Jump to content
Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Recommended Posts

Just some more thoughts about cold exposure, I don't feel like anyone has done the proper research yet to determine the effectiveness of various forms of cold exposure on BAT activation.  Many studies seem to just use cold rooms, some studies even had people sticking their legs on blocks of ice -- all of these methods might be "off base".  A proper comparative study could be hugely beneficial for science and humanity, so I hope someone runs one.  

 

The reason I'm thinking about this is because I see many reactions from people along the lines of "I couldn't do that, I hate being cold".  There's even a quote from this very thread "I don't like the idea of subjecting myself to cold, just because it's uncomfortable".  I have found that wearing a 58 degree (F) cooling vest that is very targeted to BAT and not cooling my whole body, is not in any way uncomfortable, in fact it is rather pleasant, and the more you become cold adapted, the more pleasant this becomes.  You can actually feel the BAT "kick in" and start generating heat.  Its funny because after a while in the cooing vest, its almost impossible to tell what the ambient temperature is.  Anyway, the image of a shivering guy in a freezing cold room trying to go about his daily routine probably isn't the best representation of this, but as far as I know, we really don't have data yet to say what cooling methods produce the best results.

Share this post


Link to post
Share on other sites

Gordo,

 

I agree with your that more experimentation is needed with what cold exposure techniques are best for promoting and activating BAT in people. I too find cold not unpleasant once you get used to it. I think it is a mental thing for most people. My wife absolutely hates the cold, and is constantly complaining about it. I think it is a natural human reaction to something that has been potentially detrimental or dangerous during our evolutionary history.

 

It seems with some discipline and persistence, one can really train oneself to relish the cold, rather than shrink from it. I have a fan set up behind my stationary bike, blowing on my back as we speak. The temperature here in my basement is between 58 and 59 degrees. I've been leisurely peddling away for about 20 minutes, and I'm starting to feel what can best be described as a warm tingling sensation in the upper middle of my back, along my spine and in my trapezius muscles. I speculate that it might be the BAT kicking in. What is it that you are feeling when you get the sense that your BAT is kicking in? Anything like what I describe?

 

P.S. My Cool Fat Burner (original + 'Gut Buster' combo) arrived yesterday. It is amazingly heavy! It comes with 12 phases change cold packs, each of which weighs 625g, for a total of 7.5kg of cold packs, or 16.5 lbs. Much more than the 3kg listed on the coolfatburner.com website. I'm charging up the cold packs and will test it later today.

 

--Dean

Share this post


Link to post
Share on other sites

Wow Dean, 7.5kg of PCM is more than 3 times what the techkewl came with, sounds great.  I'd like to see some pictures of everything.  Also what IS the phase change temp of those cooling packs?  I sort of had the impression that they were colder than the techkewl ones but I couldn't find that info on their site.

 

I'm not sure offhand if anyone has already mentioned this yet, but interestingly enough, BAT apparently even has a role in bone growth and bone density which may be of particular importance to anyone doing CR (but also important to everyone who lives long enough):

http://www.ncbi.nlm.nih.gov/pubmed/25388370

"Inducible brown fat is associated with higher bone mineral density, suggesting that brown fat interacts with bone growth in previously unrecognized ways." 

 

When BAT kicks in I have noticed a pleasant warming sensation mostly around my collarbones and ribs, after a cooling session and vest being removed for a little while, it is remarkable how hot those areas become.  Not sure of the best way to do it, but it would be interesting to compare skin temps at various locations say an hour after a cooling session.

 

This is probably going to vary by person, but I kind of feel like BAT around the ribs has been under-recognized by researchers.  BAT is more like muscle than fat, and anchors to bone.  The ribs at least in some people, seem to be covered with BAT, but not at the same density as the clavicle area.  The reason I think this is important is because the ribs are so close to the skin and have such big surface area compared to any other BAT "hot spots" (pardon the pun).  Remember that BAT can be "built up" but needs some foundation to start with, this makes the ribs of particular interest to me since they seem to have the most potential for "BAT growth".  I first noticed this in the cool fat burner guy's videos (but you can also see it in some before/after PET scan images from research studies, one pic included in this thread).  CFB guy's PET scan after BAT activation:

PET_Scan_Rib_BAT.png

 

Externally:

Rib_BAT_External.png

 

After a cooling session my own rib area (also clavicle area) are burning up like I imagine this guy's must be in the pic above.

 

FYI: I had a an entertaining (if somewhat surreal) experience last night wearing the cooling vest in bed while watching the movie "Everest" (where people are climbing in extreme cold and freezing to death, haha).  Good stuff, I highly recommend!

Edited by Gordo

Share this post


Link to post
Share on other sites

Almost certainly not. I'm working on a big post on this very topic, but as a preview, it appears you actually have to be cold (i.e. have reduced core body temperature) to benefit. Turning the thermostat down and bundling up almost certainly defeats the purpose.

 

I am with Khurram about being too cold disrupting QOL (especially disrupting ability to think).  Like you, Khurram, I have a very low BMI -- and I reach "shiver level" rapidly and easily.  (By way of background, as Khurram knows first hand from visiting with me, I've surfed in the cold Pacific Ocean (So. Cal.) for the past dozen years while on CR--Consequently, I've familiarized myself with & tried to incorporate cold exposure into my daily routine even when not in the water.)  I've always tried to stay just shy of chill bumps / shivering; I check my temperature (daily) to make sure it's 96.3F or 97.2F (outside of eating windows).  OTOH, I am reconsidering and would probably go to greater cold exposure degrees (pun intended) if such greater amounts would combat my DNA from turning into alphabet soup.

Share this post


Link to post
Share on other sites

A Tale of Three Rodents - Part 3: Bats

 

This is the third post in my three part series on long-lived rodents and BAT (brown adipose tissue) thermogenesis, in which I'll discuss bats. Note, in this post, lowercase 'bat' will always refer to the little flying creature, and uppercase 'BAT' will always refer to brown adipose tissue, if that weren't obvious.

 

But before discussing bats' BAT, I'll share a statistic I came across about BAT that is simply amazing, and will be quite relevant for bats. Review article [1] says the following:

 

BAT is characterised as possessing large amounts of the unique uncoupling protein (UCP) 1 which when activated enables the free-flow of protons across the inner mitochondrial membrane, resulting in the rapid dissipation of chemical energy as heat [ref]. Consequently, when maximally activated, BAT can generate up to 300 W[atts]/kg of tissue compared with 1 W[att]/kg from most other tissues [ref].

 

That 1 Watt/kg for other tissues seems on the low side - elite cyclists can generate a sustained 5-6 Watts/kg of body weight. Since their thighs are only a fraction (although a pretty large fraction) of elite cyclists' body weight, they are obviously generating a lot more than 5-6 Watts per kg of muscle fibers. But if you consider an elite cyclists body weight to be around 60kg, they are generating about 300 watts of total power (5W/kg * 60kg) that the pedals, using their entire body (e.g. cardiovascular system) to support it. It's quite astonishing how metabolically energetic BAT is. It doesn't take much to burn a lot of calories - comparable to rigorous exercise.

 

OK - back to bats. First, my bad. Bats aren't even remotely related to rodents. Sorry about that. From this page on Myths and Facts about Bats:

 

Bats are not flying mice; they are not even remotely related to rodents. Bats are such unique animals that scientists have placed them in a group all their own, called ‘Chiroptera’, which means hand-wing. Bats are grouped with primates and lemurs in a grand order called Archonta.

 

Several traits set bats apart from other mammals. No, it's not their sonar, which they share with other mammals like dolphins. Instead, bats are the only mammals to have achieved (self-)powered flight. Plus, and most relevant for our purposes, they live a very long time for their size. The little brown bat (LBB - Myotis lucifugus) is really quite tiny (see image below) - weighing in at only 5-14g. That is about 1/2 the size of naked mole rats, and 40-100x smaller than grey squirrels. But the LBB can live up to 30 years - rivaling even the naked mole rat for longevity. The (slightly) bigger big brown bat (BBB - Eptesicus fuscus, discussed below) weighs 15-20g, and doesn't live quite as long (~20 years max).

 

bat2.jpg Cute - isn't he!? :-)

 

LBBs eat 50% to 100% of their body weight in mosquitoes per night - which equates to about 5,000 and 10,000 mosquitoes! Their heart rate can vary from as low as 5-10 BPM during hibernation, to 200 BPM when at rest but not hibernating, to over 1000 BPM during flight. The LBB is an amazing creature!

 

But enough of the fascinating bat facts - the question is do long-lived bats have BAT?

 

Given how much energy they are burning simply at rest and in flight (with heart rates of 200 and 1000 BPM respectively), one might think they don't need to generate extra heat when not hibernating. And with a heart rate of on 5-10 BPM when hibernating, it would seem they can't be engaging in that much norepinephrine-induced BAT activity during that part of the year. But on the other hand, their small size and large surface area (including wings) means they radiate a lot of heat away, and they do hang out (literally) in cool, damp caves. So maybe they do require BAT to help them generate heat. 

 

So which is it? Lots of BAT, or not very much?

 

As you might have guessed by now, it appears that bats have lots of BAT!

 

I couldn't find data on LBBs specifically, but below is the table from [2], which measured the weight of various tissues & organs in Big Brown Bats (BBBs) both in summer, and during hibernation in winter:

 

ZQY3oPA.png

 

Let's compare these BAT numbers, both absolutely and in percentage terms, to rats. Below is a similar table from PMID 18593277 (discussed in this post), showing the amount of BAT in young (left column), old (middle column) and Old CRed (right column) rats. In absolute terms, the weight of BAT tissue in the BBBs and the rats is pretty similar, between 0.4g and 1g. So not all that remarkable. But then you realize that BBBs weighted ~25x less than the rats. The BAT in BBBs is between 2.8% (in summer) and 4.2% (in winter) of total body weight. That's huge! This compares with 0.1% to 0.15% of total body weight in rats. In other words, BBBs have ~30x more BAT than rats as a percentage of body weight.

 

WkUomfE.png

 

The authors of [2] suggest that the large amount of BAT the BBBs possess, especially in the winter, is critical for raising them from hibernation - basically the BAT enables them to jump-start their metabolism by burning calories stored in all that white adipose tissue to generate heat:

 

There remains little doubt that differences in time required for arousal are primarily a
consequence of seasonal differences in the mass of brown adipose tissue and therefore, in the
amounts of heat produced by this tissue. Both shunting of blood to anterior body regions
and initiation of the rewarming process depend largely on the ability of brown fat to assume
a comparatively high metabolic rate at low temperatures (Rauch 1973)...
 
Indeed, the success of [big brown bats] to elevate its body temperature in the cold depends
primarily on brown fat as a source of heat. Both nutritional blood flow studies (Rauch
1973; this study) and data from direct thermometry (Smalley and Dryer 1963; Hayward
et al. 1965; Rauch 1973; Studier 1974) suggest passive warming of organs of the posterior
body, and that shivering thermogenesis by skeletal muscle is not essential for the arousal
of this species (Hayward and Lyman 1967). 

 

But whatever the evolutionary reason, big brown bats (and almost certainly the little ones as well!), like grey squirrels and naked mole rats, have a LOT of BAT, and also like them, live a very long time relative to other small mammals.

 

Obviously this correlation between amount of BAT and extreme longevity in all three of these species does not necessarily imply causation. But when combined with all the other evidence outlined in this thread (which just reached 100 posts!) for the health & longevity benefits of increased BAT, it seems extremely suggestive to me...

 

--Dean

 

 

-----------

[1] Scientifica Volume 2013 (2013), Article ID 305763, 14 pages

 
Brown Adipose Tissue Growth and Development
 
Michael E. Symonds
 
Early Life Nutrition Research Unit, Academic Division of Child Health, School of Clinical Sciences, University Hospital, The University of Nottingham, Nottingham NG7 2UH, UK
 
Received 4 February 2013; Accepted 28 February 2013
 
Academic Editors: Y. Chagnon and G. Lopaschuk
 
 
Abstract
 
Brown adipose tissue is uniquely able to rapidly produce large amounts of heat through activation of uncoupling protein (UCP) 1. Maximally stimulated brown fat can produce 300 watts/kg of heat compared to 1 watt/kg in all other tissues. UCP1 is only present in small amounts in the fetus and in precocious mammals, such as sheep and humans; it is rapidly activated around the time of birth following the substantial rise in endocrine stimulatory factors. Brown adipose tissue is then lost and/or replaced with white adipose tissue with age but may still contain small depots of beige adipocytes that have the potential to be reactivated. In humans brown adipose tissue is retained into adulthood, retains the capacity to have a significant role in energy balance, and is currently a primary target organ in obesity prevention strategies. Thermogenesis in brown fat humans is environmentally regulated and can be stimulated by cold exposure and diet, responses that may be further modulated by photoperiod. Increased understanding of the primary factors that regulate both the appearance and the disappearance of UCP1 in early life may therefore enable sustainable strategies in order to prevent excess white adipose tissue deposition through the life cycle.
 
