∼810 days, not significantly different from the 785 days of the control-fed mice (35). So CR does not extend lifespan in B6 mice in their TNZ. Koizumi (35) thought that the explanation lay in the restricted use of torpor at the higher Ta, but Bartke (3) reports that the long-lived genotypes do not use torpor and thus maintain a high metabolism when they are exposed to 21°C. There is clearly much we do not understand about the interactions between Ta, Tb, metabolism, and longevity."



Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans.

Speakman JR, Keijer J.

Mol Metab. 2012 Nov 8;2(1):5-9. doi: 10.1016/j.molmet.2012.10.002. Review.

PMID: 24024125 Free PMC Article




It has been argued that mice should be housed at 30 °C to best mimic the thermal conditions experienced by humans, and that the current practice of housing mice at 20-22 °C impairs the suitability of mice as a model for human physiology and disease. In the current paper we challenge this notion. First, we show that humans routinely occupy environments about 3 °C below their lower critical temperature (T lc), which when lightly clothed is about 23 °C. Second, we review the data for the T lc of mice. Mouse T lc is dependent on body weight and about 26-28 °C for adult mice weighing >25 g. The equivalent temperature to that normally experienced by humans for most single housed adult mice is therefore 23-25 °C. Group housing or providing the mice with bedding and nesting material might lower this to about 20-22 °C, close to current standard practice.




Ambient temperature; Human; Lower critical temperature; Mouse; Thermoneutral; Thermoregulation



Letter-to-the-editor on "Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans".

Gaskill BN, Garner JP.

Mol Metab. 2013 May 21;3(4):335-6. doi: 10.1016/j.molmet.2013.05.003. eCollection 2014 Jul. No abstract available.

PMID: 24944886 Free PMC Article



Not so nuanced: Reply to the comments of Gaskill and Garner on 'Not so hot: Optimal housing temperatures for mice to mimic the environment of humans'.

Speakman JR, Keijer J.

Mol Metab. 2013 Jun 3;3(4):337. doi: 10.1016/j.molmet.2013.05.007. eCollection 2014 Jul. No abstract available.

PMID: 24944887 Free PMC Article

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Its very hard to tell since this is another one of your all-too-frequent posts without any helpful commentary or context :-(, but I assume you remember you posted the first, helpful paper (PMID 25362635) very early on in this thread, in fact as the second post, and I discussed it, including the passage you quote, in this subsequent post. The short summary is that the normal (68-72 °F) housing temperature for mice results in thermal stress, which is likely to make them live longer and be less prone to obesity and other maladies.


To summarize the back-and-forth debate over the Speakman & Keijer (PMID 24024125) paper (which is new and interesting - thanks!) - they argue that to mimic the kind of mild cold stress that humans are sometimes exposed to (e.g. a 68 °F home or office environment with light clothing), singly-housed mice should be kept in the range of 74-77 °F, which is somewhat below their thermoneutral temperature.  Gaskill & Garner think it should be somewhat higher in order to mimic more typical human lifestyle & preferences (e.g. since people normally turn up the thermostat or wear heavier clothes in a 68°F environment).


But both sets of researchers agree that mice housed in the mid-70F range are (at least mildly) cold stressed, and at the normal housing temperature for mice (68-72 °F) they are quite thermally stressed, particularly when housed singly, as is standard in rodent CR experiments. Not only are such low housing temperatures a bit cruel from an animal welfare perspective, they aren't a good parallel with the way we humans typically live, resulting in errors when researchers try to generalize from the results of rodent experiments to humans. 


This is exactly what I've been arguing throughout this thread - in order to mimic CRed mice in hopes of gaining longevity, we can't just copy their diet - we likely need to expose ourselves to colder temperatures than we typically do.



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Alternatives to Cold Exposure for Activating Brown Adipose Tissue (BAT)


So in this thread I've been touting the likely health benefits of cold exposure, primarily through its activating of brown adipose tissue (BAT). But for those delicate souls who resist the cold, are there alternative ways to activate BAT which might have similar benefits as cold exposure, without the physical hardship?


