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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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Todd S, 

Glad to hear you are having good luck with CompCooler vest. I continue to use mine for a couple hours each day and it is holding up very well. One thing I learned to do is to blow out any remaining water in the female couplers on the ice bag before putting it back in the freezer after a cooling session. Otherwise it freezes inside the coupler and makes it hard to attach next time. 

--Dean 

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12 hours ago, Todd S said:

Gordo,

I can confirm that plugging the USB connection from the CompCooler UniVest into an Apple 5 V charger instead of the 7.4 V battery still works for running the water circulation pump.

That is great to know, I may get one of these eventually.  The one and only review on amazon though, is pretty underwhelming.  I am wondering if it cools any better than the Techkewl vest I already own... 

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13 minutes ago, Gordo said:

The one and only review on amazon though, is pretty underwhelming.

The backpack version (which is basically the same system as Todd and I bought but packaged slightly differently) has many more and more positive reviews. What I found was that (like the "meh" reviewer), the cooling effect of the circulating water was just ok until I dampened the tee shirt I was wearing underneath. With a damp shirt, the vest will keep the entire surface of my upper torso at a constant 55-58degF for several hours.

13 minutes ago, Gordo said:

I am wondering if it cools any better than the Techkewl vest I already own

I think the advantage of the circulating ice water system is that it will keep you consistently cooler for longer than the Techkewl vest. But that may not be enough of an advantage to make it worthwhile to spring for the new vest, especially if you are satisfied with the Techkewl performance.

--Dean

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This new study [1] is a great find Mechanism - thanks! Here is a good summary from this article about the study:

The study found that brown fat could also help the body filter and remove branched-chain amino acids (BCAAs) from the blood. BCAAs (leucine, isoleucine and valine) are found in foods like eggs, meat, fish, chicken and milk, but also in supplements used by some athletes and people who want to build muscle mass.

In normal concentrations in the blood, these amino acids are essential for good health. In excessive amounts, they're linked to diabetes and obesity. The researchers found that people with little or no brown fat have reduced ability to clear BCAAs from their blood, and that may lead to the development of obesity and diabetes.

What the researchers did in more detail was to measure the levels of various amino acids in the blood of 33 healthy men before and after two hours of relatively mild, full-body cold exposure (66F/19C).  What they found was that two BCAAs (leucine and valine) dropped after cold exposure, but only in men who had active brown adipose tissue (BAT). They found the same drop in BCAAs in mice after cold exposure.

Interestingly, they found that mice who were genetically manipulated to prevent the oxidization BCAAs in their BAT mitochondria were much worse at maintaining body temperature in response to cold, suggesting that BCAA catabolism is an important factor in BAT thermogenesis. 

It complements evidence from a study [2] by Luigi Fontana (which I discussed earlier in this thread here and here) that suggested a low protein diet, and specifically one low in BCAAs like leucine and valine, appear to trigger the browning of white fat, at least when mice are housed at normal (cool for mice) temperature, resulting in improved metabolic healthy.

So in a virtuous cycle, cold exposure promotes the development of brown/beige adipose tissue (BAT) which in turn helps clear BCAAs from the bloodstream. The resultant lowering of BCAAs helps promote further browning of white fat, with the side effect of improved metabolic health.

Conversely, in a vicious cycle, large amounts of BCAAs in the diet (mostly from animals products or supplements) stymies the browning of white fat, meaning fewer BCAAs get absorbed and oxidized by BAT, leaving ever-increasing levels of BCAAs in circulation. The authors of [1] describe why increased circulating BCAAs is unhealthy:

It has been suggested that the accumulation of incompletely oxidized intermediates derived from BCAA oxidation [...] causes insulin resistance [refs]. Conversely, lowering circulating BCAA levels [...] improves glucose tolerance independently of body-weight loss in rats [refs]. Furthermore, reduced mitochondrial BCAA oxidation and subsequent intracellular accumulation of BCAA leads to constitutive activation of mTOR signalling, resulting in persistent IRS-1 phosphorylation by mTORC1 and inhibition of insulin signalling [refs].

 The authors of [1] conclude:

Active BAT acts as a significant metabolic filter for circulating BCAA and protects against obesity and insulin resistance.

--Dean

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[1] Nature: August 2019

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Takeshi Yoneshiro, Qiang Wang, […]Shingo Kajimura

Abstract

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

 

[2] Cell Rep. 2016 Jun 21. pii: S2211-1247(16)30733-1. doi:10.1016/j.celrep.2016.05.092.

Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health.
 