-------
[2] Écoscience Vol. 5, No. 1 (1998), pp. 8-17
 
Changes in body mass and fat reserves in prehibernating little brown bats (Myotis lucifugus)
Thomas H. KUNZ, John A. WRAZEN and Christopher D. BURNETT
 
 
Abstract
 
Changes in body mass, fat mass, lean dry mass, and energy content of little brown bats, Myotis lucifugus (LeConte), captured at a cave in southern Vermont, were quantified during the pre-hibernation period in late summer and autumn. Adults of both sexes showed maximum rates of increase in body mass from mid-August to mid-September, during which time the average gain was 2.3 g for males and 2.1 g for females. These gains represent 32.9% and 29.6% of the pre-hibernation body masses for adult males and females, respectively. Young-of-the-year of both sexes weighed about 1 to 2 g less than adults during most of the pre-hibernation period. In mid-September, adult females weighed significantly less than a cohort of adult females captured at a maternity roost on the same date. Adult bats reached their maximum pre-hibernating body mass in mid-September, whereas young bats reached their maximum pre-hibernating body mass one month later. From mid-July to mid-September, we found no significant differences in mean body mass between young males and females, but in mid-October when they entered hibernation, young females weighed significantly more than young males and almost as much as adult females. Young males and females arrived at the swarming-hibernation site in late summer with an average lean body mass and fat index approximately 20% lower than adults. By early October, young females achieved minimum adult levels of lean dry mass, but by the time they entered hibernation the lean mass of young males was still about 10% lower than adults. During the pre-hibernation period, lean dry mass and fat mass of all bats were significantly correlated with body mass. Regression equations derived from these data were used to estimate total energy content of bats. The acquisition of maximum fat reserves by M. lucifugus in the pre-hibernation period may be as important for successful reproduction as it is for sustaining hibernation. The fattest adult males may gain a reproductive advantage if they acquire enough energy reserves to sustain autumn mating and hibernation, and engage in multiple matings during the winter. The fattest females should gain a reproductive advantage by maximizing fat reserves before entering hibernation, and retaining sufficient energy reserves at the end of hibernation to facilitate ovulation. Relatively low survival and reduced fecundity in females at northern latitudes may reflect the relatively low fat reserves deposited by young females in their first autumn. 

Share this post


Link to post
Share on other sites

All,

 

Saul wrote:

My daily very cold showers leave me feeling cold -- but not shivering -- for several hours.

 

and Kenton wrote:

 Like you, Khurram, I have a very low BMI -- and I reach "shiver level" rapidly and easily... I've familiarized myself with & tried to incorporate cold exposure into my daily routine even when not in the water.  I've always tried to stay just shy of chill bumps / shivering; I check my temperature (daily) to make sure it's 96.3F or 97.2F (outside of eating windows). 

 

and Sirtuin wrote:

I do take cold showers regularly (primarily to escape the heat and to keep my skin moisturized) and leave a fan on, but it's difficult to avoid being fairly heat-acclimated and somewhat cold-sensitive in this environment.

 

I think there are three, closely-related but not identical, states being discussed related to cold, that could stand to be teased apart. The first is feeling cold - which is a subjective state. The second is being cold - i.e. having a low body temperature. The third is being in cold - i.e. being exposed to cold temperatures. 

 

I don't think it's possible to know definitively how these three are correlated with each other, or with BAT activity, in general or in CR folks in particular. But one thing is clear from my research - they aren't synonymous. For example, it's not unusual for CR folks to both be cold and feel cold, even when being in relatively warm ambient conditions that others find quite normal and tolerable. 

 

Here I'm going to go out on a limb, and say something people may not want to hear, but I predict being cold and feeling cold, especially when not being in cold ambient conditions, is an indication one has little BAT / BAT-activity, rather than being a positive sign of BAT synthesis or BAT activity.

 

From PMID 18593277 (discussed here), we know that old CRed rats have less BAT, as a percent of body weight, than old AL-fed rats. And as discussed in this post, PMID 23393181 found that anorexics (BMI 15.5), refed anorexics (BMI 18.8) had no detectable BAT, but were presumably both subjectively and literally colder than controls. In fact, it was only the "constitutionally lean" (CL) women (BMI 16.2) who were found to have BAT in abundance, along with a higher resting metabolic rate to support it:

 

 All CL (100%), none of the AN and refed AN (0%), and 3 of the 24 NW (12%) subjects showed [measureable BAT activity].
 
Additionally, recall from this discussion that grey squirrels have a higher body temperature than other rodents, and don't appear to suffer from feeling cold (given how playful they are outdoors in winter) despite being in extremely cold conditions. And they have lot of BAT and BAT activity, on top of living a very long time for a rodent. 
 
All this suggest that being cold (low body temperature) or subjectively feeling cold aren't sufficient for, or even necessarily correlated with, elevated BAT amount or BAT activity. In fact, they may even be inversely correlated with elevated BAT.
 
Moreover, unless you are born with genes that promote BAT (like the 'constitutionally lean' women above), being in cold for several hours per day and eating enough calories to support it, is likely to be required in order to synthesize and activate BAT, especially in very lean, older people like most of us.
 
Surfing in the chilly ocean of northern California would certainly qualify as cold exposure, and will likely promote synthesis & activation of BAT, as long as one is eating enough calories... But simply "feeling cold, or actually being cold, for several hours after a cold shower" in presumably normal ambient conditions is suggestive to me that one lacks BAT and has trouble warming up as a result, rather than a sign that one is synthesizing or activating BAT.
 
--Dean

Share this post


Link to post
Share on other sites

Hi Dean, Kenton and Gordo!

 

My body temperature is always 96.(something) or 97.(something).

 

Kenton, I was very impressed by your BMI when you went to the front of the lecture room during a

talk at CR VIII --- the distance from your front to back looked like only 3-4 inches! (Perhaps an

illusion, but no doubt -- extremely impressive!)

 

I look forward (I hope) to your presence at CR IX!

 

:)

 

-- Saul

Share this post


Link to post
Share on other sites

Here I'm going to go out on a limb, and say something people may not want to hear, but I predict being cold and feeling cold, especially when not being in cold ambient conditions, is an indication one has little BAT / BAT-activity, rather than being a positive sign of BAT synthesis or BAT activity.

 

From PMID 18593277 (discussed here), we know that old CRed rats have less BAT, as a percent of body weight, than old AL-fed rats. And as discussed in this post, PMID 23393181 found that anorexics (BMI 15.5), refed anorexics (BMI 18.8) had no detectable BAT, but were presumably both subjectively and literally colder than controls. In fact, it was only the "constitutionally lean" (CL) women (BMI 16.2) who were found to have BAT in abundance, along with a higher resting metabolic rate to support it:

 

 All CL (100%), none of the AN and refed AN (0%), and 3 of the 24 NW (12%) subjects showed [measureable BAT activity].

 

Additionally, recall from this discussion that grey squirrels have a higher body temperature than other rodents, and don't appear to suffer from feeling cold (given how playful they are outdoors in winter) despite being in extremely cold conditions. And they have lot of BAT and BAT activity, on top of living a very long time for a rodent.

Indeed. On the other hand, despite their depleting effects on BAT, we have extensive evidence that CR in rodents retards aging and extends maximum lifespan, and some limited evidence that human CR does the same (including the greater life expectancy of anorexics when concomitant substance abuse and hospitaized cases are excluded, despite the poor overall "lifestyle" of anorexics), whereas we have no interventional evidence that increasing BAT level or activity does either, or has any health benefits not attributable to obesity-avoidance. Indeed, the BMI-longevity evidence is a much bigger hurdle for the "BAT longevity" hypothesis than it is for CR, since nearly none of the lean people in the general population is doing anything remotely resembling CR, and a substantial proportion of them are constitutionally lean.

Share this post


Link to post
Share on other sites

I hadn't heard the term constitutionally leanness until today.  I tried searching this site and Google for a definition, and I am wondering if it resembles something like this:

 

People who are underweight BMI (13 -17ish), but who don't have the usual problems that accompany that weight (ie. normal menstruation, normal thyroid, normal cardiac function, normal insulin sensitivity, etc.).  Is this accurate?

Share this post


Link to post
Share on other sites

Drew,

 

I don't think there is an official definition for "constitutionally lean". As discussed in this post, the authors of PMID 23393181 defined it as follows: "constitutional leanness is a peculiar physiological condition whereby the body is resistant to fat storage, even in overfeeding conditions." 

 

--Dean

Share this post


Link to post
Share on other sites

...in the chilly ocean of northern California would certainly qualify as cold exposure ... 

 

My twin has strong CR biomarkers but only practices about 10% CR.  I wonder if it could be because he surfs in the same cold water.  As Saul noted, my BMI is fifteen and a half ish; my identical twin has a BMI of about twenty-five ish yet exhibits low WBC count, elevated TSH, (and FYI low HbA1c ), etc.  His biomarkers are roughly 80-90% as good as mine.  He eats well but restricts his calories only about 10 or 15%.

Edited by Kenton
Fix misplaced quote. I (Dean) don't have a BMI of 15.5ish!

Share this post


Link to post
Share on other sites

Michael - wonderful! Finally a skeptic chimes in on the idea that BAT and BAT-activity promotes health/longevity.  This will be fun if you've got a few cycles to spare for these discussions (he says hopefully...).

 

You wrote:

On the other hand, despite [its] depleting effects on BAT, we have extensive evidence that CR in rodents retards aging and extends maximum lifespan,

 

Regarding CR's "depleting effects on BAT" as reported in PMID 18593277. In the quote you include, I point to the discussion of that study in this post. If you look at that discussion, you'll see that Valle et al did indeed see lower amounts of BAT in CRed rodents. But they also found the BAT the CR rodents did retain was much more active i.e. had a much higher expression of UPC1 as a result of mitochondrial biogenesis. The authors conclude (my emphasis):

 

In broad terms, we observed that old restricted animals compared to old ad libitum fed ones have a reduced BAT size, even normalized per body weight, which probably is due to a lower fat content and adipocyte number in the tissue. ... As happens in liver or skeletal muscle, CR was also shown to promote mitochondrial biogenesis in BAT. On the whole, this conservation of BAT thermogenic capacity may confer several advantages, such as a higher ability to respond to cold exposure or to control body weight when food supply is restored, and, therefore, be part of the rejuvenation mechanisms underlying the life-span extension induced by CR.

 

So in rodents at least (but apparently not people, at least according to the study of BAT in anorexics), CR spares some BAT, and the BAT that does remain appears to work extra hard to generate heat, in the scrawny, cold-sensitive rodents. So, far from discrediting the theory that BAT is beneficial and important for health / longevity, this study supports it, since BAT activity remains robust in CR rodents, and in fact could be argued to be a greater fraction of metabolic activity than in (well-insulated) controls.

 

But more fundamentally, when you say:

...we have extensive evidence that CR in rodents retards aging and extends maximum lifespan,

 

shouldn't you really say "we have extensive evidence that CR in rodents retards aging and extends maximum lifespan when rodents are exposed to cold conditions"?

 

As I pointed out in this post, and elaborated on in this one, PMID 9032756 yoked the weights of two groups of CR mice together so as to be identical, and kept one at thermal-neutrality (86°F) and the other at a "normal" (i.e. chilly-for-rodent) temperature of 72°F.  It was only the chilly CR mice that lived longer than controls. In fact, despite eating fewer calories than the chilly CR mice (and a heck of a lot less than AL-fed controls), the thermally-neutral CR mice didn't live any longer on average than AL-fed controls. This would seem to suggest cold exposure is a critical component of the "CR magic", despite requiring animals to eat more calories. Here again are the survival curves of the Control (CT/B6), Energy-Restricted, cool-housed (ER/B6) and Energy-Restricted, warm-housed (ERI/B6) mice:

 

Ni5cZ3p.png

 

So my question is - have there been other studies that contradict this result, i.e. that show CR extends lifespan in rodents even when housed at thermal-neutrality?

 

Next you wrote:

...whereas we have no interventional evidence that increasing BAT level or activity does either [retards aging or extends maximum lifespan], or has any health benefits not attributable to obesity-avoidance.

 

I realize it's huge, but have you read the earlier posts in this thread?

 

I'll divide my response into two sets - one for rodents and one for people.

 

Regarding your statement that there is no interventional evidence for BAT's benefits in rodents not attributable to obesity-avoidance:
  • Obviously PMID 9032756 just discussed flat-out contradicts your assertion, since CRed mice housed at what for them is an uncomfortably cool temperature ate 20% more, weighted the same, and lived 40% longer on average than equivalently-skinny CRed mice housed at a comfortably temperature. In this post, I discuss PMID 9032756 which found that housing C57BL/6 mice at "normal" (i.e. cool for them, ~68 °F) housing temperatures increases BAT expression by a factor of 22x compared with mice housed at thermal-neutrality. So between these studies, we see that cold exposure → ↑ BAT-activity → ↑ longevity even when both groups of rodents are CRed.
  • Cold exposure upregulates circulating fibroblast growth factor 21 (FGF21) in people by 37%, and FGF21 in mice BAT by a factor of 40x [1]. PMID 23066506 found that transgenic mice that overexpress FGF21 lived 40% longer than controls without the mutation, despite the FGF21-mutant mice eating a bit more than the normal mice. It's an argument in several steps (cold exposure → ↑ BAT → ↑ FGF21 → ↑ longevity), but it shows obesity-independent benefits of cold exposure & BAT.  See this post for more discussion. 
  • As discussed in this post, methionine restriction results in increased calorie intake per kg-BW, a 2 °F increase in body temperature, and a dramatic increase in UCP1 activity in BAT. As we know, methionine restriction results in multiple health benefits and  increases lifespan. Again several steps (MR → ↑ BAT activity → ↑ longevity), but suggestive of the role BAT plays in health & longevity, independent of its impact on obesity and despite it requiring consumption of more calories to support.
 
Regarding your statement that there is no interventional evidence for BAT's benefits in people not attributable to obesity-avoidance:
  • PMID: 24954193 (discussed here) found insulin sensitivity improved in parallel with BAT level in healthy male volunteers as a result of cold exposure, in a cross-over design where they served as their own controls.
  • While not interventional, in this post, I discuss PMID 26795284 which found in 4000 human subjects, "BAT activity negatively correlated with arterial inflammation (r=-0.178, p<0.01), a relationship that persisted after correcting for age and BMI (r=-0.147, p<0.01). ... high BAT was associated with a reduced risk of CVD events (P = 0.048) even after correcting for age (P = 0.037)."