Tantalizingly, the answer is "yes, perhaps". I say tantalizingly, because two compounds that seem to increase BAT activity are well-known to us - metformin and capsaicin. 





In particular, [1] found that metformin appears to reduce plasma cholesterol & triglycerides largely by upregulating BAT activity so as to burns more fatty acids. And significantly, metformin was found to increase expression of AMP-kinase in BAT. They say:


 Collectively, our results identify BAT as an important player in the TG-lowering effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be considered as a future therapeutic strategy for the treatment of dyslipidemia.


What makes this metformin-BAT connection all the more interesting is the theory that metformin may be a CR mimetic (a claim not without controversy), and has been shown to extending lifespan in rodents via increased AMP-kinase activity [2] and perhaps even diabetic humans, although both these results are pretty highly disputed, perhaps even debunked, as Michael points out in this post.


So while I personally wouldn't run out and take metformin, as I recall some pretty well-respected scientists (Spindler, IIRC?) take metformin, and someone from Big Pharma has convince enough people in Washington that metformin has enough anti-aging potential to test it in the first government-sponsored human longevity trial (popular press coverage) . In my book this makes the link between metformin and BAT quite interesting, if for no other reason than to lend additional indirect support to the theory that increased BAT activity through cold exposure is likely to be beneficial for health and longevity, perhaps through some of the same pathways as CR (e.g. AMPK).


I wonder if the benefits of metformin are confined to (or larger in) individuals with appreciable amounts of BAT. I suspect they would be...




In study [3], researchers exposed 18 healthy young men to cold and did a PET scan to figure out which of them had detectable levels of BAT. It turned out that 10 of them did (the BAT+ group), and 8 didn't (the BAT- group). Then in a randomized, cross-over design, they fed both groups capsaicin (in pill form) or placebo and measured their resting energy expenditure. They found that only the BAT+ group exhibited increased resting energy expenditure from ingesting capsaicin (relative to placebo). Here are the graphs from the full text:




In their discussion, the researchers conclude:


These results indicate that BAT is involved in the capsinoid-induced increase in EE, as proposed in small rodents (19, 20)....
Recently, Kawabata et al (19) showed in mice that capsaicin and capsinoids activated BAT thermogenesis and increased EE..
It is thus likely in humans, as in small rodents, that orally ingested capsinoids activate BAT ... and increase EE.

Our results indicate that the stimulatory effect of capsinoids on EE is largely attributable to the activation of BAT, which suggests that BAT is the site responsible for the antiobesity effect of capsinoids. This implies that capsinoids are effective in people with BAT, but not in those without detectable BAT. However, note that BAT can be recruited after chronic activation of the sympathetic nervous system. For example, prolonged cold exposure or treatment with b3-adrenoceptor agonists produces hyperplasia of BAT and ectopic induction of brown-like adipocytes in white fat pads in small rodents and dogs (17, 30–33).


In short, the effects of capsaicin appears to have been mediated by BAT. But it was a relatively small effect - only about 120kcal/day if you took a capsaicin pill once every hour for the whole day. This is less than a third of the increase in energy expenditure (406kcal/day) observed by these same researchers in BAT+ (but not BAT-) healthy young men in response to cold exposure, consisting of "2-h at 66 °F with light-clothing and intermittently putting their legs on an ice block" [4].


I found this capsaicin result interesting in light of Michael's admission that hot chili peppers (the best source of capsaicin) are one of the few "functional foods" he considers worth eating, based on results from [5] which found that in nearly 500,000 people, those who ate spicy foods nearly every day had a 14% reduced rate of all-cause mortality relative to those to eschewed spicy foods (like 102 year-old Olive Watson...). It would be interesting (although extremely difficult logistically) to determine if the mortality benefits of spicy foods are confined to (or larger in) the ~50% of the population who have detectable levels of BAT. I suspect they would be.


In summary, taking metformin and/or eating capsaicin/chili-peppers may potentiate BAT activity, but only if you've got brown adipose tissue to begin with, and to insure that you'll likely have to expose yourself to cold...





[1] Diabetes. 2014 Mar;63(3):880-91. doi: 10.2337/db13-0194. Epub 2013 Nov 22.

Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by
brown adipose tissue in mice.

