Cold Exposure & Other Mild Stressors for Increased Health & Longevity

[Kenton]

Daily Observable Mild CR Signs - hunger, lower temperature.

Daily Observable Mild CE Signs - chicken skin (close to, not necc w/shivering), tense areola and scrotal regions, cold hands/feet.

[Dean Pomerleau]

I just can't leave Kenton's reference to "tense areola & scrotal regions" as the newest post in this thread ☺. So just a quick post to get images of Kenton's naughty parts out of our minds.

 

Factoid of the day: I downloaded this thread in its entirety to make sure I have a backup copy in case (heaven forbid) these forums should ever go away... I was quite surprised to see that in the three months since it began, this thread had grown to the point that it would occupy 315 pages if printed out!

 

--Dean

[Kenton]

since you mention it, one can imagine i spent quite some time looking for words besides "hard nipples" and "shrunken sack," haha. btw, i am starting to feel thermogenesis (TG) kicking in. i'm about 10 days into mild CE. it is an empowering feeling and feels like a battery pack around my neck, upper backbone, and chest area above my armpits. it feels very good and comforting, exactly like an electric blanket. i do not feel any draining of energy or feeling of loss as my body "blows through" that energy (which I find curious).  WITH ACTIVE BAT, I THINK THE COLD IS NOT (AS) UNCOMFORTABLE. just as jumping into cold water after getting very hot from a Jacuzzi, sauna, mowing grass, or sports, feels good or even refreshing but feels terrible if one is already cold, entering into cold temps. with active BAT can feel okay as compared to not having active BAT. i've been experiencing TG on and off for the past three days, making me want to post the "CE Signs" on how I try to stay in the CE zone. I also have a few more signs - cramping lower legs/feet at night in the cold (expected and proving to be transitory, and yes i do get all my electrolytes) and less tossing, turning, and thinking in bed while sleeping per my FitBit (interpreted to mean that, frankly, my body may not want to move to cold parts of sheets, etc.), the thinking being less because my mind is preoccupied on staying warm (expected to be transitory as i acclimate).  btw, it's ironic that when i started CR i tried so hard to fight TG (even pre and post prandial TG) and tried so hard to gain adipose for insulation purposes so i would not have TG while surfing. (if i had known then what i think we know now i would have not worried about all that TG, but then it's the only way we could understand a person like me being able to cut energy intake). hmm, could it be that all the BAT creating TG i used to have from surfing (and just liking to be cold) may be coming back quicker now from some analogy of muscle memory.

[Kenton]

...In short, by dramatically attenuating Insulin / IGF-1 signalling, CR prevents ... but also shuts down important anabolic activities like synthesizing BAT, bone, immune, muscle and brain cells. This is why many thoughtful CR practitioners harbor some concerns about ... cognition. In fact, there have been endless discussions ... on concerns about bones, brains and/or brawn☺... As a result, the combination of CR + CE provides the anabolic bone, brain and immunity benefits of mTOR activity, without the downsides associated with elevated insulin and IGF-1.

 

CE appears to help you preserve your "you."

[Sthira]

Y'all really paid $160 for that thing? Ain't there a cheaper alternative? Or sew one together yourself?

[TomBAvoider]

To what degree is CE a factor in human longevity historically? From my understanding, the various "blue zones" of extraordinary human longevity seem to generally be in what one may term "temperate" climate zones. The Mediterranean region (including islands like Sardinia), Okinawa, Southern California, Costa Rica etc. do not seem to be regions where CE occurs naturally, compared to, say, Greenland, or Siberia etc. Furthermore, might it not be the case that in peoples who have historically occupied temperate/tropical climate zones, there would be less need for BAT? I have seen that graph comparing amounts of BAT between South Asians and Caucasians, wherein the Caucasians had generally larger BAT areas - stands to reason, if South Asians have less need for BAT on purely climactic grounds. I have not seen any data for people of African origin, wrt. BAT. But if say, people of predominantly Asian or African background have less BAT, does that mean they have a statistically smaller chance of achieving great longevity? Or greater longevity along the BAT pathway only? Is BAT - or more broadly CE - a primary factor in longevity at all? Fwiw, the longest-living male currently, at 112 years old, resides in Israel, and has done so since 1950 - I would surmise not a lot of opportunity for CE compared to Northern Europe, f.ex.

 

Bottom line, I wonder to what degree CE has a role in longevity - is it just one particular optional pathway, or is it a necessary factor such that a direct inhibitor (or opposite) of CE is actively deleterious, if, say, you reside in a habitually hot place year round (say, Central Africa), your chances of extreme longevity drop to zero absent air conditioning. Have there been equivalent experiments where we have CR'd rats with hot feet vs CR'd rats with cold feet - assuming we can extrapolate to humans?

[Kenton]

Sthira wrote: "Y'all really paid $160 for that thing ...." 

----

H*!l no - I don't have one but I DO have BAT.

Edited April 14, 2016 by Kenton

[Dean Pomerleau]

Sthira,

 

Y'all really paid $160 for that thing? Ain't there a cheaper alternative? Or sew one together yourself?

 

Yes, you can make one yourself. Judge for yourself the viability of the DIY route for a cooling vest.

 

Does that mean even you Sthira are seriously considering giving cold exposure a try? Now all we need to do is convince Al and Khurram ☺. I don't think Michael is paying attention either way ☹.

 

--Dean

[Sthira]

"Even you" Sthira, haha: Yes I'm totally considering it. I hate the cold, but ur arguments are great, I think. And if my body learns to adapt -- which might be fun and interesting -- then that'll add a new aspect to my already eccentric thing I've got going on. The price of the thing is what's keeping me down. Michael Rae? Who is Michael Rae? Does he ever write short, easy posts for dim-shits like me, or is it all about the every-word-and-sentence-carefully-slaved-over thing only?