Fontana L(1), Cummings NE(2), Arriola Apelo SI(3), Neuman JC(4), Kasza I(5),
Schmidt BA(3), Cava E(6), Spelta F(7), Tosti V(7), Syed FA(3), Baar EL(3),
Veronese N(8), Cottrell SE(9), Fenske RJ(4), Bertozzi B(10), Brar HK(3), Pietka
T(10), Bullock AD(11), Figenshau RS(11), Andriole GL(11), Merrins MJ(12),
Alexander CM(5), Kimple ME(13), Lamming DW(14).
 
 
Protein-restricted (PR), high-carbohydrate diets improve metabolic health in
rodents, yet the precise dietary components that are responsible for these
effects have not been identified. Furthermore, the applicability of these studies
to humans is unclear. Here, we demonstrate in a randomized controlled trial that 
a moderate PR diet also improves markers of metabolic health in humans.
Intriguingly, we find that feeding mice a diet specifically reduced in
branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and
body composition equivalently to a PR diet via metabolically distinct pathways.
Our results highlight a critical role for dietary quality at the level of amino
acids in the maintenance of metabolic health and suggest that diets specifically 
reduced in BCAAs, or pharmacological interventions in this pathway, may offer a
translatable way to achieve many of the metabolic benefits of a PR diet.
 
Copyright © 2016. Published by Elsevier Inc.
 
DOI: 10.1016/j.celrep.2016.05.092 
PMID: 27346343

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Thanks Mechanism for the great find,  and thanks Dean  for the additional details and analysis! 

 

Quote

after two hours of relatively mild, full-body cold exposure (66F/19C).  

That indeed is very mild by Siberian standards!    I would love to know what different  effects you get with  much colder exposure for shorter time periods,  but there is so little information available comparing different protocols for systematic cold exposure training. 

 

Why brown fat is good for people's health

https://www.sciencedaily.com/releases/2019/08/190821135238.htm

 

Quote

Researchers next need to determine whether uptake of BCAAs by brown fat can be controlled by environmental factors -- such as exposure to mildly cold temperatures (65 degrees Fahrenheit) or consumption of spicy foods -- or by drugs.

 

Drugs!   😈

Edited by Sibiriak

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Great summary Dean, I thought you would appreciate it too.  And Sibiriak  -  I love your irreverent humor.  True enough while I favor “natural” approaches over drugs  whenever possible at multiple levels and for many reasons ( though they are usually not mutually exclusive)  - when technology advances to intervene with greater efficacy and safety, I would not hesitate either - even the “D” word.  

The challenge is that evolution has had a head start of hundreds of millions of years coupled with massive parallel statistical reshuffling for both safety and efficacy -  for most lifestyle conditions and most of the time nature is still much smarter than us!

Edited by Mechanism

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The thermonuclear housing debate - current standing in 4 Links

Forgive me Dean for any redundancy, but a recent commentary strung together very nicely the current standing of the research landscape.  I think including them here, in sequence, as a shortcut for those new to the issue to quickly get up to speed on the controversy and state of the science may be helpful.  

And fortunately the debate is narrowing with increased consensus that indeed ( as #4 concludes): “mice should be housed slightly below thermoneutrality to best mimic humans thermal conditions.”

1) Here is Speakman’s original 2013 paper and argument that thermonuclear housing is adequate ( discussed previously along with critiques and reposted here to recapitulate the story line ). 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757658/?report=reader#__ffn_sectitle

 

2) 2018 experimental data - with a very elegant design - from Jan Nedergaard investigating Speakman’s hypothesis and calling into question his conclusion

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784327/?report=reader#__ffn_sectitle

 

3) Speakman’s 2019 follow up experiment and response to Nedergaard — despite the tone, please observe on a close read that the conclusions have more commonalities than differences with the Nedergaard study.  Indeed they revise upward their estimate optimal temperature from the original first publication.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599456/?report=reader#__ffn_sectitle

 

4) Hot off the press now: Nedergaard’s response.   For CRONIES looking for a quick bottom line, if you read nothing else, start here and work your way back to the other links provided to fill in details and examine the raw data for yourself

Here the authors summarize their own work cited above from 2018 evaluating Speakman’s hypothesis, and cite the 2019 by Keijer / Speakman work emphasizing that both publications found that for mice the daily metabolic rate at 30 °C is about 1.7-1.8 times higher than their BMR — approximately the same ratio as found in free dwelling persons.  

This makes the case for their conclusion that: “thermoneutrality is the optimal housing temperature for mouse metabolic studies directed to being translatable into humans.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667698/#__ffn_sectitle

Of course much more work remains to establish the extent of impact, for what medical conditions, interventions, and populations, so there is a lot more detail to fill in here

I have found much of the utility of this thread pertains not only to this but moreover, on a practice level, to incrementally address and better characterize who benefits, by how much, and for what magnitude ( dose/duration/frequency) of different CE exposures along a multitude of potential health-related dependent variables of interest.