Geerling JJ(1), Boon MR, van der Zon GC, van den Berg SA, van den Hoek AM, Lombès
M, Princen HM, Havekes LM, Rensen PC, Guigas B.


Free Full text: http://diabetes.diabetesjournals.org/content/63/3/880.long

Metformin is the first-line drug for the treatment of type 2 diabetes. Besides
its well-characterized antihyperglycemic properties, metformin also lowers plasma
VLDL triglyceride (TG). In this study, we investigated the underlying mechanisms
in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein
metabolism. We found that metformin markedly lowered plasma total cholesterol and
TG levels, an effect mostly due to a decrease in VLDL-TG, whereas HDL was
slightly increased. Strikingly, metformin did not affect hepatic VLDL-TG
production, VLDL particle composition, and hepatic lipid composition but
selectively enhanced clearance of glycerol tri[(3)H]oleate-labeled VLDL-like
emulsion particles into brown adipose tissue (BAT). BAT mass and lipid droplet
content were reduced in metformin-treated mice, pointing to increased BAT
activation. In addition, both AMP-activated protein kinase α1 (AMPKα1) expression
and activity and HSL and mitochondrial content were increased in BAT.
Furthermore, therapeutic concentrations of metformin increased AMPK and HSL
activities and promoted lipolysis in T37i differentiated brown adipocytes.
Collectively, our results identify BAT as an important player in the TG-lowering
effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and
subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be
considered as a future therapeutic strategy for the treatment of dyslipidemia.

PMID: 24270984



[2] Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192.

Metformin improves healthspan and lifespan in mice.

Martin-Montalvo A(1), Mercken EM, Mitchell SJ, Palacios HH, Mote PL,
Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M,
Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR,
Bernier M, de Cabo R.

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736576/

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes.
Here we show that long-term treatment with metformin (0.1% w/w in diet) starting
at middle age extends healthspan and lifespan in male mice, while a higher dose
(1% w/w) was toxic. Treatment with metformin mimics some of the benefits of
calorie restriction, such as improved physical performance, increased insulin
sensitivity, and reduced low-density lipoprotein and cholesterol levels without a
decrease in caloric intake. At a molecular level, metformin increases
AMP-activated protein kinase activity and increases antioxidant protection,
resulting in reductions in both oxidative damage accumulation and chronic
inflammation. Our results indicate that these actions may contribute to the
beneficial effects of metformin on healthspan and lifespan. These findings are in
agreement with current epidemiological data and raise the possibility of
metformin-based interventions to promote healthy aging.

PMCID: PMC3736576
PMID: 23900241



[3] Am J Clin Nutr. 2012 Apr;95(4):845-50. doi: 10.3945/ajcn.111.018606. Epub 2012

Feb 29.

Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the
activation of brown adipose tissue in humans.

Yoneshiro T(1), Aita S, Kawai Y, Iwanaga T, Saito M.

Author information:
(1)Laboratory of Histology and Cytology, Department of Anatomy, Hokkaido
University Graduate School of Medicine, Sapporo, Japan.


Free full text: http://ajcn.nutrition.org/content/early/2012/02/28/ajcn.111.018606.full.pdf+html

BACKGROUND: Capsinoids-nonpungent capsaicin analogs-are known to activate brown
adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE) in
small rodents. BAT activity can be assessed by [¹⁸F]fluorodeoxyglucose-positron
emission tomography (FDG-PET) in humans.

OBJECTIVES: The aims of the current study were to examine the acute effects of
capsinoid ingestion on EE and to analyze its relation to BAT activity in humans.
DESIGN: Eighteen healthy men aged 20-32 y underwent FDG-PET after 2 h of cold
exposure (19°C) while wearing light clothing. Whole-body EE and skin temperature,
after oral ingestion of capsinoids (9 mg), were measured for 2 h under warm
conditions (27°C) in a single-blind, randomized, placebo-controlled, crossover

RESULTS: When exposed to cold, 10 subjects showed marked FDG uptake into adipose
tissue of the supraclavicular and paraspinal regions (BAT-positive group),
whereas the remaining 8 subjects (BAT-negative group) showed no detectable
uptake. Under warm conditions (27°C), the mean (±SEM) resting EE was 6114 ± 226
kJ/d in the BAT-positive group and 6307 ± 156 kJ/d in the BAT-negative group
(NS). EE increased by 15.2 ± 2.6 kJ/h in 1 h in the BAT-positive group and by 1.7
± 3.8 kJ/h in the BAT-negative group after oral ingestion of capsinoids (P <
0.01). Placebo ingestion produced no significant change in either group. Neither
capsinoids nor placebo changed the skin temperature in various regions, including
regions close to BAT deposits.

