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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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On 7/12/2019 at 2:31 AM, Ron Put said:

What are you cold guys averaging for protein

I've ranged from 10% on a vegan diet in the winter to 20% vegetarian diet this summer. I find cold yogurt extremely refreshing (it carries many electrolytes). Eating lots of fats allows enough calories with relatively little protein.

Edited by mccoy

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A Healthy Gut Microbiome Boosts BAT via Butyrate

This new study [1] found that depleting mice of their gut microbiome via antibiotics or a germ-free diet and environment greatly reduced their BAT and subcutaneous beige fat. Repopulating their gut microbiome or simply feeding them the short-chain fatty acid butyrate (which is produced by gut bacteria) restored their BAT, beige fat and thermogenic capacity. The authors conclude:

Our results indicate that gut microbiota contributes to upregulated thermogenesis in the cold environment and that this may be partially mediated via butyrate.

Once again a factor linked to good health (healthy bacteria in the gut) is associated with boosting BAT and beige fat.

--Dean

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis, with the factors mentioned in this post highlighted in red:

  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
  • Anthocyanin-rich foods - Blackberries, cherries, blueberries, raspberries, plums
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
  • Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
  • Rutin-rich foods - Buckwheat, apple peels, citrus fruit, mulberries, aronia berries, cranberries, peaches, rooibos tea, amaranth leaves, figs
  • Certain Fungi - Cordycepin but not shitake mushrooms
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • Healthy Gut Microbiome - Short chain fatty acids (e.g. Butyrate)
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
  • Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
  • Low gluten diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
  • Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
  • Low protein diet
  • Drugs / Supplements - metformin, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, melatonin, alpha-lipoic acid (ALA)
  • Medicinal Herbs - ginger root, ginseng, cannabidiol / hemp oil / medicinal marijuana, balloon flower root (Platycodon Grandiflorus)
  • Time Restricted Feeding - most calories at breakfast
  • Exercise & elevated lactate / lactic acid
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • Low testosterone / castration in mice (and men?)
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]
  • [being of genotype TT for rs1800592, TT for FTO SNP rs1421085 and AA for rs4994 as reported by 23andMe]

 

[1] Cell Rep. 2019 Mar 5;26(10):2720-2737.e5. doi: 10.1016/j.celrep.2019.02.015.

Microbiota Depletion Impairs Thermogenesis of Brown Adipose Tissue and Browning
of White Adipose Tissue.

Li B(1), Li L(1), Li M(2), Lam SM(3), Wang G(2), Wu Y(2), Zhang H(4), Niu C(3),
Zhang X(2), Liu X(1), Hambly C(5), Jin W(6), Shui G(3), Speakman JR(7).

The relation between gut microbiota and the host has been suggested to benefit

metabolic homeostasis. Brown adipose tissue (BAT) and beige adipocytes facilitate
thermogenesis to maintain host core body temperature during cold exposure.
However, the potential impact of gut microbiota on the thermogenic process is
confused. Here, we evaluated how BAT and white adipose tissue (WAT) responded to 
temperature challenges in mice lacking gut microbiota. We found that microbiota
depletion via treatment with different cocktails of antibiotics (ABX) or in
germ-free (GF) mice impaired the thermogenic capacity of BAT by blunting the
increase in the expression of uncoupling protein 1 (UCP1) and reducing the
browning process of WAT.
Gavage of the bacterial metabolite butyrate increased
the thermogenic capacity of ABX-treated mice, reversing the deficit. Our results 
indicate that gut microbiota contributes to upregulated thermogenesis in the cold
environment and that this may be partially mediated via butyrate.

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

DOI: 10.1016/j.celrep.2019.02.015 
PMID: 30840893 

 

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Dog Breed Longevity Linked to Mitochondrial Uncoupling

Study [1] is a fascinating exploration of why small dog breeds live so much longer (2.5x) than large breeds. They did genome-wide analysis and cultured (fibroblast) cells from dogs of various breeds to see how they differed.

The figure below summarizes their finding. In short, they found that small long-lived dog breeds have evolved to have less coupled mitochondria, which results in greater proton leak across mitochondrial membrane, which generates heat to keep the small dogs warm. This results in a higher metabolic rate in small, long-lived dogs, but also less ROS production, which they suggest is an important contributor to their longevity.

Cold exposure also triggers greater mitochondrial uncoupling to generate heat, not only in BAT and beige fat, but also in human skeletal muscles [2], where oxidative damage is thought to be a significant contributor to aging. If I had to point to one pathway by which cold exposure is likely to contribute to slowing the aging process, it would be through decreased oxidative damage as a result of increased mitochondrial uncoupling.

