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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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And finally a study suggesting you can get too much of a good thing.

https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-018-0748-x

 

The study shows that exposure to  -20°C,  4 hours per day across 1-2 weeks is dangerous to lab rats and that's no wonder. Unlike the previous studies in milder temperatures, we are definitely out of the hormesis region. Exposure to that temperature in naked humans would cause hypothermia and death in many (most?) individuals. 

Edited by mccoy

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Rats survive our winters here in Chicago just fine and one can often see them out foraging at night for garbage in our alleys.  My guess is it isn't just the exposure to the temperatures but the forced exposure in a cage and the shift from 20C to -20C.  This probably reduces acclimatization and elevates stress hormones higher.

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CE does much for metabolic syndrome and has some interesting connections to longevity pathways but in the slim, active and already metabolically heathy population, who knows. And much like CR the risk/benefit ratio may shift in older adulthood and/or geriatric years.

 

It is interesting that as intriguing as the CE literature is, that the Blue Zones and many other longer lived societies are not necessarily facing extremes of temperature albeit less controlled than in the West.

 

By first principals and the little we know, there’s good reason to expect a J-curve ( to CE extent, frequency and duration) influenced by genres, epigenetics/environment, age, etc but the exact curve for a given person is the $M question. Hence the art of integrating the literature at all levels of evidence with biomarkers, other objective, and subjective assessment.

Edited by Mechanism

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It is interesting that as intriguing as the CE literature is, that the Blue Zones and many other longer lived societies are not necessarily facing extremes of temperature albeit less controlled than in the West.

Also interesting to note that for MEN, the top 2 countries in the world for life expectancy are Switzerland and Iceland.

I enjoyed this article: 

Type in the latitude and longitude for longevity, and you’ll arrive at Iceland. Here’s why.

 

 

Its harder to do latitude/longevity analysis in humans since you have to make so many adjustments (like socio-economic, development/access to healthcare).  But to quote Dean from a while back:

 

This study [1] 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.

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

[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.
 
 
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

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Thanks for info Gordo, I enjoyed the Men’s Health article - which put out many interesting hypotheses on some of the factors that may be at play WRT longevity in Iceland - and appreciated the link back to Dean’s review of the provocative latitude correlation by species study. I was very grateful for the latter especially as I had a recollection of Dean’s reference but did not have it on hand.

 

Just as with CR ( which I know you share skepticism in the magnitude of any benefit), CE benefit may vary by species. Though I do not propose a mechanistic argument like Aubrey has on longer lived species having less of an imperative towards CR-induced LE than shorter lived organism ( due to famines representing a smaller percentage of organism reproductive years and less likely to impact survival via CR adaptation), I would not be surprised if this too varies by species, should we be convinced the association with lattitude in consistency is causative and that lower temperatures is the mechanism.

Indeed, that very same study showed an association ( or even non significant trend) in only some of the species. This may imply it was “missed” due to data quality issues in the minority that did not show he trend or alternatively that it simply is not universal ( or both).

 

 

Something the Blue Zones tell us though - at least if we are persuaded there are not some unique genetics at play which is a proposition undermined by migration studies to the contrary - is that CE does not appear to be a requirement per se for very advanced age. Given the unique metabolic impact of brown and beige fat, the benefit of any CE probably depends not only on genetics, but likely as much on the degree to which an individual is is either overweight and/or has other metabolic syndrome attributes such as having impaired insulin sensitivity.

 

Not to say that there are no benefits for scenarios outside of elevated BG and insulin resistance, etc, and the CE thread introduces a number of potential other gains to be had.... but in a healthy slim population these may or may not be clinically significant for incremental health quality gains beyond that otherwise healthy lifestyle.

 

For most of here insulin sensitivity per se is not a problem, but impaired OGTT is common, especially for those practicing a greater extent of caloric restriction. For the latter group, I find it noteworthy, as MR pointed out in the past, the interesting twist that while they have a greater post-prandial glucose excursion/elevation which on the face of things is not a good thing, they also metabolically and via biomarker and %CR more closely matched the very rodent model species that appeared to most benef from CR!

 

Bottom line though is it is unlikely to hurt, and seems to help at least for some attributes of metabolic syndrome, so like dietary, exercise, sleep, and stress interventions there CE ( or at the other end of the spectrum Sauna) hormetic interventions have potential roles to play in the set of tools available for lifestyle health biohacking.

 

Thanks Gordo, I always enjoy your posts!

Edited by Mechanism

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As a sequel to mechanism's reasonings, here are some personal speculations on the subject:

 

  • I've been leading two major experiments with CE, when I was 15 to 28, and very recently for the last two years. What I observed on myself:
  1. Undeniable boosting of the immune system, with much less propensity to get sick, especially bacterial, viral infections (this together with an healthy diet and exercise)
  2. Greater hunger, with propensity to eat more carbs.Lately, this might have elevated my fasting BS level, I'll have to confirm that

#1 above would boost longevity, whereas #2 would tend to decrease it, but not necessarily (are there controlled trials where, barring pdiabetes and pre-diabetes cases, a positive correlation has been shown with fasting BG and the longevity biomarkers?)

 

Also, many other details should be evaluated, which usually are not:

  • Should CE be continuos or intermittent
  • Should it be severe, moderate, intermittent and severe, moderate or continuos, severe and continuos and so on
  • Definition of degrees of severity of CE, temperature wise, time of exposure-wise, medium (air, water, ice...)
  • Should we interrupt CE during the warm season or not.

Intermittent, brief exposure cause noradrenaline surges, are they good or bad for longevity?

 

More bland, prolonged exposures probably cause a more tenuos increase in noradrenaline and other adaptations, are they better for longevity and maybe worse for immunity boosting?