CONCLUSION: Capsinoid ingestion increases EE through the activation of BAT in
humans. This trial was registered at http://www.umin.ac.jp/ctr/as UMIN

PMID: 22378725



[4] Obesity (Silver Spring). 2011 Jan;19(1):13-6. doi: 10.1038/oby.2010.105. Epub

2010 May 6.

Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy
adult men.

Yoneshiro T(1), Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, Saito M.

Author information:
(1)Department of Nutrition, School of Nursing and Nutrition, Tenshi College,
Sapporo, Japan.

Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose
(FDG)-positron emission tomography (PET) in adult humans. Thirteen healthy male
volunteers aged 20-28 years underwent FDG-PET after 2-h cold exposure at 19 °C
with light-clothing and intermittently putting their legs on an ice block. When
exposed to cold, 6 out of the 13 subjects showed marked FDG uptake into adipose
tissue of the supraclavicular and paraspinal regions (BAT-positive group),
whereas the remaining seven showed no detectable uptake (BAT-negative group). The
BMI and body fat content were similar in the two groups. Under warm conditions at
27 °C, the energy expenditure of the BAT-positive group estimated by indirect
calorimetry was 1,446 ± 97 kcal/day, being comparable with that of the
BAT-negative group (1,434 ± 246 kcal/day). After cold exposure, the energy
expenditure increased markedly by 410 ± 293 (P < 0.05) and slightly by 42 ±
114 kcal/day (P = 0.37) in the BAT-positive and -negative groups, respectively. A
positive correlation (P < 0.05) was found between the cold-induced rise in energy
expenditure and the BAT activity quantified from FDG uptake. After cold exposure,
the skin temperature in the supraclavicular region close to BAT deposits dropped
by 0.14 °C in the BAT-positive group, whereas it dropped more markedly (P < 0.01)
by 0.60 °C in the BAT-negative group. The skin temperature drop in other regions
apart from BAT deposits was similar in the two groups. These results suggest that
BAT is involved in cold-induced increases in whole-body energy expenditure, and,
thereby, the control of body temperature and adiposity in adult humans.

PMID: 20448535



[5] Lv J, Qi L, Yu C, Yang L, Guo Y, Chen Y, Bian Z, Sun D, Du J, Ge P, Tang Z, Hou W, Li Y, Chen J, Chen Z, Li L; China Kadoorie Biobank Collaborative Group. Consumption of spicy foods and total and cause specific mortality: population based cohort study. BMJ. 2015 Aug 4;351:h3942. doi: 10.1136/bmj.h3942. PubMed PMID: 26242395; PubMed Central PMCID: PMC4525189. (See also the Rapid Response by Prof. Nicholas D Moore).

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In my continuing obsession with cold exposure, I did some more research into compounds that can activate brown adipose tissue (BAT), in addition to metformin and capsaicin discussed in the previous post.


It turns out that caffeine [1][2] and especially caffeinated green tea [3][4][5], also activates BAT!  Of course all these studies except for [4] were performed in rodents, which naturally possess significant amounts of BAT, particularly when housed at chilly (for them) typical lab temperatures. Study [4] was in humans, and showed that caffeinated green tea promoted more thermogenesis than its caffeine content would predict. Study [4] is from 1999, a decade before it was discovered that (some) humans have BAT, so they weren't even in a position to speculate that the increased thermogenesis was likely a result of activating BAT. But we know now that is probably the mechanism.


Of course, like with metformin and capsaicin, you need to have brown adipose tissue before green tea can activate it - which again probably requires cold exposure. 