 

Finally, you say:

...we have extensive evidence that CR in rodents retards aging and extends maximum lifespan,

 

Michael, you and I both know that the (sad) elephant in the room is that CR didn't extend lifespan in the species we care much more about, rhesus monkeys, beyond its effects on obesity avoidance. Perhaps it was because the monkeys were housed at thermal neutrality, as discussed here...

 

If CR works in cold-housed rodents but not in warm-housed rodents or warm-housed monkeys, doesn't that suggest something about what it might take for CR to work in people?

 

--Dean

 

--------

[1]   J Biol Chem. 2011 Apr 15;286(15):12983-90. doi: 10.1074/jbc.M110.215889. Epub

2011 Feb 13.
 
Thermogenic activation induces FGF21 expression and release in brown adipose
tissue.
 
Hondares E(1), Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya 
F.
 
Author information: 
(1)Department of Biochemistry and Molecular Biology and Institute of Biomedicine,
University of Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición,
08028 Barcelona, Catalonia, Spain. hondareselayne@ub.edu
 
 
FGF21 is a novel metabolic regulator involved in the control of glucose
homeostasis, insulin sensitivity, and ketogenesis. The liver has been considered 
the main site of production and release of FGF21 into the blood. Here, we show
that, after thermogenic activation, brown adipose tissue becomes a source of
systemic FGF21. This is due to a powerful cAMP-mediated pathway of regulation of 
FGF21 gene transcription. Norepinephrine, acting via β-adrenergic, cAMP-mediated,
mechanisms and subsequent activation of protein kinase A and p38 MAPK, induces
FGF21 gene transcription and also FGF21 release in brown adipocytes. ATF2 binding
to the FGF21 gene promoter mediates cAMP-dependent induction of FGF21 gene
transcription. FGF21 release by brown fat in vivo was assessed directly by
analyzing arteriovenous differences in FGF21 concentration across interscapular
brown fat, in combination with blood flow to brown adipose tissue and assessment 
of FGF21 half-life. This analysis demonstrates that exposure of rats to cold
induced a marked release of FGF21 by brown fat in vivo, in association with a
reduction in systemic FGF21 half-life. The present findings lead to the
recognition of a novel pathway of regulation the FGF21 gene and an endocrine role
of brown fat, as a source of FGF21 that may be especially relevant in conditions 
of activation of thermogenic activity.
 
PMCID: PMC3075644
PMID: 21317437

Share this post


Link to post
Share on other sites
I could not find the below paper in PubMed, but it sure gave me the sense that messing with mouse thermoregulation is not a good model of the human condition.  We do not get torpor.

 

I too will chose comfort.

 

 


"BAT weight also increased in mice exposed to

extremely warm temperatures of 35 and 37.5 degrees C, environments

that are well above the limits of normothermy for mice and must

have certainly been stressful.'


 

 

Journal of Thermal Biology Volume 37, Issue 8, December 2012, Pages 654–685

Review

Thermal physiology of laboratory mice: Defining thermoneutrality

C.J. Gordon


 

Abstract

 

In terms of total number of publications, the laboratory mouse (Mus musculus) has emerged as the most popular test subject in biomedical research. Mice are used as models to study obesity, diabetes, CNS diseases and variety of other pathologies. Mice are classified as homeotherms and regulate their core temperature over a relatively wide range of ambient temperatures. However, researchers find that the thermoregulatory system of mice is easily affected by drugs, chemicals, and a variety of pathological conditions, effects that can be exacerbated by changes in ambient temperature. To this end, a thorough review of the thermal physiology of mice, including their sensitivity and regulatory limits to changes in ambient temperature is the primary focus of this review. Specifically, the zone of thermoneutrality for metabolic rate and how it corresponds to that for growth, reproduction, development, thermal comfort, and many other variables is covered. A key point of the review is to show that behavioral thermoregulation of mice is geared to minimize energy expenditure. Their zone of thermal comfort is essentially wedged between the thresholds to increase heat production and heat loss; however, this zone is above the recommended guidelines for animal vivariums. Future work is needed to better understand the behavioral and autonomic thermoregulatory responses of this most popular test species.

 

Highlights

 

Laboratory mice have become the predominant test species in most disciplines of biomedicine.

 

Mice are housed at temperatures that subject them to moderate cold stress.

 

Their temperature and metabolisms stability is susceptible to a variety of drugs and pathological conditions.

 

This review focuses on the thermoneutral zone of laboratory mice.

 

The impact of temperature on growth, reproduction, organ development, and behavior is explored in detail.

 

Keywords

 

Ambient temperature; Metabolic rate; Evaporative water loss; Core temperature; Telemetry; Selected temperature; Huddling; Brown adipose tissue; Thermal conductance; Growth; Reproduction; Fever; Aging

 

"4.6. Torpor

 

Mice andseveralotherspeciesofrodentswillundergotorpor

when deprivedoffoodorplacedonacaloricallyrestricteddiet

(Koizumi etal.,1992; Swoap andGutilla,2009; Solymar etal.,

2010). Torporimpliesastateofinactivityandreducedrespon-

siveness tostimuli.Duringtorpormicedisplayastateof heterothermy,

definedasthepatternoftemperatureregulationwhere

core temperaturevariation,eithernycthemerallyorseasonally

(e.g., hibernation),exceedsthelimitsofhomeothermy(IUPS

Thermal Commission,2001).Comparedtotheratwhichunder-

goes amildreductioninbodytemperaturewithcaloricrestriction

or deprivation(forreview, Gordon, 1990), thecoretemperatureof

mice deprivedoffoodcanplummet,stabilizingatafewdegrees

above theprevailingambienttemperatureandremainatthat

level forseveralhours.Toexemplifytorporinmice,thetime

course ofcoretemperaturealongwithheartrateandmetabolic

rate intelemeteredfemaleC57BL/6Jmiceatanambienttem-

perature of19 1C isshown(Fig. 16A andB).Onecansee

precipitous fallsincoretemperature,heartrate,andmetabolic

rate after 6 hoffooddeprivation.Metabolicrateandheartrate

are reducedbyatleast75%oftheirnormallevelsandremain

stablized duringthetorporresponse.Interestingly,themice

recover spontaneouslyafter 16 hinspiteofthecontinuation

of fooddeprivation(fordetails,see Swoap andGutilla,2009).

The fallincoretemperatureduringtorporwilldependonthe

prevailing ambienttemperatureandthermalcharacteristicsof

the cage(e.g.,bedding,nestingmaterial,airmovement,etc.).For

example, thereductioninbloodpressureandheartrateoffasted

mice maintainedatthermoneutralityisnotnearlyasmarkedas

when theyarefastedat23 1C (Williams etal.,2002). Core

temperature offooddeprivedmicemaintainedat28 1C falls

to 341 after thefirstdayoffasting,recovers,andthenfallagain

to 29 1C aftertheseconddayoffasting(Kanizsai etal.,2009).

Torpor isconsideredtobeaprotectiveresponseinmice,

allowing fortheconservationofenergyreservesduringtimesof

food restrictions.Clearly,thereductionsinrestingmetabolicrate

during torporimprovethechancesofsurvivinglongboutswhen

food isunavailable(see Fig. 16A). Thispatternappearstobe

typical forfood-deprivedmice.Theabilitytoenterandrecover

from torporpresentsaremarkablechallengetothemouse’s

thermoregulatoryandcardiovascularsystemwhichisjustbegin-

ning tobeunderstood(Swoap andGutilla,2009).

 

It iswellknownthatcaloricrestrictioncanleadtoamarked

improvement inlifespaninrodentsandothermammals

(Turturro etal.,1999; Speakman andMitchell,2011). Theanti-

aging effectsofcaloricrestrictionhavebeenattributedinpartto

the reductionsinbodytemperaturewhich,inturn,reduce

metabolism andgenerationofoxygenradicals.Inadditiontoits

use inanti-agingstudies,caloricrestrictionisalsousedto

maintain miceandotherrodentsatafixedweightsothatthey

will performinanoperanttaskparadigmusingfoodasreinforce-

ment. Koizumi etal.(1992) monitored coretemperatureby

telemetry inmaleandfemaleB6micethatwerecalorically

restricted withdailyallotmentsoffoodthatessentiallymain-

tained bodyweightat20gcomparedto 40 gincontrolanimals.

The 24hbodytemperatureofthecaloricallyrestrictedmicewas

reduced dramaticallybythistreatment(Fig. 17A). Forexample,

control micemaintaintheircoretemperaturebetween35–39 1C,

24 hperday,whereascaloricallyrestrictedmicemaintainedtheir

temperature inthis35–39 1C rangeforonly12h/dayandarange

of 23–27 1C for3–6h/day.Inastudyfromthesamelaboratory,

6 montholdmicethathadbeenrearedonadietthatwas 60%

of theadlibfedanimalshadabodyweightthatwas58%ofthead

lib group.Whenfedatthestartofdarkcycle,coretemperature

was similarbetweengroupsbutthenplummetedatthemidpoint

of thedarkphaseandrecoveredslowlyduringtheday(Fig. 17B).

It isinterestingtonotethatthistreatmentwasassociatedwith

significant prolongationinlifespanandmarkedsuppressionin

the mitoticindexofcellsintheintestine,indicatingareductionin

cell turnover.Interestingly,thetorpidresponsewasessentially

blocked whenmicewerehousedatathermoneutraltemperature

of 30 1C althoughthemitoticindexhadnotcompletelyrecovered

by thisthermoneutraltreatment(Koizumi etal.,1992).

 

4.6.1. Torpor-cautionwhenusingfastingmiceforcalorimeter

studies

 

An overnightfastisatypicalprotocolforthemeasurementof

the basalmetabolicrateinclinicalstudies;however,such

procedures shouldbeappliedwithcautioninstudiesofsmall

mammals thathaveevolvedatorpormechanismtosurvive

periods oflimitedornofood.Inviewofthetorporresponsewith

such briefperiodsoffooddeprivation,onemustquestionessen-

tially anystudywheremicearefastedforproceduressuch

as bloodcollection,determinationofmetabolicrate,etc.Ifa

significant reductionincoretemperatureandmetabolicrateis

observed in6hthenthereislikelyapatternofphysiolo-

gical responseleadinguptothisevent.Thedecreaseinbody

temperature willdependontheprevailingambientconditionsas

well asthemicroenvironmentofthecage(e.g.,housingcondi-

tions ofvivariumlistedin Table 2). Alltogether,anymeasurement

of aparameterdirectlylinkedtometabolismsuchasblood

glucose inafastedmouseshouldbedonewhiletakingthese

factors intoconsideration.Asdiscussedearlier,theclassicstudy

by Herrington (1940) utilized micethatwerefooddeprivedforup

to 12hbytheendofthemetabolicmeasurements.Whiletheir

metabolic dataappeartoreflecttypicalvaluesformice,one

should questionhowthemetabolicprofilemaybeinfluenced

by thedurationoffooddeprivation.Ifthemicearehandledand

manipulated duringthemetabolictests,metabolicrateandbody

temperature probablyremainatnormallevelsbutthishas

apparently notbeenevaluated."

 

"Whenthemouse’s

thermal environmentdeviatesaboveorbelowtheidealzoneof

thermal comfortandmetabolicthermoneutrality,thereisgreater

stress onotherorgansandregulatorysystemsnotdirectlylinked

to thermoregulation.Thecriticalquestionis,‘‘howdoesthe

thermoneutral zoneformetabolicheatproduction,coretempera-

ture, andzoneofthermalpreferencecorrespondwiththeoptimal

temperature zonesfororgangrowthanddevelopment?

 

7.1. Brown adipose tissue

 

Brown adiposetissue(BAT)wouldappeartobeanorganthat

has evolvedprimarilyasasourceofheatgenerationforthermo-

regulation inrodentsandotherspecies.BATisanessentialorgan

for nonshiveringthermogenesisinmice,rats,andmanyother

species. Heldmaier(1974)demonstratedtherelationship

between ambienttemperatureandweightofBATwithapattern

that isakintoathermoneutralzone(Fig. 27). Albinoand

genetically hairlessmicewereadaptedtoeachtemperaturefor

four weeks.Itisimportanttonotethatthemicewerehoused

individually onawirescreenfloorwithnobedding.Thus,itis

difficult tocomparethesedatatothatofmicehousedinatypical

environment ofavivarium.Eliminatinganybeddingfornest

building allowedtheauthortostudythesoleeffectsoftempera-

ture acclimationonBATdevelopment.TheweightofBAT

increased inanearlinearfashionastemperaturedecreasedbelow

30 1C. Interestingly,BATweightalsoincreasedinmiceexposedto

extremely warmtemperaturesof35and37.5 1C, environments

that arewellabovethelimitsofnormothermyformiceandmust

have certainlybeenstressful.Itwasnotedthathistologically,the

BAT inwarmadaptedmicedifferedmarkedlyfromcoldaccli-

mated mice.BATofcoldexposedmicewashighlydevelopedand

multilocular. BATofthewarmacclimatedmicewasunilocular,

looking morelikewhiteadiposetissue.ItisalsoclearthatBAT

hypertrophy isexacerbatedinhairlessmiceexposedtothecolder

temperatures butthereislittledifferenceinBATweightat

temperatures of21 1C andgreater.Morerecently, Zhao etal.