[Dean Pomerleau]

Sthira,

 

Yes I'm totally considering it. I hate the cold, but ur arguments are great, I think.

 

Welcome aboard! Stay tuned for my next post which will provide yet more evidence for the benefits of CE...

 

Michael Rae? Who is Michael Rae? Does he ever write short, easy posts for dim-shits like me, or is it all about the every-word-and-sentence-carefully-slaved-over thing only? 

 

If your idea is to dump on Michael until he feels compelled to respond, count me in ☺.

 

My attempts to gently push his buttons, even trash talking on his precious DHA-Accelerated Aging Hypothesis thread, doesn't seem to be working...

 

--Dean

[Sthira]

Maybe we should steal his vitamix, tie him up in a hammock and shove McDonalds french fries in his nostrils until he looks up from magic and says hi. That is, every post need not be a life-changing all-encompassing three-week-perfectly-written hero's splash into this shit. The "science" is gonna all change anyway.

 

Aww fuck, I edit now to add Dean's prob gonna say this is OT and start another thread started by me, entitled like "where the fuck is Michael Rae?"

Edited April 10, 2016 by Sthira

[Dean Pomerleau]

Latitude & Longevity

 

Tom,

 

Thanks for joining these discussions! Your input will be greatly appreciated, including your great set of initial questions. To wit:

 

To what degree is CE a factor in human longevity historically? From my understanding, the various "blue zones" of extraordinary human longevity seem to generally be in what one may term "temperate" climate zones. The Mediterranean region (including islands like Sardinia), Okinawa, Southern California, Costa Rica etc. do not seem to be regions where CE occurs naturally, compared to, say, Greenland, or Siberia etc. Furthermore, might it not be the case that in peoples who have historically occupied temperate/tropical climate zones, there would be less need for BAT? I have seen that graph comparing amounts of BAT between South Asians and Caucasians, wherein the Caucasians had generally larger BAT areas - stands to reason, if South Asians have less need for BAT on purely climactic grounds. I have not seen any data for people of African origin, wrt. BAT. But if say, people of predominantly Asian or African background have less BAT, does that mean they have a statistically smaller chance of achieving great longevity? Or greater longevity along the BAT pathway only? Is BAT - or more broadly CE - a primary factor in longevity at all? Fwiw, the longest-living male currently, at 112 years old, resides in Israel, and has done so since 1950 - I would surmise not a lot of opportunity for CE compared to Northern Europe, f.ex.

 

Epidemiological studies in humans based on geography are notoriously difficult, given all the other aspects of diet & lifestyle, not to mention genetics, that vary dramatically among people from one region of the globe to another.

 

Much better data comes from studies of other species which vary less in both genetics, diet & lifestyle than humans, but that nonetheless span a wide range of latitudes. Which brings me to a study I've been meaning to post about for a couple months, but it's always been superseded by other more compelling and directly relevant topics in this thread. Now seems like the perfect opportunity to talk about this study [1], which analyzed data from both controlled laboratory experiments and free-living populations of many species that spanned a wide range of latitudes, to see how longevity within-species correlated with climate. Here is what they did and what they found:

 

We compiled data for 30 species under laboratory conditions and for 67 free-living species (1,081 populations). These data represent 4 phyla and 23 orders from around the globe. The dataset contained representatives from terrestrial, freshwater, and marine environments, and of widely different average longevities [minimum average lifespan 11.6 d (Acartia tonsa), maximum 190.0 yrs (Margaritifera margaritifera)]. Latitude and lifespan were positively correlated in 85% of the species, although the relationship was statistically significant in only 39% of the cases. It is worth noting that under a null model without a latitudinal gradient in lifespan, the chances of obtaining 85% positive slopes are exceedingly small (χ2 = 27.597, P < 0.0001). Moreover, for all species with significant regressions, lifespan increased with latitude. As discussed below, it appears that much of this latitudinal variation may be explained by temperature using the MTE.

 

To summarize, in species that span a wide range of latitudes, the within-species longevity is pretty strongly correlated with how far north (or south in the southern hemisphere) an individual lives. That is, cooler environments → increased lifespan across a huge range of land, freshwater and marine species.

 

Although less compelling because it wasn't an interventional study, the wide range of species which exhibited a longer lifespan in cold climates is suggestive, particularly when linked with the evidence discussed here that people's HbA1c improves in winter months.

 

I will address the second part of your thoughtful response in my next post, before moving on to the exciting new angle on the benefits of CE I promised Sthira...

 

--Dean

 

-----------

[1] Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13860-4. doi:

10.1073/pnas.0900300106. Epub 2009 Jul 30.

Latitudinal variation in lifespan within species is explained by the metabolic
theory of ecology.

Munch SB(1), Salinas S.

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728985/

Many ectotherms exhibit striking latitudinal gradients in lifespan. However, it
is unclear whether lifespan gradients in distantly related taxa share a common
mechanistic explanation. We compiled data on geographic variation in lifespan in
ectotherms from around the globe to determine how much of this intraspecific
variation in lifespan may be explained by temperature using the simple
predictions of the metabolic theory of ecology. We found that the metabolic
theory accurately predicts how lifespan varies with temperature within species in
a wide range of ectotherms in both controlled laboratory experiments and
free-living populations. After removing the effect of temperature, only a small
fraction of species showed significant trends with latitude. There was, however,
considerable residual intraspecific variation indicating that other, more local
factors are likely to be important in determining lifespan within species. These
findings suggest that, given predicted increases in global temperature, lifespan
of ectotherms may be substantially shortened in the future.