I find it really intriguing (and encouraging) that three compounds known to promote health and possibly lifespan, metformin, capsaicin, and green tea, all seem to have their effect, at least in part, via activating brown adipose tissue.





[1] J Nutr Sci Vitaminol (Tokyo). 1990 Apr;36(2):173-8.

Caffeine activates brown adipose tissue thermogenesis and metabolic rate in mice.
Yoshioka K(1), Yoshida T, Kamanaru K, Hiraoka N, Kondo M.
Author information: 
(1)First Department of Internal Medicine, Kyoto Prefectural University of
Medicine, Japan.
To clarify the effect of caffeine on brown adipose tissue (BAT) thermogenesis, we
measured guanosine-5'-diphosphate (GDP) binding, a thermogenic indicator of BAT, 
and oxygen consumption in BAT mitochondria as well as BAT temperature and resting
metabolic rate (RMR) in mice. Intraperitoneal injection of caffeine (60 mg/kg)
significantly elevated BAT temperature with less effect on core temperature, and 
increased significantly GDP binding and oxygen consumption in BAT mitochondria,
and RMR. These results suggest that caffeine activates BAT thermogenesis, which
may contribute to the increase of RMR.
PMID: 2388099
[2] Int J Obes. 1991 May;15(5):317-26.
Peripheral mechanisms of thermogenesis induced by ephedrine and caffeine in brown
adipose tissue.
Dulloo AG(1), Seydoux J, Girardier L.
Author information: 
(1)Centre Medical Universitaire, Department of Physiology, University of Geneva, 
The peripheral mechanisms by which ephedrine and caffeine influence thermogenesis
were investigated in innervated rat interscapular brown adipose tissue (IBAT) by 
assessing its rate of oxygen consumption (MO2) in vitro. Dose-response
measurements with tissues from intact or sympathectomized (6-OHDA) animals
indicate that the thermogenic effects of low concentrations of ephedrine and also
of caffeine are entirely dependent upon the presence of intact sympathetic nerve 
endings, and thus depend on presynaptic mechanisms. Direct postsynaptic
stimulation of thermogenesis is only apparent at much higher concentrations,
namely greater than 1 microM for ephedrine and greater than 2mM for caffeine. At 
subminimal concentrations that neither ephedrine nor caffeine influenced basal
tissue respiration, they induced a 4-5-fold increase in basal MO2 when
administered in combination, a synergistic response prevented by pre-treatment of
the rat with 6-OHDA. Synergistic increases in IBAT respiration were also obtained
when subminimal concentration of ephedrine was added to 3-propylxanthine (a
specific inhibitor of phosphodiesterase), to 8-phenyltheophylline (a potent
adenosine receptor antagonist) or to adenosine deaminase (for enzymatic
inactivation of endogenous adenosine). Conversely, the marked synergism in
thermogenic response with ephedrine + caffeine was reduced in the presence of
2-chloroadenosine (an adenosine analogue). In tissues from fasted rats, the
ephedrine + caffeine synergism in thermogenic response, although attenuated, was 
nevertheless present. These studies therefore demonstrate that ephedrine, at
doses comparable with therapeutic use, stimulates thermogenesis in BAT via
sympathetically released NA. In addition, a synergistic interaction between
caffeine and ephedrine on BAT thermogenesis is explained by ephedrine's
enhancement of sympathetic neuronal release of NA, together with caffeine's dual 
ability to antagonize adenosine and to inhibit cellular phosphodiesterase
PMID: 1885257


[3] Int J Obes Relat Metab Disord. 2000 Feb;24(2):252-8.

Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine 
and sympathetic activity.
Dulloo AG(1), Seydoux J, Girardier L, Chantre P, Vandermander J.
Author information: 
(1)Institute of Physiology, University of Fribourg, Fribourg, Switzerland.
The thermogenic effect of tea is generally attributed to its caffeine content. We
report here that a green tea extract stimulates brown adipose tissue
thermogenesis to an extent which is much greater than can be attributed to its
caffeine content per se, and that its thermogenic properties could reside
primarily in an interaction between its high content in catechin-polyphenols and 
caffeine with sympathetically released noradrenaline (NA). Since
catechin-polyphenols are known to be capable of inhibiting
catechol-O-methyl-transferase (the enzyme that degrades NA), and caffeine to
inhibit trancellular phosphodiesterases (enzymes that break down NA-induced
cAMP), it is proposed that the green tea extract, via its catechin-polyphenols
and caffeine, is effective in stimulating thermogenesis by relieving inhibition
at different control points along the NA-cAMP axis. Such a synergistic
interaction between catechin-polyphenols and caffeine to augment and prolong
sympathetic stimulation of thermogenesis could be of value in assisting the
management of obesity. International Journal of Obesity (2000) 24, 252-258
PMID: 10702779




[4] Am J Clin Nutr. 1999 Dec;70(6):1040-5.

Efficacy of a green tea extract rich in catechin polyphenols and caffeine in
increasing 24-h energy expenditure and fat oxidation in humans.
Dulloo AG(1), Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, Chantre P,
Vandermander J.
Author information: 
(1)Department of Physiology, Faculty of Medicine, University of Geneva.
BACKGROUND: Current interest in the role of functional foods in weight control
has focused on plant ingredients capable of interfering with the sympathoadrenal 
OBJECTIVE: We investigated whether a green tea extract, by virtue of its high
content of caffeine and catechin polyphenols, could increase 24-h energy
expenditure (EE) and fat oxidation in humans.
DESIGN: Twenty-four-hour EE, the respiratory quotient (RQ), and the urinary
excretion of nitrogen and catecholamines were measured in a respiratory chamber
in 10 healthy men. On 3 separate occasions, subjects were randomly assigned among
3 treatments: green tea extract (50 mg caffeine and 90 mg epigallocatechin
gallate), caffeine (50 mg), and placebo, which they ingested at breakfast, lunch,
and dinner.
RESULTS: Relative to placebo, treatment with the green tea extract resulted in a 
significant increase in 24-h EE (4%; P < 0.01) and a significant decrease in 24-h
RQ (from 0.88 to 0.85; P < 0.001) without any change in urinary nitrogen.
Twenty-four-hour urinary norepinephrine excretion was higher during treatment
with the green tea extract than with the placebo (40%, P < 0.05). Treatment with 
caffeine in amounts equivalent to those found in the green tea extract had no
effect on EE and RQ nor on urinary nitrogen or catecholamines.
CONCLUSIONS: Green tea has thermogenic properties and promotes fat oxidation
beyond that explained by its caffeine content per se. The green tea extract may
play a role in the control of body composition via sympathetic activation of
thermogenesis, fat oxidation, or both.
PMID: 10584049
[5] J Nutr Biochem. 2003 Nov;14(11):671-6.

Green tea reduces body fat accretion caused by high-fat diet in rats through
beta-adrenoceptor activation of thermogenesis in brown adipose tissue.

Choo JJ(1).

Author information:
(1)Department of Foods and Nutrition, Kunsan National University, Kunsan,
Cheollabuk-do 573-701, South Korea. jjchoo@kunsan.ac.kr

The aim of the present study was to investigate body fat-suppressive effects of
green tea in rats fed on a high-fat diet and to determine whether the effect is
associated with beta-adrenoceptor activation of thermogenesis in brown adipose
tissue. Feeding a high-fat diet containing water extract of green tea at the
concentration of 20g/kg diet prevented the increase in body fat gain caused by
high-fat diet without affecting energy intake. Energy expenditure was increased
by green tea extract which was associated with an increase in protein content of
interscapular brown adipose tissue.
The simultaneous administration of the
beta-adrenoceptor antagonist propranolol(500 mg/kg diet) inhibited the body
fat-suppressive effect of green tea extract. Propranolol also prevented the
increase in protein content of interscapular brown adipose tissue caused by green
tea extract. Digestibility was slightly reduced by green tea extract and this
effect was not affected by propranolol. Therefore it appeared that green tea
exerts potent body fat-suppressive effects in rats fed on a high-fat diet and the
effect was resulted in part from reduction in digestibility and to much greater
extent from increase in brown adipose tissue thermogenesis through
beta-adrenoceptor activation.

PMID: 14629899

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