(2010) found aneardoublingintheweightofBATinmaleSwiss

mice housedindividuallywithsawdustshavingsastheirexpo-

sure temperaturewasreducedfrom23to15to8toO 1C intwo

week intervals.Thiswasassociatedwithsignificantelevationsin

serum T3 levels andreductionsin T4."

 

"11.1. Conclusion: Mice are unique thermoregulators

 

Thermal physiologists strive to study the many facets of

thermoregulation of species with a rich variety of morphological

adaptations. Volumes have been written about animals with

unique thermoregulatory characteristics, such as arctic and tropical

mammals that have remarkable tolerances to extremely

high or low ambient or body temperatures. Likewise, evolution,

natural history, and selective breeding are all attributes that make

the mouse a unique thermoregulator. Researchers that use mice

as a human surrogate are certainly aware of the many caveats

that limit extrapolation from mouse to human. Mice are not

miniaturized versions of rats or humans in terms of their

thermoregulatory system despite the fact that their average core

temperatures differ by just 1 1C. We should consider the mouse as

a unique thermoregulator with its small size, narrow thermoneutral

zone, preference for comparatively warm ambient temperatures,

and ability to allow core temperature to vary widely

in some environments or regulate in others. This is especially true

in the use of mice and other rodents to study human metabolic

syndrome, as discussed in recent excellent reviews by Overton

(2010) and Cannon and Nedergaard ( 2011). In view of the recent

growth in the use of mice as test organism for most biomedical

disciplines, we need to have a better understanding of their

thermoregulatory characteristics."

Edited by AlPater

Share this post


Link to post
Share on other sites

Thanks Al.

 

You quoted from the paper that warm temperatures increased BAT too:

 

"BAT weight also increased in mice exposed to
extremely warm temperatures of 35 and 37.5 degrees C, environments
that are well above the limits of normothermy for mice and must
have certainly been stressful."
 
What you left out was the next sentence, which showed the warm-induced BAT looked more like regular (white) fat and quite different from cold-induced BAT:
 
It was noted that histologically, the
BAT in warm adapted mice differed markedly from cold acclimated
mice. BAT of cold exposed mice was highly developed and
multilocular. BAT of the warm acclimated mice was unilocular,
looking more like white adipose tissue.
 

So it doesn't look like warm-exposure results in the same kind of BAT as cold-exposure after all.

 

--Dean

Share this post


Link to post
Share on other sites

For any non-wimps out there who are willing to entertain the idea of cold exposure, a couple new studies out this week may be of interest.

 

First off, [1] measured BAT and BAT-activity in men who were either Young & Lean (age ~25m, BMI ~22), Young & Obese (age ~25, BMI ~32), or Old & Lean (avg age ~54, BMI ~23).

 

They found the old-lean subjects (like us!) had less BAT-activity (left) and BAT-volume (right) than young-lean or young-obese. Here are the graphs:

 

H0vsZxT.png

 

Notice in particular the entire old-lean group had virtually zero BAT volume (right graph). Visually, you can see the BAT volume for typical members of the three groups is pretty strikingly different:

 

v8kx5GP.png''

 

The Young Obese (right) had less BAT than the Young Lean (middle), but the real dramatic difference is between the Old Lean (left) and the other two groups.  And the skinniest dude in the Old Lean group had a BMI of 21.7!

 

Given how much leaner most serious CRers are than any of the men in the Old Lean group in this study, and given that most CRers report having trouble with thermoregulation (i.e. feeling cold and having low body temperature), it seems likely most of us have virtually no BAT, unless we take steps to actively promote it...

 

Fortunately, the second study out this week [2] might suggest an answer for how to do just that. It found the combination of mild cold exposure & capsaicin worked synergistically to promote the conversion of white adipose tissue (WAT) into BAT-like 'beige' adipose tissue in mice.

 

First, on the issue of 'brown' vs. 'beige' adipose tissue, this paper observes that 'beige' adipose tissue in people appears to be the human-equivalent of 'brown' adipose tissue in rodents:

 

Rodents and humans possess two distinct forms of UCP1-positive thermogenic
adipocytes: classical brown adipocytes and beige adipocytes (also referred to as brite
adipocytes). While classical brown adipocytes and beige adipocytes share many functional
characteristics (i.e., thermogenesis), they are distinct cell types at developmental, anatomical,
and molecular levels. Classical brown adipocytes are prenatally derived from a subset of
dermomyotom, whereas beige/brite adipocytes postnatally emerge within white adipose tissue
(WAT) in response to a certain environmental cues, such as chronic cold exposure, exercise,...
 
Of note, it has been shown that molecular signatures of adult human BAT resemble mouse beige
adipocytes (12, 14-17)... Furthermore, chronic cold exposure up to 6 weeks was able to recruit
new active BAT depots in adult humans who did not possess appreciable levels of BAT depots
before cold exposure (18-20). Importantly, an emergence of the newly recruited BAT was
associated with an increase in cold-stimulated energy expenditure or with improved post-
prandial insulin sensitivity. These studies suggest that adult human BAT is largely composed of
the recruitable form of thermogenic adipocytes, that is, beige adipocytes. Hence, understanding
molecular circuits that preferentially promote beige adipocyte biogenesis may provide a new
opportunity of anti-obesity therapies for obese or old subjects who do not possess active BAT
depots. 

 

So that's interesting. 

 

But onto what the study found. They fed mice a high fat diet, and divided them into three housing temperature groups (cool-housed 17°C, regular temperature (RT)-housed 23°C, or neutral-temperature-housed 30°C) and two capsaicin groups, depending on whether they got capsaicin (CSNs+) or not (CSNs-). So that makes six different groups. Here are the body weights of the six groups over time. 

 

dO7BVZG.png

 

First off - notice at the thermoneutral housing temperature of 30°C (right graph), capsaicin did not impact body weight. In fact the capsaicin group weight slightly more by the end of the study than the control (CSN-) group. They ignore this thermal neutral 30 °C group throughout the rest of the analysis, which is unfortunate. But this alone suggests that capsaicin only boosts BAT when coupled with cold exposure. 

 

Perhaps the most interesting thing is that the combination of cold exposure and capsaicin (CE+Cap) had a bigger impact than the sum of the two treatments when applied individually - i.e. the two treatments were synergistic. That can be seen in the graph above on the left, and is called out in the paper as follows:

 

Strikingly, the anti-obesity effect by capsinoids was significantly enhanced under mild cold at
17°C (Fig. 1A). This anti-obesity effect by the combination of capsinoids and mild cold
exposure was synergistic because capsinoids supplementation under 17°C led to a 31%
suppression of diet-induced body weight gain compared to control mice, whereas capsinoids or
mild cold exposure alone reduced body weight gain by 14% and 12%, respectively. The synergy
is statistically significant based on the analysis by interaction plot (P=0.03). This synergistic anti-
obesity effect was independent of changes in energy intake and behavior because no major
difference was observed in food intake and locomotor activity between vehicle and capsinoids
treated groups both at ambient and cold temperature (Fig. S1A and B).

 

Check out the highlighted text at the bottom. The CE+Cap group gained 31% less weight, without a significant difference in food intake or physical activity.

 

And it wasn't just weight that CE+Cap dramatically and synergistically impacted. Here is a graph of fasting glucose (left), fasting insulin (middle) and BAT-thermogenesis-induced oxygen consumption (right). As you can see, the CE+Cap group (i.e. CSNs+ @ 17 °C) had a lot lower fasting glucose and insulin, and a lot more oxygen consumption resulting from BAT stimulation.

 

kzCfRJC.png

 

The authors of [2] go on to suggest that cold exposure and capsaicin may increase BAT development via two distinct, rather complicated neural pathways, illustrated here:

 

DVKEAP3.png

 

 

Interestingly, study [3] found that in people, six weeks of mild cold exposure (17 °C for 2h/d) or six weeks of capsaicin supplementation (9mg capsinoids / day), tested independently, both resulted in about a 200kcal/day boost in cold-induced thermogenesis (CIT), as can be seen in the graphs below:

 

4lnsdHY.png

 

Note what [3] found was not that capsaicin increased energy expenditure in general. Capsaicin increased energy expenditure in response to cold exposure (i.e. cold-induced thermogenesis, or CIT). So here again, it was cold exposure plus capsaicin that had the effect. 

If [2] translates from mice to people, than the combination of chronic cold exposure and capsaicin may even be enough to boost BAT in us skinny old CRers.

 

Recall, as Michael pointed out in this post, this study [4] found daily chilli pepper consumption was associated with a 14% reduction in all-cause mortality.

 

I already eat a modest amount of chilli powder and fresh chilli peppers, but I've gone ahead and ordered this capsaicin supplement to really test the idea of combining cold exposure and capsaicin.

 

--Dean 

 

------------

[1] J Nucl Med. 2016 Mar;57(3):372-7. doi: 10.2967/jnumed.115.165829. Epub 2015 Nov

25.
 
Differences in Sympathetic Nervous Stimulation of Brown Adipose Tissue Between
the Young and Old, and the Lean and Obese.
 
Bahler L(1), Verberne HJ(2), Admiraal WM(3), Stok WJ(4), Soeters MR(5), Hoekstra 
JB(3), Holleman F(3).
 
 
Brown adipose tissue (BAT) could facilitate weight loss by increasing energy
expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through
the sympathetic nervous system (SNS). Older or overweight individuals have less
metabolic BAT activity than the lean and young, but the role of the SNS in this
decline is unknown. We aimed to determine whether this lower metabolic BAT
activity in older or overweight individuals can be explained by a lower SNS
response to cold.METHODS: This was a prospective observational study. We included
10 young obese, 11 old lean, and 14 young lean healthy men. All subjects
underwent (18)F-FDG PET/CT and (123)I-meta-iodobenzylguanidine ((123)I-mIBG)
SPECT/CT after an overnight fast and 2 h of cold exposure. Metabolic BAT activity
was expressed as volume and as SUVmax of (18)F-FDG. BAT SNS activity was
expressed as volume and as the ratio between (123)I-mIBG uptake in BAT and a
reference region (SQUVmax of (123)I-mIBG).
RESULTS: SUVmax, BAT volume, and SQUVmax were significantly different between
young and old (SUVmax, 7.9 [range, 4.2-17.3] vs. 2.9 [range, 0.0-4.0]; volume,
124.8 [range, 10.9-338.8] vs. 3.4 [range, 0.0-10.9]; and SQUVmax, 2.7 [range,
1.9-4.7] vs. 0.0 [range, 0.0-2.2], respectively) (all P < 0.01) but not between
lean and obese (SUVmax, 7.9 [range, 4.2-17.3] vs. 4.0 [range, 0.0-13.5] [P =
0.69]; volume, 124.8 [range, 10.9-338.8] vs. 11.8 [range, 0.0-190.2] [P = 0.64]; 
and SQUVmax, 2.7 [range, 1.9-4.7] vs. 1.7 [range, 0-3.5] [P = 0.69],
respectively). We found a strong positive correlation between BAT activity
measured with (18)F-FDG and (123)I-mIBG in the whole group of BAT-positive
subjects (ρ = 0.82, P < 0.01).
CONCLUSION: Both sympathetic drive and BAT activity are lower in older but not in
obese men.
 
PMID: 26609175

 

---------

[2] Diabetes. 2016 Mar 2. pii: db150662. [Epub ahead of print]

 
A synergistic anti-obesity effect by a combination of capsinoids and cold
temperature through promoting beige adipocyte biogenesis.
 
Ohyama K(1), Nogusa Y(2), Shinoda K(3), Suzuki K(2), Bannai M(4), Kajimura S(5).
 
 
Beige adipocytes emerge postnatally within the white adipose tissue (WAT) in
response to certain environmental cues, such as chronic cold exposure. Because of
its highly recruitable nature and relevance to adult humans, beige adipocytes
have gained much attention as an attractive cellular target for anti-obesity
therapy. However, molecular circuits that preferentially promote beige adipocyte 
biogenesis remain poorly understood. Here, we report that a combination of mild
cold exposure at 17°C and capsinoids, a non-pungent analog of capsaicin,
synergistically and preferentially promotes beige adipocyte biogenesis and
ameliorate diet-induced obesity. Gain- and loss-of-function studies show that the
combination of capsinoids and cold exposure synergistically promotes beige
adipocyte development through the β2-adrenoceptor signaling pathway. This
synergistic effect on beige adipocyte biogenesis occurs through an increased
half-life of PRDM16, a dominant transcriptional regulator of brown/beige
adipocyte development. Our observations document a previously unappreciated
molecular circuit that controls beige adipocyte biogenesis and suggest a
plausible approach to increase whole body energy expenditure by combining dietary
components and environmental cues.
 
PMID: 26936964
 
------------
[3] J Clin Invest. 2013 Aug;123(8):3404-8. doi: 10.1172/JCI67803. Epub 2013 Jul 15.
 
Recruited brown adipose tissue as an antiobesity agent in humans.
 
Yoneshiro T(1), Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T,
Saito M.
 
Author information: 
(1)Department of Anatomy, Hokkaido University Graduate School of Medicine,
Sapporo, Japan. yoneshiro@med.hokudai.ac.jp
 
 
Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to 
cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron
emission tomography and computed tomography, we previously reported that BAT
decreases with age and thereby accelerates age-related accumulation of body fat
in humans. Thus, the recruitment of BAT may be effective for body fat reduction. 
In this study, we examined the effects of repeated stimulation by cold and
capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT 
activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure
(EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity
independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 
weeks resulted in a parallel increase in BAT activity and CIT and a concomitant
decrease in body fat mass. Changes in BAT activity and body fat mass were
negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks
increased CIT. These results demonstrate that human BAT can be recruited even in 
individuals with decreased BAT activity, thereby contributing to body fat
reduction.
 