PMCID: PMC2728985
PMID: 19666552

[Dean Pomerleau]

Sthira,

 

Maybe we should steal his vitamix, tie him up in a hammock and shove McDonalds french fries in his nostrils ...

 

If he doesn't respond soon, maybe I'll try that when I see him at the upcoming conference ☺.

 

Aww fuck, I edit now to add Dean's prob gonna say this is OT and start another thread started by me, entitled like "where the fuck is Michael Rae?" 

 

Now there's an idea... No - don't worry Sthira, I learned my lesson last time I used (and edited) one of your posts to wantonly fork a new thread... I'm glad you seem to have forgiven me. ☺

 

--Dean

[Sthira]

I'll only forgive you if you buy me one of these stupid $160 cold torture vest things. I promise I'll wear it for a week (then lose it in a swamp somewhere)

[Dean Pomerleau]

Tom,

 

Have there been equivalent experiments where we have CR'd rats with hot feet vs CR'd rats with cold feet - assuming we can extrapolate to humans?

 

Another great question. The answer is an unequivocal YES!

 

In fact, just such a study forms the bedrock of this entire thread. It's a study by Koizumi & Walford (PMID: 9032756) first discussed here and here, and in greater detail & more recently here.

 

TL;DR - CR mice housed at a cool (i.e. normal lab) temperature weighed half as much as controls, ate 20% more calories than the weight-matched warm-housed (i.e. @ thermal neutrality) CR mice, and had a median lifespan of 1143 days, which was 40% longer than either the cool-housed AL-fed controls (778 days) or the warm-housed CR mice (810 days), which were statistically indistinguishable from each other.

 

--Dean

[TomBAvoider]

Interesting. Thank you, Dean. I was of course aware of the original "rats with cold feet" study as it was discussed way back when (btw. are the archives scheduled for a resurrection?). However, I did not examine it closely enough wrt. applicability to my own CR practice. I do wonder about one thing though - we know that CR initiated in later life - or more generally just initiated - needs to happen on a more gradual slope; my question is - is the practice of CE comparable? i.e. are there special considerations in initiating CE therapy at a more advanced age, and does it need to be eased into on a schedule of even years?

[Dean Pomerleau]

Tom,

 

Another good question about the optimal onset of CE. I think we know even less about that than we do about optimal CR onset. Interestingly, in virtually all the rodent CE studies, the protocol is extremely abrupt onset, and usually in young mice/rats. And most CR studies (even adult onset ones) keep rodents at chilly-for-rodents "normal" lab temperature all their lives, long before starting the CR protocol. I don't know of any data one way or the other about the impact of gradually easing into cold exposure relative to abrupt onset CE.

 

I do know for me anyway it's a lot more psychologically stressful to gradually wading into a cold pool relative to an abrupt plunge, but it can be a shock to the system!

 

--Dean

[Dean Pomerleau]

Sthira wrote:

Y'all really paid $160 for that thing? Ain't there a cheaper alternative? Or sew one together yourself?

For any newcomers to this thread, Sthira is referring to my deluxe Cool Fat Burner cooling vest, discussed in detail here.

 

For anyone interested in purchasing a cooling vest for less than the $160 dollars I paid for the deluxe model, the original model (just covering upper back, chest and shoulders) can be had for $86. It's what I've been using most of the time, although it's still cold here in Pennsylvania and I expect to start using the full system when it warms up.

 

Gordo has an alternative version from Techkewl, discussed in my post linked above.

 

--Dean

[TomBAvoider]

It does appear that CE is relatively less explored than CR. It looks as if BAT activation is the pathway here, but I wonder to what degree overall lowering of body temperature contributes - just being on CR we tend to have lower body temperature quite apart from CE - and we know that lower body temperature might tamp down on inflammatory processes. BAT activation is specific to trying to elevate body temperature, but perhaps only to prevent hypothermia. In the various cold rat studies, is there any measurement as to the body temperature of the CE'd rats vs CR'd rats? We do know that CE'd rats eat a bit more than CR'd rats, it would be fascinating if they were also hotter as a result of BAT activation! If so, that would be a double whammy of "opposite" effect compared to CR'd rats - more calories, and higher body temperature!

[Dean Pomerleau]

Tom,

 

It does appear that CE is relatively less explored than CR. It looks as if BAT activation is the pathway here, but I wonder to what degree overall lowering of body temperature contributes - just being on CR we tend to have lower body temperature quite apart from CE - and we know that lower body temperature might tamp down on inflammatory processes. BAT activation is specific to trying to elevate body temperature, but perhaps only to prevent hypothermia. In the various cold rat studies, is there any measurement as to the body temperature of the CE'd rats vs CR'd rats? We do know that CE'd rats eat a bit more than CR'd rats, it would be fascinating if they were also hotter as a result of BAT activation! If so, that would be a double whammy of "opposite" effect compared to CR'd rats - more calories, and higher body temperature!

 

Ah - the question of feeling (subjectively) cold vs. being (literally) cold vs. being in cold but being warm. The short answer is I don't think there is enough information to definitively say which of these is most important if CE is to improve health & longevity.

 

Here are a few important clues that we do know:

• CR w/o CE in rodents →   ↔ BAT, ↔ body temperature, ↔ longevity and ↔ cancer (Koizumi & Walford - PMID 9032756)
• CR w/  CE in rodents →    ↑ BAT,   ↓ body temperature,   ↑ longevity  and ↓ cancer

These results suggest CR + CE may be beneficial because of increased BAT and/or reduced body temperature, but can't really distinguish between which of the two are (most) important.