--Dean

Screenshot_20190713-131034_Chrome.jpg

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

[1] Geroscience. 2019 Apr;41(2):229-242. doi: 10.1007/s11357-019-00062-6. Epub 2019

Apr 1.

Cellular energetics and mitochondrial uncoupling in canine aging.

Nicholatos JW(1), Robinette TM(2), Tata SVP(2), Yordy JD(2), Francisco AB(2),
Platov M(2), Yeh TK(2), Ilkayeva OR(3), Huynh FK(3), Dokukin M(4), Volkov D(4),
Weinstein MA(5), Boyko AR(2), Miller RA(6), Sokolov I(4)(5), Hirschey MD(3),
Libert S(7).

The first domesticated companion animal, the dog, is currently represented by

over 190 unique breeds. Across these numerous breeds, dogs have exceptional
variation in lifespan (inversely correlated with body size), presenting an
opportunity to discover longevity-determining traits. We performed a genome-wide 
association study on 4169 canines representing 110 breeds and identified novel
candidate regulators of longevity. Interestingly, known functions within the
identified genes included control of coat phenotypes such as hair length, as well
as mitochondrial properties, suggesting that thermoregulation and mitochondrial
bioenergetics play a role in lifespan variation. Using primary dermal
fibroblasts, we investigated mitochondrial properties of short-lived (large) and 
long-lived (small) dog breeds. We found that cells from long-lived breeds have
more uncoupled mitochondria, less electron escape, greater respiration, and
capacity for respiration.
Moreover, our data suggest that long-lived breeds have 
higher rates of catabolism and β-oxidation, likely to meet elevated respiration
and electron demand of their uncoupled mitochondria. Conversely, cells of
short-lived (large) breeds may accumulate amino acids and fatty acid derivatives,
which are likely used for biosynthesis and growth. We hypothesize that the
uncoupled metabolic profile of long-lived breeds likely stems from their smaller 
size, reduced volume-to-surface area ratio, and therefore a greater need for
thermogenesis. The uncoupled energetics of long-lived breeds lowers reactive
oxygen species levels, promotes cellular stress tolerance, and may even prevent
stiffening of the actin cytoskeleton. We propose that these cellular
characteristics delay tissue dysfunction, disease, and death in long-lived dog
breeds, contributing to canine aging diversity.

DOI: 10.1007/s11357-019-00062-6 
PMCID: PMC6544733
PMID: 30937823 
 

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

[2] PLoS One. 2008 Mar 12;3(3):e1777. doi: 10.1371/journal.pone.0001777.

Human skeletal muscle mitochondrial uncoupling is associated with cold induced
adaptive thermogenesis.

Wijers SL(1), Schrauwen P, Saris WH, van Marken Lichtenbelt WD.

Author information: 
(1)Department of Human Biology, Nutrition and Toxicology Research Institute
Maastricht (NUTRIM), Maastricht University, The Netherlands.
S.Wijers@hb.unimaas.nl

BACKGROUND: Mild cold exposure and overfeeding are known to elevate energy
expenditure in mammals, including humans. This process is called adaptive
thermogenesis. In small animals, adaptive thermogenesis is mainly caused by
mitochondrial uncoupling in brown adipose tissue and regulated via the
sympathetic nervous system. In humans, skeletal muscle is a candidate tissue,
known to account for a large part of the epinephrine-induced increase in energy
expenditure. However, mitochondrial uncoupling in skeletal muscle has not
extensively been studied in relation to adaptive thermogenesis in humans.
Therefore we hypothesized that cold-induced adaptive thermogenesis in humans is
accompanied by an increase in mitochondrial uncoupling in skeletal muscle.
METHODOLOGY/PRINCIPAL FINDINGS: The metabolic response to mild cold exposure in
11 lean, male subjects was measured in a respiration chamber at baseline and mild
cold exposure. Skeletal muscle mitochondrial uncoupling (state 4) was measured in
muscle biopsies taken at the end of the respiration chamber stays. Mild cold
exposure caused a significant increase in 24h energy expenditure of 2.8% (0.32
MJ/day, range of -0.21 to 1.66 MJ/day, p<0.05). The individual increases in
energy expenditure correlated to state 4 respiration (p<0.02, R(2) = 0.50).
CONCLUSIONS/SIGNIFICANCE: This study for the first time shows that in humans,
skeletal muscle has the intrinsic capacity for cold induced adaptive
thermogenesis via mitochondrial uncoupling under physiological conditions.
This
opens possibilities for mitochondrial uncoupling as an alternative therapeutic
target in the treatment of obesity.