PMCID: PMC3726164
PMID: 23867622
 
---------
[4] BMJ. 2015 Aug 4;351:h3942. doi: 10.1136/bmj.h3942. 
 
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. 
 
 
PubMed PMID: 26242395;
PubMed Central PMCID: PMC4525189.

Share this post


Link to post
Share on other sites

All,

 

In this post I discussed study [1], which found that cold exposure not only increases BAT in mice so they can burn more calories to stay warm, but it also shifts their gut microbiome and microvilli of their intestine in a way that makes them more efficient at extracting calories from food to support the extra calories required for thermogenesis. Surprisingly, doing a "microbiota transplant" (i.e. poop transplant) from cold adapted mice to warm-housed mice caused them to develop more brown/beige adipose tissue, increase their thermogenesis, improved their insulin sensitivity, and increased their gut's calorie extracting efficiency too.

 

Al Paper pointed me to a new commentary [2] in the New England Journal of Medicine about the significance of [1]. It has a few interesting (and potentially relevant for us) details I'd overlooked. First off, here is the graphical abstract of [1] that is included in [2], showing in pictures the results I described in words above:

 

VG8ueC9.png

 

Here is a quote about the main results of [1]:

 

 This new work shows that prolonged cold exposure induces a massive increase in the
absorptive surface of the gut, in association with reduced apoptosis of the cells making up its
microvilli. Once again, this effect could be achieved simply by transplanting cold-adapted
gut microbiota to germ-free hosts. 

 

What I hadn't noticed when I read [1] originally were the details of the gut bacteria changes that happened as a result of cold exposure, described as following in [2]:

 

Which specific components of the microbiota mediate this effect? The authors show that cold
causes a profound increase in the ratio of Firmicutes to Bacteroidetes, as well as almost a 
complete loss of Verrucomicrobia species, including Akkermansia muciniphila; such changes have
been noted previously in mouse models of obesity and are associated with increased energy
extraction from food.3 When A. muciniphila was added back to the cold-adapted flora, the
effect of cold on increased gut absorption was blocked.

 

Why is this result particularly noteworthy? Because there are species of gut bacteria that uBiome.com measures - so (and several of us) have personal data on this over time and in comparison with others. In particular, I had a uBiome test done in November of 2013, and then two (a couple weeks apart) in late October and early November of last year - which nicely controls for seasonal variations. 

 

As I discussed in this post, I appear to have 2x more Firmicutes relative to Bacteroidetes in my latest tests, and be enriched in Firmicutes relative to the general population. Between 2013 and 2015, my firmicutes went up from 62% of my total bacteria to a two-test average of 74% of my total bacteria. Regarding the other type of bacteria explicitly mentioned, the Verrucomicrobia species, and in particular Akkermansia muciniphila - in 2013 Verrucomicrobia accounted for 1.11% of my bacteria, which was about half the 2.07% of the typical person in uBiome's database. As of 2015, my Verrucomicrobia level had dropped to a two-test average of 0.38%, which is only about 1/5th the level a typical person. 

 

Both of these shifts (i.e. an ↑ in Firmicutes and ↓ in Verrucomicrobia) are in the same direction as the cold-exposed mice. Interestingly, as of the date of those two 2015 tests, I wasn't yet intentionally engaged in my cold exposure experiments. It will be interesting to see if/when I get my next round of uBiome tests whether I've shifted even further in the direction of the cold-adapted gut microbiome.

 

Regarding calorie extraction efficiency as a result of cold exposure. Over the last several months that I've been doing intentional cold exposure, I've gained three pounds (115 → 118 lbs, BMI 17.2 → 17.7), despite not obviously or intentionally eating more calories. But I I don't weigh and track all my food these days, so I can't rule out extra calories as the cause of the modest weight gain.

 

Does anyone else, cold-adapted or not, have uBiome data on Firmicutes and Verrucomicrobia they'd be willing to share? Zeta, I know you've had a uBiome test. Care to share (if you're feeling better, I hope)?

 

--Dean

 

 

-------------
[1] Cell. 2015 Dec 3;163(6):1360-74. doi: 10.1016/j.cell.2015.11.004.
 
Gut Microbiota Orchestrates Energy Homeostasis during Cold.
 
Chevalier C, Stojanovic O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, Rigo D, Fabbiano S, Stevanovic A, Hagemann S, Montet X, Seimbille Y, Zamboni N, Hapfelmeier S, Trajkovski M.
 
 
Highlights
 
Cold exposure leads to marked changes in the gut microbiota composition
 
Cold microbiota transplantation increases insulin sensitivity and WAT browning
 
Cold exposure or cold transplantation increase the gut size and absorptive capacity
 
Reconstitution of cold-suppressed A. muciniphila reverts the increased caloric uptake
 
Abstract
 
Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Transplantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promoting the white fat browning, leading to increased energy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is transferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis-the effect diminished by co-transplanting the most cold-downregulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand.
 
PMID: 26638070
 
-------------
[2] N Engl J Med 2016; 374:885-887 March 3, 2016 DOI: 10.1056/NEJMcibr1515457
 
Burning Fat by Bugging the System
 
Evan D. Rosen, M.D., Ph.D.
 

Share this post


Link to post
Share on other sites

Cool Fat Burner Review

 

All,

 

I've had my Cool Fat Burner (CFB) system for about a week and have been using it consistently so I figured it was time to do a review. First, I want to give a shout out to Eric, the person behind the CFB. From all the great videos of experiments he's done on himself, he's definitely a man after my own heart! Plus, after I ordered my CFB, I emailed him a link to this thread, and he was kind enough to send me a 4-pack set of soft cool packs, to add to the 12 solid "hybrid hardcore" packs I ordered with the Combo System I purchased ( $158, but $185 w/ tax & shipping) . Each of them weights about 625g, so all 16 add up to 10kg, or 22lbs of cooling packs. That's a lot of cool!

 

The first thing I did was an experiment to compare the two different types of cooling packs with a regular ice pack from my freezer, and with a block of ice, in terms of how long it took them to warm up. Here is a picture of the setup, with all four cold packs on a table in my 60 °F basement:

 

3FQmN4z.png

 

 

The block of ice is on the lower right (frozen in a plastic container), the regular cold pack is in the upper left (labelled 'Ultra'). The solid "hybrid hardcore" CFB pack is the white one on the lower left, and the flexible "soft" CFB pack is the blue one in the upper right. The orange thing is the non-contact thermometer I used to measure temperature (at the middle spot of each pack) every 20 minutes during the experiment, as measured by the timer shown in the lower right.

 

Here is a graph of the temperatures of the three packs and the block of ice during the six hours after I took them out of the freezer:

 

e7ONTOE.png

 

As you can see, at the time of the first 20 minute reading, the two CFB packs were significantly colder than regular cold pack and the block of ice. I was very surprised by this, so I measured all four of them multiple times and the difference persisted. In fact, for almost 4 hours the two CFB packs remained colder than either the block of ice or the regular cold pack. You'll also notice that at around 1.5 hours, the CFB soft pack (purple line) started warming up somewhat faster than the solid pack (blue line). Keep in mind though these were sitting out on a table in a cold room, so they stayed colder longer than they would if pressed against a warm human body.

 

Overall, I was very impressed with how well the CFB packs kept their cool. In fact, I may even consider using them to keep my food cold next time I travel! The solid "hybrid hardcore" packs stay cold longer than the flexible pack, but the flexible packs have the advantage of conforming to your body right away (see below). So it might be worthwhile to get some of each.

 

Now the review of the CFB system itself. As I indicated above, I bought the Combo Package, which included the original "Cool Fat Burner" (CFB) and the "Cool Gut Buster" (CGB). Here is the picture of the two from the CFB website:

 

combo-25-per-off-265x240.jpg

 

 

I bought both in size "medium" which seems a perfect fit for my 5'9", slim frame. As you can see from the picture, the CFB wraps over your shoulders, putting 4 cold-packs on your upper chest, neck and upper back area, where much of the brown adipose tissue in people is located. The CGB has straps that go over the shoulders and hangs down around your abdomen, below the level covered by the CFB. Together they cover my entire torse completely, as shown in the pictures below. The medium size CGB has pockets for 6 cold-packs. So when I'm wearing the CFB and CGB together (as shown below), that's a total of 10 packs, or almost 14 lbs of ice packs. It's really quite intense, even for me, whose been engaged in cold exposure for a while now. Here are a few pictures of me in full regalia:

 

Ucd0DSM.png  HgbYhUp.png  vIYSRWv.png

 

The third photo, with hat and gloves, is how I typically dress while using the CFB/CGB, to keep my head and hands warm as Eric recommends. The white patches you see around my neck area and towards the bottom in the middle image is frost on the outside of the vests from the cold packs underneath. As I said, it's pretty intense... As you can see, I'm wearing a t-shirt between the CFB/CGB and my skin. I haven't yet got up the courage to try wearing them without a shirt, like Eric does. That would really be intense.

 

Other than the intense cold (which I find exhilarating!), the CFB and CGB are quite comfortable to wear. They can be made quite loose or quite snug, depending on how you adjust the velcro straps, and this can be used to adjust the intensity of the cooling experience.

 

Regarding which packs to use for which pockets. I've found the six pockets of the CGB can be filled with the solid packs, since at least on me, they hang pretty straight down, i.e. don't have to conform to a curved belly. For the four pockets of the CFB, I've found putting the soft, flexible packs in the two pockets on the back works best. That way they conform to the two bones that stick out in the upper back, and allow me to comfortably lean back against the seat of my stationary bike right away, which I pedal leisurely to keep from getting too cold while wearing the CFB/CGB. I find putting two of the solid packs in the front pockets of the CFB works well, especially if I freeze them with a slight curve so they conform to my chest.

 

Regarding how long the packs stay cold when in use. I've been wearing the gear now for about 2 hours while composing this message and doing other stuff on the computer. The cold is still intense. Looking down, I still see the frost on the outside of the CFB on my chest as shown in the images above. So the cold lasts for a long time, at least in my basement man-cave, which is 62°F this afternoon.

 

How's it feel? Cold! In shorts and a t-shirt, but with the hat and gloves on, and with leisurely pedalling on my stationary bike, I can keep from shivering. But I've got a serious case of the goosebumps and the hairs on my arms and legs are really standing on end! 

 

Overall, I highly recommend the CFB/CGB for anyone who wants to experiment with cold exposure. If you want to save money and can do without the highest intensity cooling experience, you could go with just the CFB, rather than both the CFB/CGB combination. But I think you'll definitely want to get an extra set of 4 cold packs on top of the 4 that come with it. I'd probably recommend a set of 4 solid ones and a set of 4 soft ones. That way you can have two of each type in the CFB while the other two sets of two are charging in the freezer for uninterrupted cooling!

 

In short, if anything can promote and activate BAT in older, thin people like us, it will be the CFB/CGB. But if you are new to cold exposure, I definitely recommend taking it slow, working your way up to sending several hours wearing the gear, and keeping your hands, feet and head warm.

 

--Dean

Share this post


Link to post
Share on other sites

Thanks for the great review plus the other study info.  The CFB is FAR colder (and heavier) than the cooling vest I've been using.  I'm tempted to buy one for comparison purposes, but am also thinking it might be over the top and if I wanted that much cold why not just use some standard blue liquid gel cooling packs. The vest I have produces a very comfortable temp even against bare skin, and is very light weight -- probably more "palatable" for an average person although you'll probably get more BAT growth with the more extreme vest.  Would REALLY love to see some actual data on that though.

 

Regarding the study with capsaicin, observing a synergistic effect with cold exposure...  The study mentioned supplementation with 9mg capsinoids / day.  Any idea what that translates into as far as either common supplement forms or hot pepper form?  Note this one seems like a good deal, 250 caps, 500mg of 40,000 heat unit pepper.  The review comments are hilarious, I also noted some comments about the glucose lowering effect.  

 

I have also upped my hot pepper consumption, but may do even more now.

 

Edited by Gordo

Share this post


Link to post
Share on other sites

Gordo,

 

I agree. The CFB is pretty hardcore. A lot less stylish and "user friendly" than the TechKewl vest you bought, but probably also more likely to stimulate BAT synthesis and activation. Today was my weekly venture from my neighborhood to grocery shop at Aldi's and to stock up on durian at the Asian Market. It was still cool outside (~50 °F) and I had the windows open in the car, but I also decided to wear the CFB for extra cooling in the car. It worked well. But I took it off before going in the store(s). In contrast, It looks like you could easily wear the TechKewl vest around town, especially if you wear a shirt over it. 

 

Regarding the potency of the capsaicin capsules necessary to promote BAT activation. The Nature's Way "Cayenne 40,000 H.U." supplements I ordered came today. Haven't tried them yet - I'm waiting until I eat tomorrow morning. On the bottle it says "450mg cayenne pepper" per capsule, and in the text it says "guaranteed 0.25% capsaicin". So each capsule would have a little over 1 mg of capsaicin. Recall in study [1], the researchers gave subject 9mg of capsinoids/day. The capsinoids are a proprietary blend derived from a special cultivar of sweet peppers (CH-19 variety), that aren't very pungent, but that supposedly have a lot of capsaicin-like compounds that activate the sympathetic nervous system in the same way / degree as capsaicin, without the 'burn'. From the full text of [2] by the same authors as [1] (and the developers of this special capsinoid-rich CH-19 pepper, sold in capsule form in the US only by one company and not direct to consumer, but only through "healthcare professionals" - i.e. potential conflict of interest...) :

 

Capsinoids (capsiate, dihydrocapsiate, and nordihydrocapsiate) are capsaicin-like compounds found in a nonpungent type of red pepper, “CH-19 Sweet” (8, 9). Although capsinoids are much less pungent than capsaicin, they are as potent as capsaicin at increasing sympathetic nerve activity, thermogenesis, EE, and fat oxidation and in reducing body fat both in small rodents and humans (10–16).