 

Should we turn to heat exposure during the summer? It is more practical and it diversifies the hormetic stressor field which we are subjecting ourselves to. Heat shock proteins have been shown to exhibit beneficial effects to health and longevity, as per Rhonda Patrick assertions. Also, heat exposure during the summer makes the occasional exposures to cold media more impactful, and that may yield additional advantages (or maybe disadvantages?).

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Nature takes the cold plunge:

Low temperature exposure induces browning of bone marrow stem cell derived adipocytes in vitro

 

"previously unknown role for leptin in the browning process"

 

FIGURES:

1

41598_2018_23267_Fig1_HTML.jpg

mMSCs differentiated adipocytes show uncoupling protein (UCP)1 and leptin expression. (a) mMSCs acquired an adipogenic phenotype confirmed by ORO staining. Scale bars: 50 μm. (b) Super-resolved structured illumination microscope image showing presence of leptin+/UCP1+ cells in AD-treated mMSC cultures. Leptin (red) and UCP1 (green) were found to be co-expressed in differentiated cells (asterisks - LDs), with DAPI nuclear counterstain (blue). Scale bars: 10 μm. n = 3 individual experiments.

 

2

41598_2018_23267_Fig2_HTML.jpg

Cellular response of mMSCs exposed to adipogenic differentiation under standard or hypothermal conditions. (a) Metabolic activity measured in AD-treated cultures maintained at 32 and 37 °C. (b) ORO staining of cells after 9 days of differentiation at 32 and 37 °C, and (c) changes in LD size distribution (mean diameter). Scale bars, 20 μm. (d) Changes in lipid content per well in cells differentiated at 32 and 37 °C. ***Comparison of the same treatments at different temperature; °°°Comparison of different treatments at the same temperature. Statistical significance was set at p < 0.05. (e) Proportion of lipid-containing cells after differentiation at 32 °C and 37 °C. Measurements (c and e) were done on 50 randomly selected micrographs per condition (n = 3 individual experiments). Data are shown as mean ± SEM. Statistical significance was set at p < 0.05.

 

3

41598_2018_23267_Fig3_HTML.jpg

Temperature-related changes in differentiating mMSCs. (a) Detection of uncoupling protein (UCP)1 protein expression in adipocytes differentiated at 37 vs 32 °C visualized with 3, 3′-diaminobenzidine (DAB) as the chromogen. Scale bar: 20 μm. (b) Image quantification of UCP1-positive cell area. Data represent the mean ± SEM. Statistical significance was set at p < 0.05. (c) Leptin immunodetection in adipogenic cells in cultures differentiated in 37 vs 32 °C visualized with 3,3′-diaminobenzidine (DAB) as the chromogen. Scale bar: 20 μm. (d) Fluorescence image of leptin (red) cytoplasmic localization in adipocytes differentiated in 37 °C (left image) and leptin nuclear localization in adipocytes differentiated at 32 °C (right image). DAPI was used to identify nuclei (blue) and asterisks indicate LDs. Image inserts show enlarged view of adipocytes in boxed areas. Scale bar: 10 μm. (e) Representative fluorescence image of leptin nuclear localization (red) in adipocytes differentiated at 32 °C. DAPI was used to identify nuclei (blue) and BODIPY was used to identify LDs (green). Insert shows enlarged view of nucleus in boxed area. Scale bar: 10 μm. n = 3 individual experiments.

 
4
41598_2018_23267_Fig4_HTML.jpg
PGC-1α immunoexpression, mitochondrial localization and bioenergetics measurement during mMSCs differentiation under different temperature conditions. (a) Fluorescence image of PGC-1α (purple) in adipocytes differentiated at 37 °C and 32 °C. DAPI was used to identify nuclei (blue) and BODIPY was used to identify LDs (green). (b) mMSC-derived adipocytes stained with MitoTracker Orange CM-H2 TRos (red) and DAPI nuclear counterstain (blue). Asterisks – LDs. Scale bar: 10 μm. (c) Relative fluorescence intensity of MitoTracker staining was determined at randomly selected images, measuring relative fluorescence intensity on whole image (d) Relative fluorescence intensity of MitoTracker staining was determined at randomly selected ROI around LDs, at distance of 3 µm from LD’s membrane. Data represent the mean ± SEM. Statistical significance was set at p < 0.05. (e) OCR following differentiation of adipocytes at 37 and 32 °C, respectively. (f) Six parameters of mitochondrial function calculated from the bioenergetics profile (basal respiration, proton leak, ATP-linked respiration, maximal capacity, spare capacity and non-mitochondrial respiration). Data represent the mean ± SEM. Statistical significance was set at p < 0.05. (g) ECAR following differentiation of adipocytes at 37 and 32 °C, respectively. (h) Quantitative ECAR analysis of adipocytes differentiated at 37 and 32 °C, respectively following treatments with mitochondrial inhibitors. (i) Coupling efficiency indicating the proportion of respiratory activity used for ATP synthesis. Bars represent mean ± SEM. Statistical significance was set at p < 0.05. (j) The metabolic profile for both adipogenic groups was determined by plotting ECAR to OCR. Bars represent mean ± SEM. Statistical significance was set at p < 0.05. n = 6 individual experiments.
 
5
41598_2018_23267_Fig5_HTML.jpg
Expression of beige and brown markers in mMSCs-derived adipocytes differentiated at 32 °C. (a) Representative image showing the prevalence of beige cell-specific marker CD137 (red), multilocular phenotype and uncoupling protein (UCP)1 expression (yellow). DAPI was used to identify nuclei (blue) and BODIPY was used to identify LDs (green). The dashed square highlights difference in staining between two adjacent adipocytes. Scale bar: 50 μm. (b) Enlarged view of the square area, with individual and merged images showing adipocytes positive for both beige selective marker, CD137 (red) and brown cell-specific marker, UCP1 (yellow). Scale bars: 10 μm. n = 3 individual experiments.
 