 

From this discussion we saw 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 very large amounts of BAT and BAT activity, on top of living a very long time for a rodent (i.e. 23 years for grey squirrel vs. ~4 years for rat). Two other very long-lived small mammals, bats (discussed here) and naked mole rats (discussed here) also have remarkably high levels of BAT tissue.

 

In contrast, 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" women (BMI 16.2) who were found to have BAT in abundance, along with a higher resting metabolic rate to support it:

 

 All [constitutionally lean] (100%), none of the [anorexics] and refed [anorexics] (0%), and 3 of the 24 [normal weight] (12%) subjects showed [measureable BAT activity].

 

So if we take either group of anorexics as proxies for CR folks (I know, not a great assumption, but it's what we've got...), it seems unlikely CR folks will have any BAT unless practicing intentional cold exposure, particularly since BAT is lower in men than women, and drops with age.

 

Elevated FGF-21 is associated with increased longevity in mice as discussed here. Human centenarians and their offspring exhibit naturally higher levels of FGF-21, as discussed here. Cold exposure (but not CR-alone) increases FGF-21 levels in rodents and people, but only in people who were cold-acclimated and therefore ready to not just maintain, but increase core body temperature in response to cold exposure, as discussed here. So once again we see that a potential  benefit of cold is only manifested in people who are cold-acclimated.

 

While not definitive, together this evidence suggests that cold-acclimation, and perhaps BAT activity specifically, is an important causal factor in the benefits of CE. Therefore simply being cold (low body temperature) or subjectively feeling cold probably aren't sufficient for, or even necessarily correlated with, CE benefits. In fact, if anything it appears the opposite may be the case - you need to be adapted to cold, and therefore not feel or be too cold in order to benefit from CE, and perhaps even to benefit from CR.

 

--Dean

[TomBAvoider]

Again, thank you Dean - this is exactly what I've been wondering about. I mean, I appreciate wanting to go on CE (or CR!), but I think there are a lot of questions to be answered first, which you have been doing with a lot of backup and citations, exactly as should be done :)!

 

This then tells me that when people are concerned about CE lowering their QOL (f.ex. Khurram), they are simply not adapted to it. If they were, QOL would not be a concern since they'd not feel subjectively cold, like those playful squirrels. Alternatively, maybe if they are unable to adapt, then maybe CE is not doing them any good, any more than those who suffer from anorexia. 

 

If that is so - i.e. people on CE experience no unpleasant sensation of coldness (if they are cold adapted) - then there is an interesting contrast with CR. Namely: the hunger hypothesis. I have been an early advocate of the hunger hypothesis - indeed, I believe it was I who introduced the idea - that the sensation of hunger is integral to a good portion of CR benefits. Incidentally, I'm more convinced than ever that this is true - and there are more and more papers coming out that highlight the vital role of ghrelin and neuropeptide-Y and other molecules in mediating many of the benefits. In any case, the contrast is - CR'd people should feel hungry, but CE'd people should not feel cold.

 

Which is a bit of relief otherwise it would have been too much of a joke - "if you want to live a long life, you must feel cold and hungry". We can modify that to: "feel hungry, but not feel cold" (but must expose yourself to cold) - complicated :)...

 

And that brings me to a survey question: do people here who practice CE feel subjectively cold in low temperatures? I am not talking about the specific times when they're intentionally getting "their rat feet cold" in order to activate BAT, but about being comfortable in low temperatures in general. From self-reports I've gleaned in this thread, it seems most people say that they keep the thermostat low (low 60's), and feel FINE, whereas their cohabitors (family, friends, workmates etc.) feel COLD during the same time - in other words, they're happy squirrels when they're not being rats with cold feet. Conclusion: they're getting CE bennies? This btw. is in an interesting contrast to the perennial office-home-bedroom battle of the sexes. Women traditionally try to move the thermostat up, and men try to move it down - I'm talking about Ad Lib people, not CR. At first glance it may seem to parallel the situation with CE - but that would imply that somehow the males of the species are activating BAT, even though they have less of it compared to women - highly unlikely. What I always thought when witnessing these battles, is that men simply eat more and are therefore burning food calories and feel hot, whereas women feel cold as they eat less - it is therefore due to excess calories and not BAT activation(?).

[Dean Pomerleau]

Tom and All,

 

One more piece of interesting and relevant information I just came across relating BAT volume and BAT activity to body temperature in humans, from [1]:

 

In our study, clavicular and subclavicular skin temperature did not correlate with BAT volume. This is likely explained by the fact that most of the clavicular BAT pool is located in the supraclavicular region ([23], and see Figure 1). Furthermore, core body temperature did not correlate with total BAT volume nor with total SUVmax. In mice, core body temperature is commonly used as a measure for BAT activity [17], and core body temperature may transiently rise by as much as 1.5°C following BAT activation. However, as is evident from the current study as well as from a previous study [12], in human subjects core body temperature does not rise following BAT activation due to cold exposure but rather stays equal, likely as a consequence of BAT activation preventing a drop in core body temperature. The lack of a rise in core body temperature could be due to the fact that the relative amount of BAT in humans is lower as compared to mice. Accordingly, in mice housed at 5°C nutrient oxidation in BAT can account for over 60% of the total energy expenditure [27], [28], as compared to 15–20% in humans [11], resulting in tremendous heat production and a subsequent rise in core body temperature. Thus, in humans, cold-induced core body temperature is likely no good measure of BAT volume.