 

So if the CH-19 sweet capsinoids are as potent as capsaicin as indicated, it would take around 8 of the capsaicin capsules per day to equal the three capsules of CH-19 Sweet capsinoids used in [1] and [2]. It's not clear how much the CH-19 Sweet capsules cost. According to this 2007 press release from the company:

 

The company says it is positioning the product for consumers who are truly dedicated to losing weight, and as such willing to spend more for Capsiate Natura. While Naulty [company president] said the pricing will be determined by individual health professionals, the daily dosage of three gelcaps should cost between $5 and $10 per day. 

 

Forgive me, but that's just ludicrous. The 180 capsaicin capsules I bought cost $10. So the 8 capsules / day required to get 9mg of capsaicin would cost less than $0.45 per day. Don't worry, I'm not going to try to get to that level. I'm going to start with one capsaicin capsule per day.

 

--Dean

 

--------

J Clin Invest. 2013 Aug;123(8):3404-8. doi: 10.1172/JCI67803. Epub 2013 Jul 15.
 
Recruited brown adipose tissue as an antiobesity agent in humans.
 
Yoneshiro T(1), Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T,
Saito M.
 
Author information: 
(1)Department of Anatomy, Hokkaido University Graduate School of Medicine,
Sapporo, Japan. yoneshiro@med.hokudai.ac.jp
 
 
Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to 
cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron
emission tomography and computed tomography, we previously reported that BAT
decreases with age and thereby accelerates age-related accumulation of body fat
in humans. Thus, the recruitment of BAT may be effective for body fat reduction. 
In this study, we examined the effects of repeated stimulation by cold and
capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT 
activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure
(EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity
independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 
weeks resulted in a parallel increase in BAT activity and CIT and a concomitant
decrease in body fat mass. Changes in BAT activity and body fat mass were
negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks
increased CIT. These results demonstrate that human BAT can be recruited even in 
individuals with decreased BAT activity, thereby contributing to body fat
reduction.
 
PMCID: PMC3726164
PMID: 23867622
 
-------------
[2] 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.
 
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
design.
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
000006073.
 
PMID: 22378725
 

Share this post


Link to post
Share on other sites

Hi Dean,

 

Yeah, certainly cogent points — but in the end, not a chain of reasoning on which I think much stock can be laid. I've followed this thread with substantial interest, and haven't wanted to weigh in too firmly because to do so would require some weed botany for which I regret to say I haven't been able to find the time. But let me (finally ...) explain my reasons for being very skeptical of two of the main kinds of data on which the argument is based. I'm going to take this slightly out of your original order for clarity:

 

 

...we have extensive evidence that CR in rodents retards aging and extends maximum lifespan

shouldn't you really say "we have extensive evidence that CR in rodents retards aging and extends maximum lifespan when rodents are exposed to cold conditions"?

 

... PMID 9032756 yoked the weights of two groups of CR mice together so as to be identical, and kept one at thermal-neutrality (86°F) and the other at a "normal" (i.e. chilly-for-rodent) temperature of 72°F. It was only the chilly CR mice that lived longer than controls. In fact, despite eating fewer calories than the chilly CR mice (and a heck of a lot less than AL-fed controls), the thermally-neutral CR mice didn't live any longer on average than AL-fed controls. This would seem to suggest cold exposure is a critical component of the "CR magic", despite requiring animals to eat more calories.

 

I broadly speaking agree with what you say here, except that I think you have probably been led to greatly exaggerate in your mind as to just how "chilly" the mice kept at normal room temperature were. Your argument rests on the argument in (1) below (and op cit in this thread) that mice at room temperature (20-22°C) are really substantially chilly critters, whereas humans in clothing at room temperature are close to thermoneutrality, and therefore (you very reasonably deduce) more like the 30°C warm-housed animals in PMID 9032756 which got drastically-reduced anticancer benefits and no increase in median lifespan (tho' you neglect to highlight, as you did in an earlier post, the fact that while the first half of the survival curve of the warm-housed CR animals is almost isomorphic with that of the controls, there remains a substantial albeit reduced effect on max LS, evident in a quite sudden and dramatic break point in the survival curve at around 850 days. This is a critical distinction: the implication is a blunting of some of the specific health benefits of CR in the warm-housed mice (in this case, evidently, a blunting of protection against tumorigenesis), while still preserving much of the effect on aging per se).

 

However, the core premise behind this line of argument does not seem to be on strong footing, and indeed seems (to my admittedly somewhat superficial (for lack of time) reading) to be mistaken.

 

(2) takes on the argument in (1) directly:

 

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. ...

 

The thermoneutral zone is the region where basal energy expenditure generates more than enough heat to balance heat losses due to the difference between ambient (Ta) and body temperatures (Tb). At the lower margin of this region (called the lower critical temperature or Tlc) heat requirements to maintain Tb and basal metabolic rate are exactly matched. At higher temperatures basal metabolic rate provides too much heat [MR emphasis] and this needs to be dissipated. Generally this is achieved by elevating evaporative water loss. At some upper critical temperature (Tuc) however other mechanisms need to be recruited and these paradoxically require an elevation of metabolism. Below Tlc metabolic rates must be higher than basal levels to balance heat loss, hence metabolic rate increases linearly as temperature declines and the gradient of this relationship reflects the degree of external insulation. ...

 

The thermoregulatory curve for naked humans has a lower critical temperature averaging about 28 °C ... Light clothing such as would typically be worn indoors consisting of a long sleeved shirt or blouse (Clo=0.2) and light trousers (Clo=0.25) provide together 0.45 Clo units of insulation [54]. The effect of such clothing would be to lower the lower critical temperature by 5.1 °C ... [to] a lower critical temperature of 22.9 °C.

 

Humans, however, seldom operate at basal metabolic rate. Studies using doubly labelled water show that routinely our energy expenditure is about 1.6–1.8× basal requirements. If we lived at our lower critical temperature defined from basal metabolism, we would be under continuous mild heat stress, so we normally seek out cooler temperatures than thermoneutral, where our routine heat production is balanced by a thermal gradient that generates an equivalent heat loss. This is why buildings are regulated at 19–21 °C (about 3 °C below the lower critical temperature) rather than within the thermoneutral zone (which for a lightly clothed individual is 23–27 °C). ...

 

Mouse Tlc 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.

The mice in PMID 9032756 were singly-housed at 20–22°C; the paper does not discuss bedding arrangements, but the use of bedding (usually softwood shavings) in government and academic animal housing protocols is routine (though not dictated by animal welfare guidelines).

 

It seems clear, therefore, that the mice housed at 30°C in PMID 9032756 are really rather toasty, and those at room temperature are only very modestly cooler-housed than a human in normal room temperatures. This merits CR folk bearing a certain amount of temperature discomfort, but doesn't imply that the benefits are abolished if we aren't either exposed to the autumn elements naked or wearing ice vests. And again: even 30°C housing didn't abolish the benefits of CR, and very few humans with modestly healthy lifestyles and good access to medical care die before the population median life expectancy.

 

If you wish to do a deep dive into this particular subject, and the arguments in (1), you will have a fine opportunity to discuss them at the Ninth Conference of the Calorie Restriction Society International, which I am pleased to know that you are attending: the renowned Dr. John Speakman, author of numerous provocative studies on CR and related subjects and the lead author of (1), will be one of our many exciting scientific presenters.

 

 

On the other hand, despite [its] depleting effects on BAT, we have extensive evidence that CR in rodents retards aging and extends maximum lifespan

Regarding CR's "depleting effects on BAT" as reported in PMID 18593277. In the quote you include, I point to the discussion of that study in this post. If you look at that discussion, you'll see that Valle et al did indeed see lower amounts of BAT in CRed rodents. But they also found the BAT the CR rodents did retain was much more active i.e. had a much higher expression of UPC1 as a result of mitochondrial biogenesis. The authors conclude (my emphasis):

 

As happens in liver or skeletal muscle, CR was also shown to promote mitochondrial biogenesis in BAT. On the whole, this conservation of BAT thermogenic capacity may confer several advantages, such as a higher ability to respond to cold exposure or to control body weight when food supply is restored, and, therefore, be part of the rejuvenation mechanisms underlying the life-span extension induced by CR.

 

Yeah. The problem with this is twofold. The first is unwittingly revealed by the authors' statement that "CR was also shown to promote mitochondrial biogenesis in BAT ... As happens in liver or skeletal muscle." The problem is that this finding, which is widely cited, is actually quite uncertain: most of the studies reporting this rely entirely on increased expression of genes involved in mitochondrial biogenesis (nitric oxide synthesis, TFAM, and above all PGC-1α); and the studies that actually count mitochondrial number are inconsistent, with most (even when they find confirm the increased expression of biogenesis-involved genes) finding no effect.(3) A substantial increase in mitochondrial numbers, activity, oxygen consumption, and possibly BAT-driven thermogenesis also seems to be in contradiction with the very well-established finding of a lack of effect of long-term CR on specific metabolic rate — ie, the amount of metabolic activity per unit metabolically-active mass.

 

So while I have no specific criticisms to level against the methods used or laboratory competence of Valle et al, I retain a substantial skepticism that mitochondrial biogenesis is actually occurring in these mice's BAT (or muscle or liver, which they don't of course report).

 

Regarding your statement that there is no interventional evidence for BAT's benefits in rodents not attributable to obesity-avoidance:

 

Obviously PMID 9032756 just discussed flat-out contradicts your assertion, since CRed mice housed at what for them is an uncomfortably cool temperature ate 20% more, weighted the same, and lived 40% longer on average than equivalently-skinny CRed mice housed at a comfortably temperature.

 

It doesn't really, both for the reason given and because there was no measurement of BAT quantity or activity in the PMID 9032756 study, let alone a linkage made to its effect on LS. That is, even if we agree (as I certainly do, and have advocated for many years as you know) that this study provides substantial reason to remain "uncomfortably cool" (albeit not to the extreme that the chain of reasoning you've been following suggests), there is no specific link being made to its effects on BAT, which (for reasons given) are unclear in CR rodents, as is their causal relationship to the anti-aging effects of CR or the role of cool temperatures in realizing its full benefits. (I will emphasize again that even at 30°C, the key effect on maximum lifespan, and the late effect on the survival curve, remains substantially intact).

 

Additionally, I just can't mechanistically see how increasing BAT quantity or activity would exert an effect on aging per se. When Valle et al say,

 

On the whole, this conservation of BAT thermogenic capacity may confer several advantages, such as a higher ability to respond to cold exposure or to control body weight when food supply is restored, and, therefore, be part of the rejuvenation mechanisms underlying the life-span extension induced by CR.

... that appears to me to be a complete, bald-faced non sequitur. What in the world does "a higher ability to respond to cold exposure or to control body weight when food supply is restored" have to do with "rejuvenation [sic!] mechanisms underlying the life-span extension induced by CR" ??

 

It's not an overwhelming counterpoint, but several studies find that overexpression of uncoupling proteins has no substantial effect on mean LS, and none at all on maximum — notably (4):

 

In the present investigation we describe the life span characteristics and phenotypic traits of ad libitum-fed mice that overexpress UCP2/3 (Positive-TG), their non-overexpressing littermates (Negative-TG), mice that do not expression [sic] UCP2 (UCP2KO) or UCP3 (UCP3KO), and wild-type C57BL/6J mice (WT-Control). We also included a group of C57BL/6J mice calorie-restricted to 70% of ad libitum-fed mice in order to test partially the hypothesis that UCPs contribute to the life extension properties of CR.

 

Mean survival was slightly, but significantly, greater in Positive-TG, than that observed in Negative-TG or WT-Control; mean life span did not significantly differ from that of the UCP3KO mice. Maximal life span did not differ among the ad libitum-fed groups. Genotype did not significantly affect body weight, food intake, or the type of pathology at time of death.

 

Calorie restriction increased significantly mean and maximal life span, and the expression of UCP2 and UCP3. The lack of difference in maximal life spans among the Positive-TG, Negative-TG, and UCP3KO suggests that UCP3 does not significantly affect longevity in mice.

By contrast, I can certainly see (as you have highlighted elsewhere) plenty of mechanisms whereby reduced body temperature — when not counteracted by overly-warm ambient temperature — could be responsible for the impairment of CR's effects on tumorigenesis in PMID 9032756, particularly since by far the greatest effect is on lymphomas: cancer is a disease of cell proliferation, and restricted energy by any means impairs cell proliferation (hence the modest effect of exercise against some cancers). It is notable in this regard that CR humans have typical signs thereof, consistent with the rodent model: very low WBC (particularly relevant for an effect on lymphomas); slow wound healing; slow-growing, weak or soft nails, etc.

 

This could also affect some of the other proliferative lesions that CR is known to retard, and as you've also noted, the sheer slowing of chemical reactions could even somewhat contribute to the anti-aging effect per se.

 

And, again, there is the health benefit of obesity-avoidance from the increased energy expenditure imposed by cool temperature, irrespective of the tissue-specific mechanisms thereof.