6
41598_2018_23267_Fig6_HTML.jpg
Leptin nuclear localization in UCP1+ mesenchymal stem cell-derived adipocytes differentiated at 32 °C. (a) Representative image showing double staining for leptin (red) and uncoupling protein (UCP)1 (purple). DAPI was used to identify nuclei (blue) and BODIPY was used to identify LDs (green). Scale bar: 100 μm. (b) Enlarged view of the square area, with individual and merged images showing adipocytes nuclei positive for leptin (red) and positive for UCP1 (purple). Arrows indicate nucleus positive for leptin and UCP1 cytoplasmic expression in the same cell differentiated at 32 °C. Scale bar: 10 μm. n = 3 individual experiments.
 
7
41598_2018_23267_Fig7_HTML.jpg
Real-time PCR analysis of gene expression during mMSCs differentiation under different temperature conditions. (a) Expression levels of general adipocytes markers: AdipoQFABP4and PPARγ. Data represent the mean ± SEM of three replicas. Statistical significance was set at p < 0.05. (b) Expression levels of beige lineage markers: CITED1CD137 and P2RX5. Data represent the mean ± SEM of three replicas. Statistical significance was set at p < 0.05. (c) Expression levels of brown lineage markers: UCP1PRDM16CIDEALHX8COX8b and RIP140. Data represent the mean ± SEM of three replicas. Statistical significance was set at p < 0.05. (d) Expression levels of TRPV1TRPV2 and TRPV4. Data represent the mean ± SEM of three replicas. Statistical significance was set at p < 0.05. (e and f) Representative images showing double staining of TRPV1 (purple) and UCP1 (green) protein expression in adipocytes differentiated at 37 (e) and 32 °C (f) DAPI was used to identify nuclei (blue) and asterisks present LDs. Scale bars: 5 μm. n = 3 individual experiments.

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Popular press coverage of the above Nature article has some interesting quotes from one study author:

There's more evidence that exposing yourself to cold temperatures could trigger weight loss

 

Harnessing the power of brown fat

"It has been known for quite some time that exposure to lower temperatures can promote the formation of brown fat, but the mechanism of this has not yet been discovered," study author Virginie Sottile, an associate professor at the University of Nottingham in the UK, said in a statement. "The trigger was believed to be the body's nervous system and changes in the way we eat when we are cold. However, our study has shown that even by making fairly modest changes in temperature, we can activate our stem cells to form brown fat at a cellular level."

That finding is promising for three reasons. First, it helps reveal more about the mechanism that causes brown fat to be produced in the cold. Second, it shows that those changes can happen with a difference of a few degrees: In the study, cells turned into brown fat instead of white at 89.6 degrees Fahrenheit (32 Celsius) instead of the normal human body temperature of 98.6 degrees (37 Celsius). Third, the research suggests that the production of brown fat can be triggered by environmental change and doesn't rely on special cells that always produce brown fat.

"The good news from these results is that our cells are not pre-programmed to form bad fat and our stem cells can respond if we apply the right change in lifestyle," Sottile said."

This study doesn't tell us how much cold people need to expose themselves to in order to produce brown fat instead of white. But it's another piece of data in support of the idea that exposing yourself to the cold — a practice that's becoming more popular— has some real health implications.

Studies of this brown-fat-production mechanism may even eventually reveal a way to trigger brown fat production with a drug instead of cold exposure, which can be extremely uncomfortable.

CEGarbageCan.jpg

(I'm totally diggin' the garbage can method of cold exposure!!!)

The health benefits of the cold

Growing numbers of people are opting to take cold showers and ice baths due to beliefs that cold exposure can transform the body. Some extremists even go hiking or mountain climbing in cold weather without much protective clothing.

The idea behind this "environmental conditioning," as Dutch fitness guru Wim Hof explains it, is that our bodies evolved to be challenged by factors like extreme cold and heat. In modern conditions that lack those stresses, our overall stress response may go haywire. That's why Hof, also known as "Iceman," advocates for a combination of environmental conditioning andcontrolled breath work; he says the practice can have a transformative effect on health.

In Silicon Valley, the cold shower movement has gotten so popular that — of course — there's now an app to help people do it.

While it may sound like a pseudoscience trend, there is some evidence that programs like Hof's might have real effects. Some data indicates that Hof's regimen has led to measurable benefits in certain individuals including better fat-burning capabilities, weight loss, an improved immune system, and the ability to counteract some effects of Type 2 diabetes.

Scientists still have a long way to go to fully understand how the cold impacts us, but this new study lends support to the idea that there really is something beneficial about being cold.

So even when it's frigid or snowy outside, there's no excuse to avoid being outdoors.

CESiberianStyle.jpg(Siberian method also good  :rolleyes: )

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Silicon Valley’s tech elites are adopting uncomfortable habits to condition their bodies

 

58c6c485c140776f028b4bcb-960-720.jpg

 

 

  • Silicon Valley tech elites are adopting some of the latest and most extreme techniques for performance enhancement.
  • These techniques include immersion in freezing water, fasting, and attending camps that have participants crawl through snake-filled boxes.
  • The basic idea is to learn techniques for coping with mental and physical stress.

 

From athletics to business, learning to deal with stress is an essential key to improving performance. That's because stress can push people to perform at their best — or cause them to shut down.

So it's no surprise that in the metrics-obsessed world of Silicon Valley, tech elites are turning to the latest in performance science and psychology to learn to adapt to stress — even by doing physically and mentally uncomfortable things.

Stress-adapting techniques for devotees of the latest in performance science include immersion in freezing cold temperatures, forgoing food for 15 hours a day, and attending training camps with elite athletes, where they crawl through snake-filled boxes or do improv.