 

Summary: Cold-acclimated rodents have more BAT relative to their body weight than humans. So while rodent body temperatures sometimes rise in response to cold, cold-acclimated people with active BAT are usually just able to maintain their body temperature in response to cold exposure, rather than raise it. But in cold-acclimated people, skin in the neck and upper back regions where BAT-deposits are located is measurably warmer.

 

This likely explains why those of us who are cold-acclimated don't feel subjectively as cold in response to a cold environment, and why we report feelings of warmth in our shoulders, upper chest and back after cold exposure.

 

--Dean

 

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

[1] PLoS One. 2014 Jun 12;9(6):e98822. doi: 10.1371/journal.pone.0098822. eCollection

2014.

 

Supraclavicular skin temperature as a measure of 18F-FDG uptake by BAT in human

subjects.

 

Boon MR(1), Bakker LE(1), van der Linden RA(2), Pereira Arias-Bouda L(3), Smit

F(3), Verberne HJ(4), van Marken Lichtenbelt WD(5), Jazet IM(1), Rensen PC(1).

 

Free full text: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098822

 

BACKGROUND: Brown adipose tissue (BAT) has emerged as a novel player in energy

homeostasis in humans and is considered a potential new target for combating

obesity and related diseases. The current 'gold standard' for quantification of

BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of

this technique is limited by cost and radiation exposure. Given the fact that BAT

is a thermogenic tissue, mainly located in the supraclavicular region, the aim of

the current study was to investigate whether cold-induced supraclavicular skin

temperature and core body temperature may be alternative markers of BAT

activation in humans.

SUBJECTS/METHODS: BAT volume and activity were measured in 24 healthy lean

adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake

with PET-CT. Core body temperature was measured continuously in the small

intestine with use of an ingestible telemetric capsule and skin temperature was

measured by eighteen wireless iButtons attached to the skin following ISO-defined

locations.

RESULTS: Proximal and distal (hand/feet) skin temperatures markedly decreased

upon cold exposure, while supraclavicular skin temperature significantly

increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced

supraclavicular skin temperature positively correlated with both total

(R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and

clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not.

CONCLUSIONS: Supraclavicular skin temperature as measured by iButtons may have

predictive value for BAT detection in adult humans. This is highly desirable

considering the increasing interest in pharmacological interventions to stimulate

BAT in human subjects.

TRIAL REGISTRATION: NTR 2473.

 

PMCID: PMC4055666

PMID: 24922545

[Dean Pomerleau]

Cold Exposure Boosts Beneficial AMPK

 

The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status. In response to a sensed energy deficit (i.e. cellular ADP > ATP), AMPK stimulates pathways which increase immediate energy production (glucose transport, fatty acid oxidation) and switches off other pathways (e.g. mTOR) which sequester energy via anabolic activities (lipogenesis, protein synthesis, gluconeogenesis). AMPK is upregulated by CR & fasting. It seems to serve as a master signalling pathway that shifts the body into "hunker down" mode by upregulating  maintenance & repair activities while downregulating growth-related activities. Experiments in mammals have demonstrated that AMPK boosts autophagy via downregulation of mTOR signaling, which augment the quality of cellular housekeeping. Many studies with lower organisms have revealed that increased AMPK activity can extend lifespan. AMPK declines with age, and this decline has many downsides summarized in this figure from [1]:

 

 

Exercise boosts AMPK in muscle cells. While AMPK doesn't help to build muscle mass, since it shuts down the mTOR pathway responsible for protein synthesis, but it does improves muscle repair after exercise via a combination of increased autophagy to clear out dysfunctional organelles, and by increasing mitochondrial biosynthesis [2][3[6][7]. In fact, due to its catabolic effects and downregulation of mTOR, long-term CR (at least without exercise) can impair cardiac function,and this impairment is worse in mutant mice that lack AMPK [4]. This review [5] is a good overview of how CR impacts the AMPK and mTOR pathways, which results in a "tradeoff between the survival and maintenance vs. growth, particularly in skeletal muscle where ... losses in skeletal muscle mass and function are observed with advancing age."

 

In short, AMPK is an signalling enzyme which appears critical for maximizing health and longevity, and for minimizing the negative effects of CR-induced catabolism of important tissues, like heart and other muscle tissue. 

 

In this post on the synergy of CR and CE, I used this diagram to illustrate that both CR and CE boost AMPK, suggesting further that CE does it via boosting adiponectin and SIRT1:

 

 

But if you look carefully you'll notice CE also activates PKA, which tends to inhibit AMPK - so the net effect of cold exposure on AMPK wasn't entirely clear. 

 

Fortunately, looking further into the effects of cold exposure on AMPK, it appears that CE does indeed increase AMPK activity (along with UCP-3) in skeletal muscles and as a result improves muscle glucose uptake independent of the Insulin/IGF-1/mTOR pathway [8]. Even more dramatic is CE's impact on AMPK levels in both brown and white adipose tissue. Study [9] found "AMPK activity in brown adipose tissue was higher than in any tissue yet reported (3-fold the level in liver)." Furthermore, chronic cold exposure (1-2 weeks) resulted in a 50-75% increase in AMPK in BAT over its already high baseline level, and a doubling of AMPK in WAT, as can be seen in the following graph from [9]:

 

 

 

In summary, it appears that cold exposure does indeed upregulate the level and/or activity of AMPK in skeletal muscles, as well as both brown and white adipose tissue - an important benefit of both CE and CR.

 

--Dean

 

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

[1]  Ageing Res Rev. 2012 Apr;11(2):230-41. doi: 10.1016/j.arr.2011.12.005. Epub 2011 

Dec 15.

 

AMP-activated protein kinase (AMPK) controls the aging process via an integrated 

signaling network.