 

References

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

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

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

PMID: 25362635 Free Article

http://physiologyonline.physiology.org/content/29/6/413.long

 

2: Speakman JR, Keijer J. Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans. Mol Metab. 2012 Nov 8;2(1):5-9. doi: 10.1016/j.molmet.2012.10.002. Review. PubMed PMID: 24024125; PubMed Central PMCID: PMC3757658.

http://dx.doi.org/10.1016/j.molmet.2012.10.002

 

3: Gouspillou G, Hepple RT. Facts and controversies in our understanding of how caloric restriction impacts the mitochondrion. Exp Gerontol. 2013 Oct;48(10):1075-84. doi: 10.1016/j.exger.2013.03.004. Epub 2013 Mar 21. Review. PubMed PMID: 23523973.

https://www.researchgate.net/profile/Gilles_Gouspillou/publication/236075772_Facts_and_Controversies_in_Our_Understanding_of_How_Caloric_Restriction_Impacts_the_Mitochondrion/links/00b7d51a571e6a15be000000.pdf

 

4: McDonald RB, Walker KM, Warman DB, Griffey SM, Warden CH, Ramsey JJ, Horwitz BA. Characterization of survival and phenotype throughout the life span in UCP2/UCP3 genetically altered mice. Exp Gerontol. 2008 Dec;43(12):1061-8. doi: 10.1016/j.exger.2008.09.011. Epub 2008 Sep 27. PubMed PMID: 18854208.

Share this post


Link to post
Share on other sites

Thanks Michael,

 

i once got a Chinese fortune cookie, whose fortune was:

 

'THERE IS A TENDENCY TO CARRY ACTIVITIES TOO FAR'.

 

To me it seemed to me that the below paper has not yet been thrown into the fray and may contribute.

 

If it matters, mice were kept at 24°C.
 
In conclusion, UCP3 overexpression and/or its associated phenotypes appear to delay some aspects of the CR response. This finding of delayed adaptation in UCP3Tg mice raises the general question of how pharmacologic uncoupling would impact other adaptive responses. While uncoupling may be beneficial in some cases such as with the ability of muscle to adapt to a high fat diet, the present study suggests that the impact could be to delay adaptive changes to some challenges. In addition to the primary goal of our study, we also present strong evidence that short term CR, as with longer term CR, is not associated with an extensive remodelling of the mitochondria nor an increase in mitochondrial content in mouse skeletal muscle; thus, the remodelling reported to occur in other tissues does not reflect a fundamental response to CR in mice.
 
 
Exp Gerontol. 2012 May;47(5):361-71. doi: 10.1016/j.exger.2012.02.008. Epub 2012 Mar 3.
Calorie restriction in mice overexpressing UCP3: evidence that prior mitochondrial uncoupling alters response.
Estey C1, Seifert EL, Aguer C, Moffat C, Harper ME.
PMID: 22406134 [PubMed - indexed for MEDLINE] PMCID: PMC4203376 Free PMC Article
 
Abstract
 
Calorie restriction (CR) without malnutrition is the only intervention to consistently increase lifespan in all species tested, and lower age-related pathologies in mammals including humans. It has been suggested that uncoupling of mitochondrial oxidative phosphorylation, using chemical uncouplers, mimics CR, and that overlapping mechanisms underlie the phenotypic changes induced by uncoupling and CR. We aimed to critically assess this using a unique mouse model of skeletal muscle-targeted UCP3-induced uncoupling (UCP3Tg), and focused our studies mainly on skeletal muscle mitochondria. Compared to ad libitum fed Wt mice, skeletal muscle mitochondria from ad libitum fed UCP3Tg mice showed higher basal uncoupling and lower H(2)O(2) emission, with unchanged maximal oxidative phosphorylation, and mitochondrial content. UCP3Tg CR mice showed some tendency for differential adaptation to CR, with lowered H(+) leak conductance and evidence for higher H(2)O(2) emission from skeletal muscle mitochondria following 2 weeks CR, and failure to lower H(2)O(2) emission after 1 month CR. Differential adaptation was also apparent at the whole body level: while UCP3Tg CR mice lost as much weight as Wt CR mice, the proportion of muscle lost was higher in UCP3Tg mice. However, a striking outcome of our studies was the absence of change with CR in many of the parameters of mitochondrial function and content that we measured in mice of either genotype. Overall, our study raises the question of whether CR can consistently modify skeletal muscle mitochondria; alterations with CR may only be apparent under certain conditions such as during the 2 wk CR intervention in the UCP3Tg mice.

Share this post


Link to post
Share on other sites

All,

 

I'm in the process of putting together a big post in response to Michael's thoughtful contribution above. But in the meantime, I thought this study [1] pointed to by Al on the CR email list can serve as a useful addition to the list of BAT stimulators. It found that in mice, a diet supplemented with gluten reduces UCP1 expression in BAT, and promoted obesity despite no increase in energy intake. The obesogenic effect of gluten was particularly strong when the diet was high in fat.

 

I'll once again observe how uncanny it is that diet & lifestyle practices that are considered health-promoting, almost invariably seem to also promote BAT quantity and/or activity.

 

Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:
  • Cold exposure - by far the best BAT inducer/activator
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine (see below).
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Other foods - green tea, roasted coffee, cacao beans / chocolate
  • Avoiding gluten
  • Drugs - metformin, caffeine
  • Exercise
  • Fasting
  • Low protein diet
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]

 

----------

[1] Wheat gluten intake increases weight gain and adiposity associated with

reduced thermogenesis and energy expenditure in an animal model of obesity.
 
Freire RH, Fernandes LR, Silva RB, Coelho BS, de Ara?jo LP, Ribeiro LS,
Andrade JM, Lima PM, Ara?jo RS, Santos SH, Coimbra CC, Cardoso VN,
Alvarez-Leite JI.
Int J Obes (Lond). 2015 Oct 7. doi: 10.1038/ijo.2015.204. [Epub ahead of
print]
PMID: 26443339
 
Abstract
 
BACKGROUND/OBJECTIVES:
 
The association between gluten and body weight is inconsistent. Previously,
we showed that a gluten-free diet reduces weight gain without changing food
intake in mice fed high-fat diets. In the present study, we investigated the
effects of gluten intake on fat metabolism, thermogenesis and energy
expenditure in mice fed a standard or high-fat diet.
 
METHODS:
 
Mice were fed four different experimental diets during 8 weeks: a
control-standard diet (CD), a CD added with 4.5% of wheat gluten (CD-G), a
high-fat diet (HFD) and a HFD added with 4.5% of wheat gluten (HFD-G). After
8 weeks, the mice received 99mTc-radiolabeled gluten orally to study gluten
absorption and biodistribution or they underwent indirect calorimetry. After
killing, subcutaneous and brown adipose tissues (SAT and BAT) were collected
to assess thermogenesis-related protein expression. Lipid metabolism was
studied in adipocyte cultures from the four groups.
 
RESULTS:
 
Despite having had the same energy intake, CD-G and HFD-G mice exhibited
increased body weight and fat deposits compared with their respective
controls. 99mTc-GLU or its peptides were detected in the blood, liver and
visceral adipose tissue, suggesting that gluten can even reach
extraintestinal organs. Uncoupling protein-1 expression was reduced in the
BAT of HFD-G and in the SAT of CD-G and HFD-G mice. Indirect calorimetry
showed lower oxygen volume consumption in CD-G and HFD-G groups compared
with their controls. In HFD mice, daily energy expenditure was reduced with
gluten intake. Gluten also reduced adiponectin, peroxisome
proliferator-activated receptor (PPAR)-Alpha and PPARGamma and
hormone-sensitive lipase in cultures of isolated adipocytes from HFD mice,
whereas in the CD-G group, gluten intake increased interleukin-6 expression
and tended to increase that of tumor necrosis factor.
 
CONCLUSIONS:
 
Wheat gluten promotes weight gain in animals on both HFD and CD, partly by
reducing the thermogenic capacity of adipose tissues.

Share this post


Link to post
Share on other sites

 

Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans

Paul Lee, Ron Bova, Lynne Schofield, Wendy Bryant, William Dieckmann, Anthony Slattery, Matt A. Govendir, Louise Emmett, Jerry R. Greenfield

Cell Metabolism. Publication stage: In Press Corrected Proof

[No PMID yet]

 

Highlights
  • Brown fat utilizes glucose as substrate fuel to produce heat in humans
  • Human brown fat exhibits a thermogenic circadian rhythm
  • Brown fat circadian rhythm is glucose responsive
  • Low brown fat abundance is associated with greater glycaemic fluctuations
Summary

High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans [(Lee et al., 2010, Matsushita et al., 2014), stimulation of glucose uptake in hBAT by cold and insulin (Orava et al., 2011), and improvement of insulin sensitivity following hBAT recruitment (Chondronikola et al., 2014, Lee et al., 2014b)], leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. 

 

In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms. ...

 

gr1.jpg

 

During oral glucose tolerance test (OGTT), BAT temperature progressively increased and mean temperature was significantly greater than baseline after 60 min (E). Supraclavicular temperature response (gSTR)  [a surrogate for BAT activity] correlated positively with glucose-induced thermogenesis (GIT) (F). p < 0.05, ∗∗p < 0.01.

 

We explored this possibility [that the human BAT circadian rhythm might modulate systemic glucose homeostasis] by performing simultaneous continuous STR and subcutaneous glucose monitoring over a 12 hr period in 15 volunteers (27 ± 4 years old, 12 men, BMI 23 ± 3 kg/m2). They were stratified into three groups based on BAT activity and differed only by BAT status ... Among individuals with the highest BAT abundance (BAThigh), a negative correlation (R2 = 0.31, p < 0.0001) was detected between glucose and STR (Figure 3B), with STR leading glycaemic changes by three time periods (Figure 3D). In contrast, glucose correlated positively with STR (R2 = 0.10, p < 0.001) among individuals with low BAT abundance (BATlow) (Figure 3C), and glycaemic changes preceded STR evolution among these individuals (Figure 3F). No relationships were detected between STR or glucose excursions among volunteers devoid of any BAT (BATneg) (Figures S2A–S2D). BAT activity did not relate to maximal or mean glycaemia (Table S1) but correlated negatively with overall glycaemic variability (Figure 3E), which was greatest among BATneg individuals ...

 

gr3.jpg

 

Both BAThigh (B) and BATlow © individuals manifested significant cross-correlations between STR and glucose. (D) and (F) are cross-correlation plots between glucose excursion and STR. A positive lag indicates that the first series (i.e., glucose) leads the second series (i.e., STR), while a negative lag indicates that the first series (i.e., glucose) follows the second (i.e., STR). In this regard, STR tracked glucose excursions among BATlow volunteers as signified by weakly positive correlative coefficients (F). In contrast, STR led changes in glycaemia among BAThigh subjects, with strongly negative correlation coefficients (D). In other words, STR is a leading indicator among BAThigh individuals and predicts glucose level best three periods later. Total BAT activity correlated negatively with glucose variability (E).

 

Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes.

 

Share this post


Link to post
Share on other sites

Michael wrote:

Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans

Paul Lee, Ron Bova, Lynne Schofield, Wendy Bryant, William Dieckmann, Anthony Slattery, Matt A. Govendir, Louise Emmett, Jerry R. Greenfield

Cell Metabolism. Publication stage: In Press Corrected Proof

[Big cut-and-paste from full text of paper]

 

Thanks Michael, you beat me to it. But no commentary on your part to accompany it?  I was in the middle of incorporating this paper into my big post in reply to your earlier post, but I guess I'll address it here now rather than wait to include it in my big post. 

 

I was going to use this Lee et al paper [1],  in response to your previous comment:

 I just can't mechanistically see how increasing BAT quantity or activity would exert an effect on aging per se

 

First off, I'm never quite sure what you mean by "aging per se" (see this thread for discussion). But I'm going to assume you mean "accumulation of damage resulting from metabolic processes". By this definition it seems that [1] suggests just such a mechanism.

 

There is a lot going on in [1], and I'm still trying to digest it all, especially some of the biochemistry. But I'm going to do my best to highlight some of the most important stuff I got out of it.

 

First, the authors brough 15 relatively young (~27 years), mostly male (13/15),  healthy and relatively thin (BMI ~23) volunteers into their lab and measured their BAT volume and BAT activity in response to cold exposure. Not surprisingly, there was a lot of variation in the amount and activity of BAT across the subjects. They decided to divide them into three groups, BAThigh, BATlow  and BATneg, representing people with high, low and undetectable levels of BAT, respectively. Here is part of the table from the supplemental material (pdf) representing important measurements of the three groups. I've highlighted a few differences between them: 

Pv7iFLS.png

 

First off, notice from the very first line "Number (M/F)", that all three of the BATneg group are men, and despite there being only 2/15 women in the study, one of the women had BAT that was among the three highest in the study (the other women was in the middle group). This jibes with what others have observed, namely that women are more likely to have significant amounts of BAT than men.

 

Next, notice from the top two highlighted rows just how large the variation in BAT mass and BAT activity was between the three groups. The folks in the BAThigh group had 6.5x the BAT volume and 4x the BAT activity of the BATlow group. Not surprisingly, the BATneg group had no detectable BAT or BAT activity, by definition. 

 

You'll notice that none of the other regular anthropometric measures differed between the groups. What the authors mean by "Mean exposed environmental temperature", was the mean temperatures (presumably in °C) inside their clothes during the 'circadian' part of the study, during which they measured BAT activity, glucose and a few other things continuously for 12 hours. The fact that all three groups were near 31 °C for this measure means none were systematically exposed to more cold than the others during the testing.

 

Besides BAT volume and activity, the other two measurements that varied substantially between the groups were Glucose Induced Thermogenesis (GIT) and supraclavicular temperature response (STR, i.e. their measure of BAT activity) during the oral glucose tolerance test (OGTT) that is, the row labelled "%STR during OGTT". Basically, what these two rows show is that when the subjects were fed a big standardized bolus of glucose, the BAT tissue of those in the BATlow and especially the BAThigh group kicked in, increasing its metabolic rate, burning calories and warming up the body, especially in the area around the shoulder blades where BAT is most concentrated in humans. 