DOI: 10.1371/journal.pone.0001777 
PMCID: PMC2258415
PMID: 18335051  [Indexed for MEDLINE]

 

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I have come across this study (DOI: 10.1038/35046114) which says:

https://www.researchgate.net/publication/12210344_Coenzyme_Q_is_an_obligatory_cofactor_for_uncoupling_protein_function

Coenzyme Q is an obligatory cofactor for uncoupling protein function

"Uncoupling proteins (UCPs) are thought to be intricately controlled uncouplers that are responsible for the futile dissipation of mitochondrial chemiosmotic gradients, producing heat rather than ATP. They occur in many animal and plant cells and form a subfamily of the mitochondrial carrier family. Physiological uncoupling of oxidative phosphorylation must be strongly regulated to avoid deterioration of the energy supply and cell death, which is caused by toxic uncouplers. However, an H+ transporting uncoupling function is well established only for UCP1 from brown adipose tissue, and the regulation of UCP1 by fatty acids, nucleotides and pH remains controversial. The failure of UCP1 expressed in Escherichia coli inclusion bodies to carry out fatty-acid-dependent H+ transport activity inclusion bodies made us seek a native UCP cofactor. Here we report the identification of coenzyme Q (ubiquinone) as such a cofactor. On addition of CoQ10 to reconstituted UCP1 from inclusion bodies, fatty-acid-dependent H+ transport reached the same rate as with native UCP1. The H+ transport was highly sensitive to purine nucleotides, and activated only by oxidized but not reduced CoQ. H+ transport of native UCP1 correlated with the endogenous CoQ content" 

and another study (PMID: 28811612)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557856/

Coenzyme Q10 Improves Lipid Metabolism and Ameliorates Obesity by Regulating CaMKII-Mediated PDE4 Inhibition

"BAT thermogenesis induces expression of uncoupling protein 1 (Ucp1) and other genes, promoting lipolysis, mitochondrial biogenesis, and β-oxidation of fatty acids. Our experiment showed that mRNA expression of Ucp1 and other thermogenesis-related genes was significantly increased in BAT from KKAy mice supplemented with CoQ10H2 compared with the control group, suggesting that the CoQ10H2 group had increased BAT thermogenic activity (Fig. 2C). "

I don't think they have been mentioned before

Edited by Iporuru
misspelling

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Iporuru,

Nice to hear from you! You are right, it does appear that CoQ (CoQ10 in the case of humans) is involved in mitochondrial uncoupling. While CoQ is synthesized endogenously, there is some evidence that CoQ supplements can boost BAT and WAT browning in a diabetes-prone strain of mice, improving their metabolic health [1]. So I'm adding CoQ10 to the list of potential BAT and thermogenesis promoters.

Thanks!

--Dean

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis, with the factors mentioned in this post highlighted in red:

  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
  • Anthocyanin-rich foods - Blackberries, cherries, blueberries, raspberries, plums
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
  • Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
  • Rutin-rich foods - Buckwheat, apple peels, citrus fruit, mulberries, aronia berries, cranberries, peaches, rooibos tea, amaranth leaves, figs
  • Certain Fungi - Cordycepin but not shitake mushrooms
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • Healthy Gut Microbiome - Short chain fatty acids (e.g. Butyrate)
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
  • Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
  • Low gluten diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
  • Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
  • Low protein diet
  • Drugs / Supplements - metformin, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, melatonin, alpha-lipoic acid (ALA), CoQ10
  • Medicinal Herbs - ginger root, ginseng, cannabidiol / hemp oil / medicinal marijuana, balloon flower root (Platycodon Grandiflorus)
  • Time Restricted Feeding - most calories at breakfast
  • Exercise & elevated lactate / lactic acid
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • Low testosterone / castration in mice (and men?)
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]
  • [being of genotype TT for rs1800592, TT for FTO SNP rs1421085 and AA for rs4994 as reported by 23andMe]

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

[1] Sci Rep. 2017 Aug 15;7(1):8253. doi: 10.1038/s41598-017-08899-7.

Coenzyme Q10 Improves Lipid Metabolism and Ameliorates Obesity by Regulating
CaMKII-Mediated PDE4 Inhibition.