As Christina Farr explains in a story for CNBC, this "positive stress movement," as it's known, is filled with "tech workers who claim that such radical tactics will help them live better and longer or — in Silicon Valley — work better for longer."

According to Farr, start-up founder Zachary Rapp credits an early morning run followed by a freezing cold shower and the occasional ice bath as the way to be ready for the stress that comes with 18-hour workdays.

Rapp is far from the only one engaged in this sort of activity.

5a99ce0eaae605d6038b483d-960-720.jpg

Pushing the limits of human performance

The notion that it's beneficial to learn how to cope with stress and build psychological resilience isn't new. Cultures going at least as far back as Sparta trained people by having them face a sequence of unexpected and difficult tasks.

But the modern iteration of this sort of training is backed — at least in some ways — by modern scientific research.

And while much of this sort of training has long had an appeal to elite athletes, people in the tech and business world are increasingly driven to improve their performance in similar ways.

That's why Andy Walshe, a biomechanics expert from Australia who runs a "Performing Under Pressure" clinic for Red Bull, started inviting people like Will Weisman, an executive director at Singularity University, to train with elite rock climbers and big-wave surfers. Activities at the clinic include the aforementioned snake box, solving puzzles underwater, and facing a charging bear — all in the name of improving an individual's response to stress.

 

"Better at who you are is better at what you do," Walshe previously told Business Insider.

58e2eb648af578b2008b60a2-960-720.jpg

It's the same idea that drives those who opt for ice baths or daily cold showers. The idea behind "environmental conditioning," as Dutch fitness guru Wim Hof explains it, is that our bodies evolved to be challenged by factors like extreme cold and heat. Without those stresses, our overall stress response may go haywire. That's why Hof advocates for a combination of environmental conditioning and controlled breathwork that he argues can have a transformative effect on health.

In Silicon Valley, the cold shower movement is so popular that — of course — there's an app to help people do it.

Fasting is yet another area that fascinates both scientists interested in pushing human limits and people in the tech world. There's some good data showing that fasting could potentially help cure disease and slow aging. A number of Silicon Valley elites have focused on various forms ofintermittent fasting as one potential way to get the health-boosting benefits of a fast.

As Facebook analytics director Dan Zigmond previously told Business Insider, adopting a strict schedule of only eating during a nine-hour period each day helped him lose weight and feel like he had more energy.

"It took me a couple of weeks," he said. "But I got pretty quickly used to this nine-hour diet. I just loved it. I almost immediately felt better. And I started losing weight."

In many of these cases, the science behind these things — cold immersion, intermittent fasting, or just putting yourself in a scary situation — is still emerging. Some things may turn to be excellent means of performance enhancement, others less so.

But as "crazy" as some of these challenges may seem, they're still classic examples of human performance enhancement. To get better, you have to push yourself — even if that requires being extra-creative.

__________________________________________________________________________________________________________________

Off topic - but I think someone from Business Insider has either been reading my mind, or reading the CR Society forum.  Last week they published an article on DMT and now they are doing cold exposure, haha.

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All,

 

This new study [1] (free full text) looks to me to be the best direct evidence so far that the underlying premise of this entire thread is correct, namely that the brown adipose tissue (BAT) induced by consistent cold exposure can improve both healthspan and lifespan, independent of calorie restriction.

 

The authors created a mutant strain of standard C57Bl6/J mice that produced more BAT by knocking out a particular gene (RGS14). They fed both the knockout mice and wild-type mice ad-lib for life, and measured a bunch of things including lifespan. The BAT-boosted mice lived 10% longer (both mean and maximum lifespan), and had much healthier appearance to boot relative to the unmodified (WT) mice. Here is the survival graph along with pictures of the wild type mice (WT), BAT-boosted knockout mice (RGS14 KO) and "BAT Recipient" mice:

 

I5Yr1Gf.png

 

Notice the WT mouse on the left looks old, grey and balding. The "BAT Recipient" mouse has a nice, smooth, dark shiny coat, just like the knockout mouse. The "BAT recipients" mice in the study were WT mice that received a BAT transplant at 3-4 months of age, to simulate the effects of the RGS14 knockout (i.e. boosting the amount of BAT). Many of the same metabolic and phenotypic changes were observed in the BAT transplant mice as was seen in the knockout mice. Unfortunately they didn't report the lifespan of the BAT transplant mice.

 

Some caution is in order however. First, as far as I can tell those aren't stellar lifespans for either the WT or knockout mice. Plus the authors didn't report food intake. Also, the knockout mice with genetically more BAT weighed slightly less than the WT mice, but this is unlikely to be a "crypto-CR" effect, since the knockout mice had an increased metabolic rate (eyeballing Fig 2e, about 10-15% higher metabolic rate), and so were presumably eating and burning more calories than the WT mice.

 

--Dean

 

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

[1] Aging Cell. 2018 Apr 14:e12751. doi: 10.1111/acel.12751. [Epub ahead of print]

Enhanced longevity and metabolism by brown adipose tissue with disruption of the
regulator of G protein signaling 14.

Vatner DE(1), Zhang J(1), Oydanich M(1), Guers J(1), Katsyuba E(2), Yan L(1),
Sinclair D(3), Auwerx J(2), Vatner SF(1).

Author information:
(1)Department of Cell Biology & Molecular Medicine, Rutgers University-New Jersey
Medical School, Newark, NJ, USA.
(2)Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale
de Lausanne (EPFL), Lausanne, Switzerland.
(3)Department of Genetics, Harvard Medical School, Boston, MA, USA.