Edited by Mechanism

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Cold Exposure Boosts Anti-inflammatory Treg Cells and may Inhibit mTOR

Chronic inflammation is increasingly recognized as a significant contributor to metabolic dysfuction, diseases such as diabetes and CVD, as well as the aging process itself - hence the recently coined term inflammaging

This new paper [1] found that in both mice and humans, cold exposure (2h spent just above individually-determined shivering threshold) triggers an increase in the number of Treg cells circulating in the bloodstream. Treg cells are immune system T-cells that play a beneficial regulatory role by suppressing the chronic inflammatory state thought to contribute to aging and disease.

Interestingly, people with higher circulating leptin levels (the "I'm stuffed" signaling hormone) showed less of a boost in Treg Cells following cold exposure. This is in line with the evolutionary hypothesis that CE + CR (and hence low leptin) work synergistically to improve health and longevity. 

I also found this sentence from the discussion section interesting:

The increased BORCS6 mRNA abundance in human CD4+ T cells exposed to short-term cold is in line with a concept in which physiological levels of beta3-adrenergic stimulation can exert mTORC1-inhibiting activity, thereby directly supporting the induction of human FOXP3+ Tregs.

Both CR and potential longevity boosters like rapamycin are known to work at least in part by suppressing mTOR activity, particularly the mTORC1 complex. This was the first I'd heard that adrenergic stimulation (via e.g. cold exposure) can also tamp down mTORC1 activity.

--Dean

-----------

[1] Mol Metab. 2019 Aug 5. pii: S2212-8778(19)30554-X. doi:

10.1016/j.molmet.2019.08.002. [Epub ahead of print]

Short-term cold exposure supports human Treg induction in vivo.

Becker M(1), Serr I(1), Salb VK(1), Ott VB(2), Mengel L(3), Blüher M(4), Weigmann
B(5), Hauner H(6), Tschöp MH(7), Daniel C(8).

OBJECTIVE: Obesity and type-2 diabetes (T2D) are metabolic diseases that

represent a critical health problem worldwide. Metabolic disease is
differentially associated with fat distribution, while visceral white adipose
tissue (VAT) is particularly prone to obesity-associated inflammation. Next to
their canonical function of immune suppression, regulatory T cells (Tregs) are
key in controlling adipose tissue homeostasis. Towards understanding the
molecular underpinnings of metabolic disease, we focus on how
environmental-metabolic stimuli impinge on the functional interplay between Tregs
and adipose tissue. Here, cold exposure or beta3-adrenergic signaling are a
promising tool to increase energy expenditure by activating brown adipose tissue,
as well as by reducing local inflammation within fat depots by supporting
immunosuppressive Tregs. However, in humans, the underlying mechanisms that
enable the environmental-immune crosstalk in the periphery and in the respective 
tissue remain currently unknown.
METHODS: We used combinatorial approaches of next generation humanized mouse
models and in vitro and in vivo experiments together with beta3-adrenergic
stimulation to dissect the underlying mechanisms of human Treg induction exposed 
to environmental stimuli such as cold. To test the translational relevance of our
findings, we analyzed samples from the FREECE study in which human subjects were 
exposed to individualized cooling protocols. Samples were analyzed ex vivo and
after in vitro Treg induction using qRT-PCR, immunofluorescence, as well as with 
multicolor flow cytometry and cell sorting.
RESULTS: In vivo application of the beta3-adrenergic receptor agonist mirabegron 
in humanized mice induced thermogenesis and improved the Treg induction capacity 
of naïve T cells isolated from these animals. Using samples from the human FREECE
study, we demonstrate that a short-term cold stimulus supports human Treg
induction in vitro and in vivo
. Mechanistically, we identify BORCS6 encoding the 
Ragulator-interacting protein C17orf59 to be significantly induced in human CD4+ 
T cells upon short-term cold exposure. Strong mTOR signaling is known to limit
successful Treg induction and thus likely by interfering with mTOR activation at 
lysosomal surfaces, C17orf59 improves the Treg induction capacity of human naïve 
T cells upon cold exposure.
CONCLUSIONS: These novel insights into the molecular underpinnings of human Treg 
induction suggest an important role of Tregs in linking environmental stimuli
with adipose tissue function and metabolic diseases. Moreover, these discoveries 
shed new light on potential approaches towards tailored anti-inflammatory
concepts that support human adipose tissue homeostasis by enabling Tregs.

Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.

DOI: 10.1016/j.molmet.2019.08.002 
PMID: 31427184 
 

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