 

Salminen A(1), Kaarniranta K.

 

Free full text: http://www.sciencedirect.com/science/article/pii/S1568163711000778

 

Efficient control of energy metabolic homeostasis, enhanced stress resistance,

and qualified cellular housekeeping are the hallmarks of improved healthspan and 

extended lifespan. AMPK signaling is involved in the regulation of all these

characteristics via an integrated signaling network. Many studies with lower

organisms have revealed that increased AMPK activity can extend the lifespan.

Experiments in mammals have demonstrated that AMPK controls autophagy through

mTOR and ULK1 signaling which augment the quality of cellular housekeeping.

Moreover, AMPK-induced stimulation of FoxO/DAF-16, Nrf2/SKN-1, and SIRT1

signaling pathways improves cellular stress resistance. Furthermore, inhibition

of NF-κB signaling by AMPK suppresses inflammatory responses. Emerging studies

indicate that the responsiveness of AMPK signaling clearly declines with aging.

The loss of sensitivity of AMPK activation to cellular stress impairs metabolic

regulation, increases oxidative stress and reduces autophagic clearance. These

age-related changes activate innate immunity defence, triggering a low-grade

inflammation and metabolic disorders. We will review in detail the signaling

pathways of this integrated network through which AMPK controls energy

metabolism, autophagic degradation and stress resistance and ultimately the aging

process.

 

Copyright © 2011 Elsevier B.V. All rights reserved.

 

PMID: 22186033

 

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

[2] Trends Endocrinol Metab. 2015 Jun;26(6):275-86. doi: 10.1016/j.tem.2015.02.009.

Epub 2015 Mar 26.

 

Expanding roles for AMPK in skeletal muscle plasticity.

 

Mounier R(1), Théret M(2), Lantier L(3), Foretz M(4), Viollet B(5).

 

Full text: https://sci-hub.io/10.1016/j.tem.2015.02.009

 

Skeletal muscle possesses a remarkable plasticity and responds to environmental

and physiological challenges by changing its phenotype in terms of size,

composition, and metabolic properties. Muscle fibers rapidly adapt to drastic

changes in energy demands during exercise through fine-tuning of the balance

between catabolic and anabolic processes. One major sensor of energy demand in

exercising muscle is AMP-activated protein kinase (AMPK). Recent advances have

shed new light on the relevance of AMPK both as a multitask gatekeeper and as an 

energy regulator in skeletal muscle. Here we summarize recent findings on the

function of AMPK in skeletal muscle adaptation to contraction and highlight its

role in the regulation of energy metabolism and the control of skeletal muscle

regeneration post-injury.

 

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

PMID: 25818360

 

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

[3] J Physiol. 2006 Jul 1;574(Pt 1):17-31. Epub 2006 May 11.

Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation
to exercise.

Jørgensen SB(1), Richter EA, Wojtaszewski JF.

Free full text; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1817795/

The 5'-AMP-activated protein kinase (AMPK) is a potent regulator of skeletal
muscle metabolism and gene expression. AMPK is activated both in response to in
vivo exercise and ex vivo contraction. AMPK is therefore believed to be an
important signalling molecule in regulating muscle metabolism during exercise as
well as in adaptation of skeletal muscle to exercise training. The first part of
this review is focused on different mechanisms regulating AMPK activity during
muscle work such as alterations in nucleotide concentrations, availability of
energy substrates and upstream AMPK kinases. We furthermore discuss the possible
role of AMPK as a master switch in skeletal muscle metabolism with the main focus
on AMPK in metabolic regulation during muscle work. Finally, AMPK has a well
established role in regulating expression of genes encoding various enzymes in
muscle, and this issue is discussed in relation to adaptation of skeletal muscle
to exercise training.

PMCID: PMC1817795
PMID: 16690705

 

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

[4] Biochim Biophys Acta. 2015 Feb;1852(2):332-42. doi: 10.1016/j.bbadis.2014.04.023.

Epub 2014 May 2.

 

Inhibition of AMPK accentuates prolonged caloric restriction-induced change in

cardiac contractile function through disruption of compensatory autophagy.

 

Zheng Q(1), Zhao K(2), Han X(3), Huff AF(4), Cui Q(2), Babcock SA(4), Yu S(2),

Zhang Y(5).

 

Free full text: http://www.sciencedirect.com/science/article/pii/S0925443914001100

 

Prolonged caloric restriction often results in alteration in heart geometry and

function although the underlying mechanism remains poorly defined. Autophagy, a

conserved pathway for bulk degradation of intracellular proteins and organelles, 

preserves energy and nutrient in the face of caloric insufficiency. This study

was designed to examine the role of AMPK in prolonged caloric restriction-induced

change in cardiac homeostasis and the underlying mechanism(s) involved with a

focus on autophagy. Wild-type (WT) and AMPK kinase dead (KD) mice were caloric

restricted (by 40%) for 30 weeks. Echocardiographic, cardiomyocyte contractile

and intracellular Ca²⁺ properties, autophagy and autophagy regulatory proteins

were evaluated. Caloric restriction compromised echocardiographic indices

(decreased ventricular mass, left ventricular diameters, and cardiac output),

cardiomyocyte contractile and intracellular Ca²⁺ properties associated with

upregulated autophagy (Beclin-1, Atg5 and LC3BII-to-LC3BI ratio), increased

autophagy adaptor protein p62, elevated phosphorylation of AMPK and TSC1/2,

depressed phosphorylation of mTOR and ULK1. Although AMPK inhibition did not

affect cardiac mechanical function, autophagy and autophagy signaling proteins,

it significantly accentuated caloric restriction-induced changes in myocardial

contractile function and intracellular Ca²⁺ handling. Interestingly, AMPK

inhibition reversed caloric restriction-induced changes in autophagy and

autophagy signaling. AMPK inhibition led to dampened levels of Beclin-1, Atg 5

and LC3B ratio along with suppressed phosphorylation of AMPK and TSC1/2 as well

as elevated phosphorylation of mTOR and ULK1. Taken together, these data suggest 

an indispensible role for AMPK in the maintenance of cardiac homeostasis under

prolonged caloric restriction-induced pathological changes possibly through

autophagy regulation. This article is part of a Special Issue entitled: Autophagy

and protein quality control in cardiometabolic diseases.