 

free full text: https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.12751

Disruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in
mice extends their lifespan and has multiple beneficial effects related to
healthful aging, that is, protection from obesity, as reflected by reduced white
adipose tissue, protection against cold exposure, and improved metabolism. The
observed beneficial effects were mediated by improved mitochondrial function. But
most importantly, the main mechanism responsible for the salutary properties of
the RGS14 KO involved an increase in brown adipose tissue (BAT), which was
confirmed by surgical BAT removal and transplantation to wild-type (WT) mice, a
surgical simulation of a molecular knockout. This technique reversed the
phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism
and protection against cold exposure in RGS14 KO and conferring this protection
to the WT BAT recipients. Another mechanism mediating the salutary features in
the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X
SIRT3 double KO, which no longer demonstrated improved metabolism and protection
against cold exposure. Loss of function of the Caenorhabditis elegans RGS-14
homolog confirmed the evolutionary conservation of this mechanism. Thus,
disruption of RGS14 is a model of healthful aging, as it not only enhances
lifespan, but also protects against obesity and cold exposure and improves
metabolism with a key mechanism of increased BAT, which, when removed, eliminates
the features of healthful aging.

DOI: 10.1111/acel.12751
PMID: 29654651

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A moderator could move this post to its own thread, but it is sort of on topic, and this thread hasn't had a new post in months so here goes...
Back in 2016 there was some interesting new published research showing a synergistic effect between cold exposure and capsinoids, if you search this thread, you will find the references and discussion, here is one of the popular press summaries:

Cold exposure, capsinoids further beige adipocyte biogenesis

...beige adipocyte development was promoted synergistically by the combination of cold exposure and capsinoids through the β2-adrenoceptor signaling pathway. The synergistic effect occurred via an increased half-life of PRDM16, which is a dominant transcriptional regulator of the development of brown/beige adipocytes.

 
This of course naturally led to thoughts of - how can I get me some capsinoids? ;)
We already knew hot peppers are good bat activators (you can feel the heat after eating them, good sign!), but they are difficult for most people to take.  Capsinoids are the "not hot" equivalent of a hot pepper - many of the same health benefits, without the burn!  The problem is, very few sweet pepper varieties have high levels of capsinoids.  There was one Japanese research group that managed to come up with a high capsinoid pepper variety, but they decided to keep a ridiculously tight lid on it, they have an exclusive partnership with a firm that is the sole grower and extractor of the capsiniods, which are now sold in commercial weight loss supplement type products.  I did actually try to track down and reach out to these Japanese researchers, but got no where.
 
Digging deeper, I found a U.S. research team that had also been focused on this area of research.  Robert L. Jarret from the USDA/Agricultural Research Service, Jason Bolton and L. Brian Perkins from the Department of Food Science and Human Nutrition at the University of Maine.  These guys had begun a traditional selective breeding program in 2005 starting with 120 Capsicum annuum cultivars.  I had some pleasant email exchanges with these researchers.  They worked on this project for almost 10 years, until they had the highest capsinoid containing sweet pepper variety ever developed (as far as I am aware).  They gave this plant the exciting name of germplasm "509-45-1", haha.
See:
But despite my best efforts to butter them up, I still could not get any seeds from these guys.  Also there are absolutely no commercial sales for this type of pepper (that I could find anyway, after a lot of searching). But they did their work under a USDA grant, and I already knew they had turned over their resulting seeds to the US germplasm library, surely there were seeds to be had! 
 
I went through the usual hoops to request a small sample of seeds from the US germplasm library, but after a couple weeks, received a rejection letter.  Dean was also involved at this point, and he too received the same rejection.  So we tried harder, reaching out to various academic contacts and other researchers who might have been sympathetic to our cause.  No dice, got no where.  As a last ditch effort, I reached out to a guy I know at the University of Pennsylvania (I met him though a backyard fruit growers group, he has an impressive orchard but that's another story).  Long story short, this guy can get anything from the USDA (and has done so numerous times).  He got me the seeds, and I sent some to Dean.  But at this point it was already late August or September of 2016, way too late to plant them for the 2016 season, right?  Eh, nothing was going to stop us, haha.  We both immediately germinated those seeds and started planning how we'd grow them indoors with grow lights.
 
Dean's setup was way nicer than mine:
c4dEUHE.png
He used all blue lights for the initial growth phase:
VIkzyEv.png
Then added red lights for the fruiting phase:
i3TXRie.png
He even had a rotating turn table and timer for the lights.
My setup was just a bunch of mirrors I happened to have lying around, and some cheap LED lights I got from eBay, no rotation but did use a timer, it worked but Dean's plant looked way better than mine.  But we both got pretty funky looking plants:
WucL7E0.png
7XHU42s.png
Boom, first blooms.
 
There are no bees inside the house to pollinate those bad boys, so you have to do it by hand.
By the end of our best efforts, sometime in winter, we each had a few small peppers, and enough seeds to grow more plants in 2017.  I think this was around the time Dean started losing interest in all things "health extremist", and I didn't really dedicate a whole lot of effort to this anymore either, but at least I grew out a few more plants plus my original plant.  
 
This brings us to 2018.  I took what I thought were all of my seeds, and did a massive germination all at once (wet paper towel method) then transferred all the viable starts to small pots.  Now I've got maybe 20 plants growing out in the garden.  I still have only eaten a few of the peppers, I've been saving them all for the seeds, but of the ones I've eaten, they did seem to produce that BAT activating "body heat" you get from a hot pepper, but they don't burn in your mouth or throat or cause any stomach upset like a hot pepper - so in other words its exactly what I was looking and hoping for. 
 