 

It is this responsiveness of BAT to glucose that seems to be at the heart of this study's results. In short, BAT kicks in around the time that glucose spikes. I think two of the graphs that best illustrate the significance of this responsiveness of BAT to glucose actually come from Figure S2 in the supplemental material:

 

iovdkC5.png

 

What you can see is that both as a groups (i.e. high, low and negative in the graph on the left), and on a per-individual basis (scatter plot on the right), there was a consistent decrease in "glucose variability" with increase in BAT activity. What do they mean by glucose variability? They basically measured BAT activity and blood glucose levels continuously for 12 hours in the 15 subjects (which spanned a dinner meal) and found those people with the most BAT had the smallest excursions from their mean glucose during that 12h period. Look at the guy (or gal?) with the most BAT activity in the lower right of the graph on the right. His glucose excursion was very small and he had a LOT of BAT activity. In contrast, the three people who had no BAT in the BATneg group (blue triangles against the vertical axis) had very large glucose excursions / variability.

 

I'll discuss the implications of this for health shortly. But first, one other, more subtle finding that seems worth mentioning. In the BATlow group (i.e. those with some, but not too much, BAT), they found that BAT kicked in (i.e. got warmer) shortly after blood glucose went up (e.g. shortly after a meal). This makes intuitive sense - when glucose levels go up after a meal, BAT-thermogenesis kicks in to burn calories and thereby use up and lower glucose. The authors suggest that in the BATlow group, BAT may be serving as a "glucose sink" - sucking up glucose when it's high to (modestly) reduce glucose excursions (and therefore glucose variability) relative to the BATneg group.

 

The really interesting thing is that in the BAThigh group, BAT activity was a leading indicator of glucose level, by about 15 minutes. And BAT activity was positively correlated with glucose level, but shifted 15 minutes earlier. In other words, 15 minutes before glucose went up, BAT activity tended to go up in the BAThigh group. Conversely, 15 minutes before glucose went down, BAT activity tended to go down in the  BAThigh group. It's as if the "superactive BAT" (the authors' phrase) in these BAThigh folks was anticipating the upcoming glucose variation, and responding appropriately to blunt the excursion (e.g. the BAT kicked in when glucose was about to spike). This is consistent with the dramatically lower glucose variability observed in the BAThigh group, although the authors can only speculate about what the mechanism for this effect might be:

 

Since BAT activity was more than doubled in these volunteers with ‘‘superactive BAT’’ compared to BATlow individuals, it is tempting to speculate an activity-dependent BAT threshold potentiating glucose-clearing dynamics. One cannot exclude the possibility that a yet-to-be-defined systemic signal mediates glycaemic changes in BAThigh individuals.

 

But whatever the mechanism by which BAT activity reduces glucose, the authors found that BAT kicks in around the time glucose spikes, and the more BAT subjects had, the lower their glucose variability - i.e. the smaller their glucose excursions. 

 

The reason this study is so interesting and important is that this reduction in glucose excursions is likely to be a very good think from a health / longevity perspective. As Michael has pointed out in the past (on the old email list), it is the large post-meal glucose spikes that are most damaging - i.e. that result in the the most glycation, which is a type of what the SENS folks call "extracellular cross linking", one of the seven forms of damage that characterizes aging per se, at least as far as I understand it.

 

In addition, large glucose spikes are often accompanied by large releases of insulin in an attempt to clear the glucose, leading to insulin resistance and other bad effects of elevated insulin. The large insulin spike often overcompensates, causing a large drop in glucose (i.e. hypoglycemia), i.e. a large glucose excursion in the negative direction. Big glucose excursions result in glycation, and so the amount of glycated hemoglobin (HbA1c) in the blood is a measure of long-term (~1month) average glucose control, and is a strong predictor of diabetes risk.

 

In short, smaller glucose excursions & variability is a good thing for health & longevity, and this study seems to show that having active BAT is a way to reduce glucose excursions & variability.

 

Which brings me to the second cool finding in this paper. If active BAT reduces glucose excursions, and glycated hemoglobin (HbA1c) is a long-term measure of glucose excursions, and BAT is activated by cold, might it be possible to see the impact of bat activity in a large population by looking for a correlation between HbA1c levels with seasonal temperature variations? In other words, if BAT activity helps with glucose control, than HbA1c levels should be lower in the winter, when people are exposed to colder temperatures and will therefore have more (active) BAT.

 

This is exactly what the authors found, as they describe in this passage:

 

So does BAT abundance affect glycaemia over time? Because BAT is known to be most abundant in winter (Saito et al., 2009), we probed this question by examining the relationship between glycaemia and outdoor temperature in 65,535 patients who had blood tests throughout a 1-year period. Environmental temperature correlated positively with glycated haemoglobin, a measurement of overall glucose control (Figure S3).

 

Here are the two relevant graphs from Figure S3:

 

WniF1xw.png

 

As you can see, although the mean temperature doesn't vary too much in Sidney (and their temperature minimum is in the middle of the year, when it's summer here in the northern hemisphere), there is a clear positive correlation between ambient temperature and glycated hemoglobin, as measured across a large population, as shown both visually in the graph on the left, and via the positively sloping best-fit curve relating temperature to HbA1c in the graph on the right. This is obviously not definitive - there could be other explanations for the positive correlation between ambient temperature and glycated hemoglobin than reduction in BAT activity when it's warmer.  But coupled with the other results from this study, it is a very intriguing possibility.

 

What I find most interesting though is the possible implications for human CR practitioners of the beneficial effects of increased BAT activity on glucose control. As some of you may recall, there was one distinct and troubling finding that came out of Luigi Fontana's testing of a bunch of us serious CR practitioners a few years ago. A sizeable fraction of us CRers (including me), showed terrible glucose control after an oral glucose tolerance test. And those who were the most severely CRed showed the worst ability to bring glucose levels down during the OGTT [2]. Here is the graph. I am the point highlighted by the orange circle :-( :

 

JcvbEPT.png

 

My (and our) insulin sensitivity was quite high - I (we) just couldn't seem to bring my (our) glucose down when given 75g (300kcal) of glucose in a quick dose. At the two-hour mark after drinking the glucose, my serum glucose was still at 199 mg/dL, as can be seen at the bottom of my blood test spreadsheet in the column labelled 11-19-02. 

 

In summary Luigi in [2] found that we hardcore CR folks had low fasting and circulating insulin, low IGF-1 and low testosterone levels, which are thought to all be good markers from a longevity perspective. But they (especially the low insulin) may have impaired our ability to deal with glucose, especially big doses of it. This has been a nagging concern for some of us ever since Luigi's study.

 

Now we may finally have an explanation, and a possible solution, for this impaired glucose tolerance in CRers.

 

It's very likely that we older, skinny, chilly but often cold-exposure-avoiding, male CR practitioners have zero BAT, like the BATneg group in [1] who had much higher glucose variability, apparently because they lack BAT to help blunt their glucose excursions. I recall quite distinctly I was very cold-sensitive at the time of the WUSTL testing, and therefore avoided cold by bundling up. In fact, I was quite cold in the metabolic ward they housed us in while at WUSTL despite it being normal room temperature, to the point where they had to bring in a warming box for my arm so they could draw my blood for the study (an incident which I recently recounted here).

 

Fast forward to today. I'm 5 lbs skinnier today than I was during the WUSTL OGTT test (118 vs. 123) and my most recent fasting insulin level was if anything lower that it was during my visit to WUSTL (1.6 vs. 1.8 uIU/ml), and of course I'm 14 years older (meaning I should have a lot less BAT). But I'm not longer a wimp about cold.

 

So how is my glucose control?

 

I haven't done an official OGTT test since that one at WUSTL, but for kicks I measured my glucose several times after my single, really big (~3400kcal) meal this morning. I started eating at 6am and finished at 8am. Fifteen minutes after the end of the meal, I measured by glucose twice in rapid succession - the readings were 126 and 121 mg/dL. I then went for a 1.5 mile run. It was 48 °F and lightly drizzling. I ran in shorts and no shirt. Quite invigorating. When I got back, after warming my hands up enough to extract a drop of blood, I measured my glucose. It was 30min after finishing my meal. My glucose was 105 mg/dL. Pretty darn good.

 

While it's not exactly an "apples to apples" comparison, my glucose control appears to be a heck of a lot better these days than it used to be. Can I be sure this is a result of my deliberate practice of cold exposure? Clearly not. But this study [1], along with Gordon's sundae experiments provide quite a bit of support for this being the explanation. In that post, Gordon also provides further evidence besides his own anecdotal evidence (via an ice cream sundae OGTT!) about the benefits for BAT on glucose control, referencing study [3]. Quoting from the abstract of [3]:

 

We studied 7 BAT positive (BAT+) men and 5 BAT negative (BAT-) men under thermoneutral conditions and after prolonged (5-8 h) cold exposure (CE). The two groups were similar in age, body mass index, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans and support the notion that BAT may function as an anti-diabetic tissue in humans.

 

Here is a very dramatic graph from the full text of the paper showing the increase in the rate of glucose clearance under cold conditions in BAT- and BAT+ subjects:

 

YveKrCP.png

 

That is a darn impressive improvement in glucose clearance for those who've got BAT!

 

In summary, multiple lines of evidence suggest that in humans, BAT helps one to kick butt in the glucose control department. The best and perhaps the only reliable way to build up BAT, particularly in skinny, old guys like us, is via cold exposure.

 

--Dean

 

--------------------------

[1] Cell Metabolism Available online 10 March 2016, In Press, Corrected Proof

doi:10.1016/j.cmet.2016.02.007

 
Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans
 
Paul Lee1, 2, 7, , , Ron Bova3, Lynne Schofield1, 2, Wendy Bryant5, William Dieckmann6, Anthony Slattery4, Matt A. Govendir1, Louise Emmett4, Jerry R. Greenfield1, 2, 5, 7
 
 
Highlights
• Brown fat utilizes glucose as substrate fuel to produce heat in humans
• Human brown fat exhibits a thermogenic circadian rhythm
• Brown fat circadian rhythm is glucose responsive
• Low brown fat abundance is associated with greater glycaemic fluctuations
 
Summary
 
High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes.
 

---------------

[2] Age (Dordr). 2010 Mar;32(1):97-108. doi: 10.1007/s11357-009-9118-z. Epub 2009 Nov

11.
 
Effects of long-term calorie restriction and endurance exercise on glucose
tolerance, insulin action, and adipokine production.
 
Fontana L(1), Klein S, Holloszy JO.
 
Author information: 
(1)Washington University School of Medicine, St. Louis, MO 63110, USA.
lfontana@dom.wustl.edu
 
 
Calorie restriction (CR) slows aging and is thought to improve insulin
sensitivity in laboratory animals. In contrast, decreased insulin signaling
and/or mild insulin resistance paradoxically extends maximal lifespan in various 
genetic animal models of longevity. Nothing is known regarding the long-term
effects of CR on glucose tolerance and insulin action in lean healthy humans. In 
this study we evaluated body composition, glucose, and insulin responses to an
oral glucose tolerance test and serum adipokines levels in 28 volunteers, who had
been eating a CR diet for an average of 6.9 +/- 5.5 years, (mean age 53.0 +/- 11 
years), in 28 age-, sex-, and body fat-matched endurance runners (EX), and 28
age- and sex-matched sedentary controls eating Western diets (WD). We found that 
the CR and EX volunteers were significantly leaner than the WD volunteers.
Insulin sensitivity, determined according to the HOMA-IR and the Matsuda and
DeFronzo insulin sensitivity indexes, was significantly higher in the CR and EX
groups than in the WD group (P = 0.001). Nonetheless, despite high serum
adiponectin and low inflammation, approximately 40% of CR individuals exhibited
an exaggerated hyperglycemic response to a glucose load. This impaired glucose
tolerance is associated with lower circulating levels of IGF-1, total
testosterone, and triiodothyronine, which are typical adaptations to
life-extending CR in rodents.
 
PMCID: PMC2829643
PMID: 19904628
 
---------------
[3] Diabetes. 2014 Dec;63(12):4089-99. doi: 10.2337/db14-0746. Epub 2014 Jul 23.
 
Brown adipose tissue improves whole-body glucose homeostasis and insulin
sensitivity in humans.
 
Chondronikola M(1), Volpi E(2), Børsheim E(3), Porter C(3), Annamalai P(4),
Enerbäck S(5), Lidell ME(5), Saraf MK(3), Labbe SM(6), Hurren NM(3), Yfanti C(7),
Chao T(8), Andersen CR(3), Cesani F(9), Hawkins H(10), Sidossis LS(11).
 
 
Abstract
Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic
tissue owing to its ability to dissipate energy as heat. Despite a plethora of
data concerning the role of BAT in glucose metabolism in rodents, the role of BAT
(if any) in glucose metabolism in humans remains unclear. To investigate whether 
BAT activation alters whole-body glucose homeostasis and insulin sensitivity in
humans, we studied seven BAT-positive (BAT(+)) men and five BAT-negative (BAT(-))
men under thermoneutral conditions and after prolonged (5-8 h) cold exposure
(CE). The two groups were similar in age, BMI, and adiposity. CE significantly
increased resting energy expenditure, whole-body glucose disposal, plasma glucose
oxidation, and insulin sensitivity in the BAT(+) group only. These results
demonstrate a physiologically significant role of BAT in whole-body energy
expenditure, glucose homeostasis, and insulin sensitivity in humans, and support 
the notion that BAT may function as an antidiabetic tissue in humans.
 
 
PMCID: PMC4238005
PMID: 25056438

Share this post


Link to post
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now

×