Xu Z(1), Huo J(2), Ding X(2), Yang M(2), Li L(2), Dai J(2), Hosoe K(3), Kubo
H(3), Mori M(2)(4), Higuchi K(2)(5), Sawashita J(2)(5).

Our recent studies revealed that supplementation with the reduced form of

coenzyme Q10 (CoQ10H2) inhibits oxidative stress and slows the process of aging
in senescence-accelerated mice. CoQ10H2 inhibits adipocyte differentiation and
regulates lipid metabolism. In the present study, we show that dietary
supplementation with CoQ10H2 significantly reduced white adipose tissue content
and improved the function of brown adipose tissue by regulating expression of
lipid metabolism-related factors in KKAy mice, a model of obesity and type 2
diabetes
. In the liver, CoQ10H2 reduced cytoplasmic Ca2+ levels and consequently 
inhibited the phosphorylation of CaMKII. CoQ10H2 also regulated the activity of
the transcription factor C-FOS and inhibited gene expression of PDE4, a
cAMP-degrading enzyme, via the CaMKII-MEK1/2-ERK1/2 signaling pathway, thereby
increasing intracellular cAMP. This increased cAMP activated AMPK, enhanced
oxidative decomposition of lipids, and inhibited de novo synthesis of fatty
acids, inhibiting the development and progression of obesity and type 2 diabetes.
These results suggest that CoQ10H2 supplementation may be useful as a treatment
for metabolic disorders associated with obesity.

DOI: 10.1038/s41598-017-08899-7 
PMCID: PMC5557856
PMID: 28811612  [Indexed for MEDLINE]

 

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Hi Dean, this is such a long thread, it is difficult to remember where in the thread a specific mechanism is being discussed. What would be fantastic if somehow it would be possible to indicate next to each of the lists of factors influencing BAT the post number where that specific factor is discussed - now that's a huge job so maybe it's possible to somehow employ our favorite hype tech - AI - to quickly identify and generate such a list. Anyhow the value of that would be that in this way no one would again post a study that may have already been posted in the tread, as has happened to me to my great embarrassment, as I can't remember the entire thread. So for example, while metformin is listed, I don't know what context it was discussed in. For example, the recent emphasis of mitochondrial uncoupling can also be found with metformin - but metformin was discussed earlier, and my question is whether mitochondrial uncoupling was discussed wrt. metformin - or whether this study was posted or referenced in the thread:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147388/

Metformin directly acts on mitochondria to alter cellular bioenergetics

Quote:

"We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions."

Another class of drugs that might be mentioned are statins due to widespread use. Statins are associated with diabetes as well as muscle impairment and depending on the class of statin (hydrophilic or lypophilic) their mechanism of action is through mitochondrial oxidative stress. The impact of statins is non-obvious precisely because of the differing mechanisms among different classes of statins. Example 1:

https://www.genengnews.com/news/cholesterol-lowering-drugs-inhibit-brown-fat-activity/

Cholesterol-Lowering Drugs Inhibit Brown Fat Activity

Example 2:

https://www.ncbi.nlm.nih.gov/pubmed/29121499

Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis.

Example 3:

https://www.nature.com/articles/s41598-017-11070-x

Atorvastatin but Not Pravastatin Impairs Mitochondrial Function in Human Pancreatic Islets and Rat β-Cells. Direct Effect of Oxidative Stress

In general, it seems the impact of statins is a very complicatd and contradictory story, but probably statins are worth mentioning wrt. BAT on account of how many people do take statins (including myself recently).

 

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On 7/9/2019 at 8:37 AM, Dean Pomerleau said:

Moderate CE + mild CR (20%) Preserves Brown/Beige Fat & Metabolic Health

This new study [1] found that in AL-fed mice housed at room temperature (10degF below mouse thermoneutrality), aging results in "whitening" of both brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT) ... Mild CR (20% below AL) resulted in a reversal of this whitening in BAT and scWAT, along with reversing the age-related insulin resistance and inflammation ... [but] 40% CR ... did not appear to result in scWAT beiging. ...

These data seem to contrast with others (Rogers et al., [2]), which described that after 10 months of 40% CR, no BAT‐like areas were detected in scWAT from 12‐m animals. 

This seems pretty strong evidence against BAT being an important driver of retardation of aging by CR, since (despite one odd one-off study) it's well-established that more severe (in some cases up to ≈55%) CR is dose-dependently more effective than less severe CR.