Dean didn't plant any of his seeds for 2018 although his original plant may still be alive (?) they come back every year if you keep them from freezing.   Anyway, I thought I was pretty much done until the end of the growing season, but just last night I discovered a separate cache of seeds I had put aside, so now I have more seeds than I need.  You might think such a rare and difficult to acquire seed, for a plant with such valuable health promoting properties would be worth something - but there are probably only a handful of people that even know this exists, and probably almost no one looking for them, and the plant doesn't even have a proper name, so really how would anyone even find it if they were looking...
 
I don't think there is any market for the seeds so I'm offering them to anyone here that might be interested.  If anyone here will actually grow them out and not waste them, send me an IM and I'll get some out to you (US addresses only unless you are paying for the shipping).  The peppers are really small, you'd probably have to grow a ton of them to really result in any kind of serious health benefit, at this point I think its just more of a goofy novelty thing:
peppers.jpg
Probably at some future point you will actually have a lot of products on the market that contain these valuable capsinoids, but its going to take many years before that happens.  You can read more about capsinoids on wikipedia: 
 
Regards,
Gordo
Edited by Gordo

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Great story Gordo. Moreover how generous of you not only to be willing to give them away but also offer them at your own trouble, right here on the CR community forum. Alas I wish but don’t have the personal resources to followup on your kindness, but maybe, one day, if they are still around. Hopefully someone else can benefit from your offering!

Edited by Mechanism

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Bravo!  Gordo!    I second Mechanism's remarks .     Personally,  I can handle a lot of hot pepper without distress, so I'm fine with cayenne powder.

 

Perhaps Melvin West might be interested.

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Perhaps Melvin West might be interested.

 

The peppers go perfect with blood sausages, snails and sugar cane ;)

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Overexpression of Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Leads to Muscle Atrophy with Depletion of ATP

From the discussion section:

In the present study, we found that overexpression of PGC-1α in mouse skeletal muscle increased mitochondria numbers and energy expenditure, and eventually caused muscle atrophy, especially of type 2B fiber-rich muscles. PGC-1α transgenic mice showed normal mitochondrial COX and SDH activities (Figure 2, G and H) and normal respiratory chain enzymatic activities (Table 2); however, ATP content was reduced by increased uncoupling.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1780180/

 

My thoughts:

Cold exposure, caloric restriction and exercise typically boost PGC-1a by roughly a factor of two and in this study the mice over expressed it by factors of 10+.  And environmental stimuli such as thermal and dietary stress shift gene expression and metabolic pathways in broad coordinated ways which probably works out better than dramatically altering a single factor such as this large over expression of PGC-1a in isolation.

 

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Hi folks,

It's been a while, but I just had to comment on this study [1] posted by Al Pater (thanks Al!) on the connection between CR, brown/beige fat and cold exposure, particularly since it can be seen as supporting an idea I speculated way back in this post, which can be summarized as follows:

Quote

In yesterday's mega-post, I observed there is a puzzling paradox. When faced with a calorie shortfall induced by CR, endurance exercise, or gut dysbiosis that impedes calorie absorption, why would the body have evolved to increase the level of calorie-burning brown or beige fat? If calories are scare, why wouldn't it be better (from an evolutionary perspective) for the body to simply hunker down and conserve its energy resources by jettisoning the brown/beige fat, in hopes of surviving the famine?

Calorie shortfalls and cold environmental conditions co-occurred so frequently during winters in the evolutionary history of our distant ancestors, that they developed a combined, almost pavlovian response to the two stresses. Teleologically, the body could be thought of (colloquially) as saying, "Uh-oh, calories are scarce. That means cold temperatures can't be far behind. I better ramp up my thermogenic fat in preparation."

This study [1] found that CR does indeed induce the browning of white fat. This was true when the CR mice were housed at thermoneutral temperature (30°C = 86°F), and even more so when they were housed at normal room temperature (which is pretty chilly for mice). This extra beige fat allowed the CR mice to maintain their body temperature better than AL-fed mice when both were exposed to cold (6°C = 43°F) for 12 hours. The extra beige fat also dramatically improved the CR'd mice insulin sensitivity, and this was true for both seriously CRed mice (40% CR) and less dramatically CRed mice (20% CR). When the CR mice were prevented from developing beige fat (via genetic manipulation), their improved glucose tolerance and cold tolerance disappeared. 

In the discussion section, the authors address the paradox I discussed previously, namely why should animals increase the amount of calorie-burning beige fat when food is scarce, rather than conserving every calorie they can to tide them over the lean times? Here is what they say (emphasis mine):

"Browning of the fat depots enhances energy dissipation and reduces the overall adiposity, thereby contributing to the overall fat decrease during CR. Cold exposure and long-term endurance exercise are physiological stimuli that increase the browning (van Marken Lichtenbelt et al., 2009; Harms and Seale, 2013; Wu et al., 2012, 2013; Bostrom et al., 2012). The increased energy dissipation during cold exposure is physiologically justified by the need for increased heat production as a defense against hypothermia. The increased browning during exercise, on the other hand, seems paradoxical, and one explanation was that it might have evolved as a consequence of muscle contraction during shivering (Bostrom et al., 2012). We note that a common feature between the cold exposure and endurance exercise is the negative energy balance: higher energy expenditure than intake leading to fat loss. In addition, interventional microbiota depletion, either by means of antibiotics administration or in germ-free mice (Sua´rez-Zamorano et al., 2015; Chevalier et al., 2015), as well as RYGB (Neinast et al., 2015) also increase the browning to a similar extent as several endurance exercise regimens. These are also conditions of decreased caloric uptake and negative energy balance. Seen in this context, our results that CR promotes the development of functional beige fat provide insights into the regulation of the overall energy homeostasis during energy scarcity, and they suggest that white fat browning is a common feature of conditions of negative energy balance."