 

Copyright © 2014 Elsevier B.V. All rights reserved.

 

PMID: 24793415

 

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

[5] Aging Cell. 2015 Aug;14(4):511-23. doi: 10.1111/acel.12342. Epub 2015 Apr 10.

 

Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins,

dietary restriction and protein intake.

 

Sharples AP(1), Hughes DC(1,)(2), Deane CS(3,)(4), Saini A(5), Selman C(6),

Stewart CE(1).

 

Free full text: http://onlinelibrary.wiley.com/doi/10.1111/acel.12342/epdf

 

Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass

and function. Given the worldwide aging demographics, this is a major contributor

to morbidity, escalating socio-economic costs and ultimately mortality.

Previously, it has been established that a decrease in regenerative capacity in

addition to SkM loss with age coincides with suppression of insulin/insulin-like 

growth factor signalling pathways. However, genetic or pharmacological

modulations of these highly conserved pathways have been observed to

significantly enhance life and healthspan in various species, including mammals. 

This therefore provides a controversial paradigm in which reduced regenerative

capacity of skeletal muscle tissue with age potentially promotes longevity of the

organism. This paradox will be assessed and considered in the light of the

following: (i) the genetic knockout, overexpression and pharmacological models

that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the

important role of these signalling pathways in SkM growth and adaptation; (ii)

the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM

regeneration and survival under catabolic stress; (iii) the role of dietary

restriction and its impact on longevity versus skeletal muscle mass regulation;

(iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and

survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the

impact of protein feeding in combination with dietary restriction will be

discussed as a potential intervention to maintain SkM mass while increasing

longevity and enabling healthy aging.

 

© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley

& Sons Ltd.

 

PMCID: PMC4531066

PMID: 25866088

 

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

[6] Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12017-22. Epub 2007 Jul 3.

 

AMP-activated protein kinase (AMPK) action in skeletal muscle via direct

phosphorylation of PGC-1alpha.

 

Jäger S(1), Handschin C, St-Pierre J, Spiegelman BM.

 

Free full text: http://www.pnas.org/content/104/29/12017.full

 

Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose

uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene

expression in these pathways. However, the transcriptional components that are

directly targeted by AMPK are still elusive. The

peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) 

has emerged as a master regulator of mitochondrial biogenesis; furthermore, it

has been shown that PGC-1alpha gene expression is induced by exercise and by

chemical activation of AMPK in skeletal muscle. Using primary muscle cells and

mice deficient in PGC-1alpha, we found that the effects of AMPK on gene

expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself

are almost entirely dependent on the function of PGC-1alpha protein. Furthermore,

AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct 

phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are

required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These

data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the

important gene regulatory functions of AMPK in skeletal muscle.

 

PMCID: PMC1924552

PMID: 17609368

 

--------

[7] Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15983-7. Epub 2002 Nov 20.

 

AMP kinase is required for mitochondrial biogenesis in skeletal muscle in

response to chronic energy deprivation.

 

Zong H(1), Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI.

 

Free full text: http://www.pnas.org/content/99/25/15983.long

 

Mitochondrial biogenesis is a critical adaptation to chronic energy deprivation, 

yet the signaling mechanisms responsible for this response are poorly understood.

To examine the role of AMP-activated protein kinase (AMPK), an evolutionarily

conserved fuel sensor, in mitochondrial biogenesis we studied transgenic mice

expressing a dominant-negative mutant of AMPK in muscle (DN-AMPK). Both DN-AMPK

and WT mice were treated with beta-guanidinopropionic acid (GPA), a creatine

analog, which led to similar reductions in the intramuscular ATPAMP ratio and

phosphocreatine concentrations. In WT mice, GPA treatment resulted in activation 

of muscle AMPK and mitochondrial biogenesis. However, the same GPA treatment in

DN-AMPK mice had no effect on AMPK activity or mitochondrial content.

Furthermore, AMPK inactivation abrogated GPA-induced increases in the expression 

of peroxisome proliferator-activated receptor gamma coactivator 1alpha and

calciumcalmodulin-dependent protein kinase IV (both master regulators of

mitochondrial biogenesis). These data demonstrate that by sensing the energy

status of the muscle cell, AMPK is a critical regulator involved in initiating

mitochondrial biogenesis.

 

PMCID: PMC138551

PMID: 12444247 

 

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

[8] Am J Physiol Endocrinol Metab. 2004 Oct;287(4):E686-95. Epub 2004 May 27.

 

Cold-induced PGC-1alpha expression modulates muscle glucose uptake through an

insulin receptor/Akt-independent, AMPK-dependent pathway.

 

Oliveira RL(1), Ueno M, de Souza CT, Pereira-da-Silva M, Gasparetti AL, Bezzera

RM, Alberici LC, Vercesi AE, Saad MJ, Velloso LA.

 

Author information: 

(1)Department of Internal Medicine, State University of Campinas, SP 13083-970,

Brazil.