On 7/9/2019 at 8:37 AM, Dean Pomerleau said:

It appears that the severely CRed mice in [2] had there thermogenic genes up-regulated, but that wasn't sufficient to turn their subcutaneous WAT to metabolically active beige fat. ...

In other words, at normal (cold-for-mice) room temperature, both 20% CR and 40% CR upregulate expression of the genes for boosting BAT activity and the browning of scWAT. But particularly at the more severe level of CR, the "scarcity of fuel and energy reservoir" may prevent the boosting of BAT and beige fat, and therefore attenuate some of the metabolic benefits of CR, like improved glucose metabolism.

This certainly makes sense.

It's also a reminder of something I've said before and should get more care in this thread: that mere induction of genes is an inadequate indicator of fat browning. There should be data on the target proteins, and preferably on the actual phenotype of the fat and/or experimental subject. Dean, it would help if you would tare down your list to things that at least meet this criterion, and preferably tag off those shown effective in humans.

On 7/9/2019 at 8:37 AM, Dean Pomerleau said:

Relative to rodents, humans are more dependent on the beiging of subcutaneous white fat (scWAT) than increasing their true brown fat (BAT). So if serious CR prevents the beiging of scWAT, it would explain the surprisingly poor showing several of us (especially me), did on the glucose tolerance test in Luigi Fontana's 2010 study [3] of long-term CR folks, and subsequently the improvements in glucose clearance that seem to occur eating more calories coupled with consistent CE. See here for extensive discussion, including my own anecdotal improvement in glucose metabolism as a result of eating more calories in combination CE.

That's certainly one possibility, although there are many others. And anecdotally, I'm of course extremely slim, doubt I have more than a tiny shred of BAT on my skinny ass (or subscapula ;)), but when actually put to OGTT rather than surrogate markers, I have excellent glucose tolerance — and that, when there's a rationale for which I probably ought to be tested with a lower dose of glucose to be metabolically meaningful.

[1] Aging Cell [28 Mar 2019, 18(3):e12948] DOI: 10.1111/acel.12948

Long-term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity.

Corrales P 1 ,  Vivas Y 1 ,  Izquierdo-Lahuerta A 1 ,  Horrillo D 1 ,  Seoane-Collazo P 2 ,  Velasco I 1 ,  Torres L 1 ,  Lopez Y 1 ,  Martínez C 1 ,  López M 2 ,  Ros M 1 ,  Obregon MJ 3 ,  Medina-Gomez G 1   

(PMID:30920127 PMCID:PMC6516146)

---------
[2] Aging Cell. 2012 Dec;11(6):1074-83. doi: 10.1111/acel.12010. Epub 2012 Oct 24.

Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white
adipose tissue.

Rogers NH(1), Landa A, Park S, Smith RG.

DOI: 10.1111/acel.12010 
PMCID: PMC3839316
PMID: 23020201  [Indexed for MEDLINE]

--------

[3] Age (Dordr). 2010 Mar;32(1):97-108. doi: 10.1007/s11357-009-9118-z. Epub 2009 Nov11.

Effects of long-term calorie restriction and endurance exercise on glucose
tolerance, insulin action, and adipokine production.

Fontana L(1), Klein S, Holloszy JO.

DOI: 10.1007/s11357-009-9118-z 
PMCID: PMC2829643
PMID: 19904628  [Indexed for MEDLINE]
 

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New Cooling Vest Review

I've had my new circulating ice water cooling vest for a few days now, so it's time for a review. As an introduction, I happened to come across a new paper [1] on the efficacy of my old cooling vest, the Cool Fat Burner, (CFB) which I reviewed previously here.

The summary of both my own review and the paper [1] on the CFB is that it works great. With the "hard pack" ice packs it stays very cold for several hours. When I wear it while sitting around idlely, it can easily bring me to full blown shivering, particularly when I load up both the shoulder vest and the "Gut Buster" vest with ice packs (the system comes in two parts - see my review). Study [1] found that to be the case of 14 people tested, and when they were shivering the CFB boosted their metabolic rate by around 75% over their BMR.

But the CFB system has several drawbacks too. First, it is quite heavy and bulky when fully loaded with ice packs (~16lbs) - see photos in my review. Second, the flexible ice packs that you can get with the CFB are nice because they conform to your body. But they warm up much more quickly than the hard ice packs. So I end up using the hard packs for effective, long-lasting cooling. But the hard pack ice packs are rigid, so they don't conform to the body. This can result in some chaffing, and excessive cooling to the spots on the skin directly below the ice packs. I actually have a few irritation spots on my upper back that are healing after wearing my CFB with hard packs for too long early last week. Finally, it is hard to modulate the cooling by the CFB. Sometimes I just wear half the system (the shoulder portion) but that doesn't provide as much cooling as I'd like, but the full system sometimes is too much, since it induces shivering, which I'd rather stay just short of, and the lower portion rather uncomfortable to sit down in.