In short, they don't really try to explain the paradox, simply observing that under a wide range of conditions that result in a negative energy balance (including cold exposure, exercise and CR), the result is increased browning of white fat, along with other metabolic improvements, including improved glucose tolerance. Unfortunately for us, the browning of fat is more readily accomplished by rodents than humans, which probably explains why many of us have reported worse glucose control when practicing serious CR (without cold exposure).

I stand by my hypothesis, that CR and cold exposure likely co-occurred in the evolutionary past of our mammalian ancestors, so they evolved a synergistic response to the combination which is better preserved in rodents than humans. We humans may be able to trigger a similar beneficial response, but it likely requires the combination of CR and cold exposure to boost browning of white fat like observed in CRed rodents.

--Dean

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

[1]  Cell Metab. 2016 Sep 13;24(3):434-446. doi: 10.1016/j.cmet.2016.07.023. Epub 2016
Aug 25.

Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2
Immune Signaling.

Fabbiano S(1), Suárez-Zamorano N(1), Rigo D(1), Veyrat-Durebex C(1), Stevanovic
Dokic A(1), Colin DJ(2), Trajkovski M(3).

Free Full text: https://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(16)30374-6

Caloric restriction (CR) extends lifespan from yeast to mammals, delays onset of 
age-associated diseases, and improves metabolic health. We show that CR
stimulates development of functional beige fat within the subcutaneous and
visceral adipose tissue, contributing to decreased white fat and adipocyte size
in lean C57BL/6 and BALB/c mice kept at room temperature or at thermoneutrality
and in obese leptin-deficient mice. These metabolic changes are mediated by
increased eosinophil infiltration, type 2 cytokine signaling, and M2 macrophage
polarization in fat of CR animals. Suppression of the type 2 signaling, using
Il4ra(-/-), Stat6(-/-), or mice transplanted with Stat6(-/-) bone marrow-derived 
hematopoietic cells, prevents the CR-induced browning and abrogates the
subcutaneous fat loss and the metabolic improvements induced by CR. These results
provide insights into the overall energy homeostasis during CR, and they suggest 
beige fat development as a common feature in conditions of negative energy
balance.

Copyright © 2016 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2016.07.023 
PMID: 27568549

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Might seem like stating the obvious, but...

https://www.ncbi.nlm.nih.gov/pubmed/30190681

Outdoor Temperature Influences Cold Induced Thermogenesis in Humans.

Abstract

Objective: Energy expenditure (EE) increases in response to cold exposure, which is called cold induced thermogenesis (CIT). Brown adipose tissue (BAT) has been shown to contribute significantly to CIT in human adults. BAT activity and CIT are acutely influenced by ambient temperature. In the present study, we investigated the long-term effect of seasonal temperature variation on human CIT. Materials and Methods: We measured CIT in 56 healthy volunteers by indirect calorimetry. CIT was determined as difference between EE during warm conditions (EEwarm) and after a defined cold stimulus (EEcold). We recorded skin temperatures at eleven anatomically predefined locations, including the supraclavicular region, which is adjacent to the main human BAT depot. We analyzed the relation of EE, CIT and skin temperatures to the daily minimum, maximum and mean outdoor temperature averaged over 7 or 30 days, respectively, prior to the corresponding study visit by linear regression. Results: We observed a significant inverse correlation between outdoor temperatures and EEcold and CIT, respectively, while EEwarm was not influenced. The daily maximum temperature averaged over 7 days correlated best with EEcold (R2 = 0.123, p = 0.008) and CIT (R2 = 0.200, p = 0.0005). The mean skin temperatures before and after cold exposure were not related to outdoor temperatures. However, the difference between supraclavicular and parasternal skin temperature after cold exposure was inversely related to the average maximum temperature during the preceding 7 days (R2 = 0.07575, p = 0.0221). Conclusion: CIT is significantly related to outdoor temperatures indicating dynamic adaption of thermogenesis and BAT activity to environmental stimuli in adult humans. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier NCT02682706.

 

Front Physiol. 2018 Aug 23;9:1184. doi: 10.3389/fphys.2018.01184. eCollection 2018.

Edited by Gordo

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Just published article finds that "chronic exposure to low temperature impairs bone architecture".  This may be something to monitor/take precautions over for anyone doing serious CE.

https://www.ncbi.nlm.nih.gov/pubmed/30187469

Am J Phys Anthropol. 2018 Sep 6. doi: 10.1002/ajpa.23684. [Epub ahead of print]

Low temperature decreases bone mass in mice: Implications for humans.

Abstract

OBJECTIVES:

Humans exhibit significant ecogeographic variation in bone size and shape. However, it is unclear how significantly environmental temperature influences cortical and trabecular bone, making it difficult to recognize adaptation versus acclimatization in past populations. There is some evidence that cold-induced bone loss results from sympathetic nervous system activation and can be reduced by nonshivering thermogenesis (NST) via uncoupling protein (UCP1) in brown adipose tissue (BAT). Here we test two hypotheses: (1) low temperature induces impaired cortical and trabecular bone acquisition and (2) UCP1, a marker of NST in BAT, increases in proportion to degree of low-temperature exposure.

METHODS:

We housed wildtype C57BL/6J male mice in pairs at 26 °C (thermoneutrality), 22 °C (standard), and 20 °C (cool) from 3 weeks to 6 or 12 weeks of age with access to food and water ad libitum (N = 8/group).

RESULTS:

Cool housed mice ate more but had lower body fat at 20 °C versus 26 °C. Mice at 20 °C had markedly lower distal femur trabecular bone volume fraction, thickness, and connectivity density and lower midshaft femur cortical bone area fraction versus mice at 26 °C (p < .05 for all). UCP1 expression in BAT was inversely related to temperature.