 

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) 

participates in control of expression of genes involved in adaptive

thermogenesis, muscle fiber type differentiation, and fuel homeostasis. The

objective of the present study was to evaluate the participation of cold-induced 

PGC-1alpha expression in muscle fiber type-specific activity of proteins that

belong to the insulin-signaling pathway. Rats were exposed to 4 degrees C for 4

days and acutely treated with insulin in the presence or absence of an antisense 

oligonucleotide to PGC-1alpha. Cold exposure promoted a significant increase of

PGC-1alpha and uncoupling protein-3 protein expression in type I and type II

fibers of gastrocnemius muscle. In addition, cold exposure led to higher glucose 

uptake during a hyperinsulinemic clamp, which was accompanied by higher

expression and membrane localization of GLUT4 in both muscle fiber types. Cold

exposure promoted significantly lower insulin-induced tyrosine phosphorylation of

the insulin receptor (IR) and Ser473 phosphorylation of acute transforming

retrovirus thymoma (Akt) and an insulin-independent increase of Thr172

phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK).

Inhibition of PGC-1alpha expression in cold-exposed rats by antisense

oligonucleotide treatment diminished glucose clearance rates during a

hyperinsulinemic clamp and reduced expression and membrane localization of GLUT4.

Reduction of PGC-1alpha expression resulted in no modification of insulin-induced

tyrosine phosphorylation of the IR and Ser473 phosphorylation of Akt. Finally,

reduction of PGC-1alpha resulted in lower Thr172 phosphorylation of AMPK. Thus

cold-induced hyperexpression of PGC-1alpha participates in control of skeletal

muscle glucose uptake through a mechanism that controls GLUT4 expression and

subcellular localization independent of the IR and Akt activities but dependent

on AMPK.

 

PMID: 15165993

 

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

[9] J Physiol. 2007 Apr 15;580(Pt. 2):677-84. Epub 2007 Feb 1.

 

Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown

and white adipose tissue of the mouse.

 

Mulligan JD(1), Gonzalez AA, Stewart AM, Carey HV, Saupe KW.

 

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075554/

 

AMPK (adenosine monophosphate-activated protein kinase), a key regulator of

cellular energy metabolism and whole-body energy balance, is present in brown

adipose tissue but its role in regulating the acute metabolic state and chronic

thermogenic potential of this metabolically unique tissue is unknown. To address 

this, the AMPK signalling system in brown and white adipose tissue was studied in

C57Bl/6 mice under control conditions, during acute and chronic cold exposure,

and during chronic adrenergic stimulation. In control mice AMPK activity in brown

adipose tissue was higher than in any tissue yet reported (3-fold the level in

liver) secondary to a high level of expression of the alpha1 isoform. During the 

first day of cold, a time of intense non-shivering thermogenesis, AMPK activity

remained at basal levels. However, chronic (>7 days) cold caused a progressive

increase in brown adipose tissue AMPK activity secondary to increased expression 

of the alpha1 isoform. To investigate the signalling pathway involved,

noradrenaline (norepinephrine) and the beta(3)-adrenergic-specific agonist CL

316, 243 were given for 14 days. This increased uncoupling protein-1 content in

brown adipose tissue, but not AMPK activity. In white adipose tissue 15 days of

cold increased alpha1 AMPK activity 98 +/- 20%, an effect reproduced by chronic

noradrenaline or CL 316 243. We conclude that chronic cold not only increases

AMPK activity in brown and white adipose tissue, but that it does so via distinct

signalling pathways. Our data are consistent with AMPK acting primarily as a

regulator of chronic thermogenic potential in brown adipose tissue, and not in

the acute activation of non-shivering thermogenesis.

 

PMCID: PMC2075554

PMID: 17272339 

[TomBAvoider]

On a tangent, I was thinking about heat shock proteins. Those are released by all sorts of stress, including CE. But they got their name originally from heat stress. In this context, I wonder about saunas as a hormetic generator of HSP. Saunas are popular in Northern Europe, Russia etc. as a sort of folk "health therapy", though I suppose that is not meaningful in and of itself. A sauna seems about 180 degrees from CE. An interesting wrinkle is that in some of those cultures they like to combine both - first you cook in a sauna, then you plunge into ice cold water or snow - and in Russia, I think they even whip each other with nettle twigs/switches. I bet these various methods all generate HSP, though what the net effect is I have no idea.

[Gordo]

Brown Adipose Tissue Is Linked To A Distinct Thermoregulatory Response To Mild Cold In People

(Full/Preliminary article is downloadable from above, this is very recent work)

 

They found that supraclavicular skin/surface temperature measurements were a good method of measuring BAT activity.  

The last such measurement I took on myself after CE showed 96.0F.  Subjectively it felt quite hot to me at the time.  I have no idea what ranges are normal.  Unfortunately the study only seems to provide deltas.  I would really like to see their data, as they took measurements from 14 locations including the thighs which I have noticed on myself seem to be possibly the biggest source of thermogenesis and I have not seen that body part mentioned/measured in other studies.

 

There are a few other interesting findings from this study (besides all of the cool gadgets they used including circulating cooling vests, and wireless temp loggers which I have tracked down on ebay, haha).  

 

• Core body temperature decreased during cold exposure only in the people with little to no BAT.
• They found that CE significantly decreased heart rate, but again only in the BAT+ group (note that this was measured during their CE experiment and not the same as a resting heart rate measured immediately upon waking which both Dean and I have observed to be elevated compared to our pre-CE baselines).
• They noted no significant differences in systolic blood pressure while diastolic blood pressure increased in both group but the increase was significantly lower in the group with active BAT.

Edited April 13, 2016 by Gordo