DISCUSSION:

These results support the hypothesis that low temperature was detrimental to bone mass acquisition. Nonshivering thermogenesis in brown adipose tissue increased in proportion to low-temperature exposure but was insufficient to prevent bone loss. These data show that chronic exposure to low temperature impairs bone architecture, suggesting climate may contribute to phenotypic variation in humans and other hominins.

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Handb Exp Pharmacol. 2018 Aug 24. doi: 10.1007/164_2018_136. [Epub ahead of print]

Activation of Human Brown Adipose Tissue (BAT): Focus on Nutrition and Eating.

Abstract

Brown adipose tissue activation occurs most effectively by cold exposure. In the modern world, we do not spend long periods in coldenvironment, and eating and meals may be other activators of brown fat function. Short-term regulation of brown fat functional activity by eating involves most importantly insulin. Insulin is capable to increase glucose uptake in human brown adipose tissue fivefold to fasting conditions. Oxidative metabolism in brown fat is doubled both by cold and by a meal. Human brown adipose tissue is an insulin-sensitive tissue type, and insulin resistance impairs the function, as is found in obesity. Body weight reduction improves cold-induced activation of human brown adipose tissue.

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Another interesting new study looking for a link between physical activity and BAT:

https://www.ncbi.nlm.nih.gov/pubmed/30137350

J Clin Endocrinol Metab. 2018 Aug 20. doi: 10.1210/jc.2018-01312. [Epub ahead of print]

Association of objectively measured physical activity with brown adipose tissue volume and activity in young adults.

Abstract

PURPOSE:

Human BAT has gained considerable attention as a potential therapeutic target for obesity and type 2 diabetes. However, whether physical activity (PA) might be an efficient stimulus to activate and recruit brown adipose tissue (BAT) remains to be ascertained. We aimed to examine whether objectively measured PA levels were associated with BAT volume and activity in young sedentary adults. We additionally examined the association of PA levels with the skeletal muscles activity.

METHODS:

A total of 130 young healthy and sedentary adults (67% women, age: 21.9±2.1 years old, body mass index: 25±4.8 kg/m2) participated in this cross-sectional study. PA was objectively measured with a wrist-worn accelerometer (GT3X+, Actigraph, Pensacola, FL) for 7 consecutive days. Age-specific cut points were applied to classify wrist accelerations into sedentary time and different PA intensities (i.e., light, moderate, vigorous, moderate-vigorous). The participants underwent 2 hours of a personalized cold exposure to determine the cold-induced BAT volume and activity and the skeletal muscles activity by means of a 18F-fluorodeoxyglucose positron emission tomography combined with a computed tomography scan.

RESULTS:

Objectively measured physical activity intensity levels were neither associated with BAT volume and activity nor with the skeletal muscles activity (all P>0.05). The results remained after adjusting for sex, waking time, and environmental temperature.

CONCLUSIONS:

Although physical activity plays an important role in the prevention of obesity and related comorbidities, it seems that other physiological mechanisms rather than brown adipocyte activation or recruitment might moderate its beneficial metabolic effects in young sedentary adults.

PMID:
 
30137350
 
DOI:
 
10.1210/jc.2018-01312

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Newly discovered way to induce browning of white fat using the synthetic chemical reversine:

J Cell Physiol. 2018 Aug 21. doi: 10.1002/jcp.27148. [Epub ahead of print]

Reversine promotes browning of white adipocytes by suppressing miR-133a.

Kim S1, Park JW1, Lee MG1, Nam KH1, Park JH1, Oh H1, Lee J1, Han J1, Yi SA1, Han JW1.

Abstract

Brown adipocytes are characterized by a high number of uncoupling protein 1 (UCP1)-positive mitochondrial content and increased thermogenic capacity. As UCP1-enriched cells can consume lipids by generating heat, browning of white adipocytes is now highlighted as a promising approach for the prevention of obesity and obesity-associated metabolic diseases. Upon cold exposure or β-adrenergic stimuli, downregulation of microRNA-133 (miR-133) elevates the expression levels of PR domain containing 16 (Prdm16), which has been shown to be a brown adipose determination factor, in brown adipose tissue and subcutaneous white adipose tissues (WAT). Here, we show that treatment of reversine to white adipocytes induces browning via suppression of miR-133a. Reversine treatment promoted the expression of brown adipocyte marker genes, such as Prdm16 and UCP1, increasing the mitochondrial content, while decreasing the levels of miR-133a and white adipocyte marker genes. Ectopic expression of miR-133a mimic reversed the browning effects of the reversine treatment. Moreover, intraperitoneal administration of reversine in mice upregulated thermogenesis and resulted in resistance to high-fat diet-mediated weight gain as well as browning of subcutaneous and epididymal WAT. Taken together, we found a novel way to promote browning of white adipocytes through downregulation of miR-133a followed by activation of Prdm16, with a synthetic chemical, reversine.

 

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1 hour ago, Gordo said:
Handb Exp Pharmacol. 2018 Aug 24. doi: 10.1007/164_2018_136. [Epub ahead of print]

Activation of Human Brown Adipose Tissue (BAT): Focus on Nutrition and Eating.

Abstract

Brown adipose tissue activation occurs most effectively by cold exposure. In the modern world, we do not spend long periods in coldenvironment, and eating and meals may be other activators of brown fat function. Short-term regulation of brown fat functional activity by eating involves most importantly insulin. Insulin is capable to increase glucose uptake in human brown adipose tissue fivefold to fasting conditions. Oxidative metabolism in brown fat is doubled both by cold and by a meal. Human brown adipose tissue is an insulin-sensitive tissue type, and insulin resistance impairs the function, as is found in obesity. Body weight reduction improves cold-induced activation of human brown adipose tissue.

According to the above sentence in red, we should eat in the snow (or better eat a hot meal and then go in shorts in low temperatures). Doesn't sound unreasonable.

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