These shortcomings of the CFB were the reason I purchased the new circulating ice water vest on Amazon fom CompCooler.

First, I have to say the reviews were spot on in characterizing the vest as well-engineered and well-constructed. The tubing, connectors and zipper all seem quite rugged. The adjustments make it so that the M/L size should fit most CR folks (unfortunately I notice the M/L is sold out at the moment for the black vest on Amazon, although M/L appears available in the beige model).

Here are a few pictures of the vest. Notice in the first one the on/off switch for the pump on the front left of the vest. This is very helpful for modulating the degree of cold, since when you turn the pump off, the water in the tubing warms up due to body heat.

20190714_125831.jpg

Here you can see the tubing running around the inside of the vest, including over the shoulder and upper back area, where most human BAT is located.20190714_135430.jpg

Here is a front and side view of me wearing the vest:

20190714_135405.jpg  20190714_135342.jpg

There is definitely a bump on the back - that's where the ice-filled reservoir is (see below). It is fine to sit in a chair and lean back with, but would be quite uncomfortable to lie down on, and I'd be nervous about damaging the reservoir by laying down on it.

Here is a shot of the back zipped up and unzipped. The interior of the pouch is lined with some kind of silver insulating material to help keep the reservoir cold longer. The battery is located in a pouch near the  top and the water pump is located in a pouch at the bottom. 

20190714_132923.jpg20190714_140148.jpg

The way it works is you put the mostly-full water reservoir in the freezer. In a few hours it's fully frozen. You then add ~200ml of tap water to the reservoir to prime the pump, and then hook it up inside the pouch on the back. Here is a picture of the pouch once I've put the frozen reservoir in. You can see me connecting the tubing, which clicks into the coupling on the reservoir with a nice snap to let you know it is sealed and secure. I've had no problem with leakage or condensation and I don't expect too.

20190714_135030.jpg

Then you put it on, zip it up, and hit the switch on the front lapel to start the pump. Almost instantly you can feel the cold water circulating through the tubing that lines the vest. At first I tried wearing it without a shirt to maximize cooling. But I found it to be a little itchy, so I started wearing a t-shirt under the vest. This attenuated the cooling a bit too much for me. What I found works great is to dampen the chest and back of my t-shirt. That way, the cold water running through the tubing cools the damp areas of the t-shirt which in turn cools my skin. This wasn't possible with the CFB vest because the ice-packs would freeze the damp t-shirt, and potentially damage the skin underneath. Since the water in the tubing is close to freezing, but not below 32F, freezing of the t-shirt isn't a problem.

With this tweak, and a fan blowing on the rest of my body while sitting, I can easily get to the point of shivering even though my house temperature is around 75F. But by selectively turning off the pump for short periods occasionally, I can keep myself from the point of shivering but with serious goosebumps for ~3h hours straight before having to change the ice reservoir. I bought a spare reservoir, so I can get six hours of cooling with fully charged reservoirs (indoors that is - less if you're out in the heat which I haven't tried yet). By the time the second reservoir has melted, the first one has somewhat refrozen in the freezer - but not completely. What I do is dump out some of the water and replace it with ice cubes from my freezer, and I'm good to go for another couple hours. The reservoir pouch has enough spare room that I can add an ice pack against the reservoir to keep it cold longer.

The battery lasts about 8 hours of continuous use, which is about the maximum I've warn it in a day. I bought a spare battery but haven't really needed it. Gordo this version doesn't have the USB connector for running the pump from on wall power, which was mentioned in the Q&A for the backpack version. The pump is pretty quiet - a soft gurgling very much like an aquarium pump (which it probably is!). The system weights about 10lbs with the full reservoir, quite a bit less than the CFB. Plus it's a lot less unweildy. I can easily walk with it on my treadmill desk, which was a bit awkward with the full CFB rig.

Overall, I'm very pleased with the new vest. At around $300 with the spare reservoir and battery, it was more expensive than the CFB, but I like it a lot better. In fact I haven't used my CFB since the new vest arrived and don't plan to.

I haven't tried the KewlTech vest that Gordo uses, so I can't compare. I suspect you might be able to achieve a similar degree of cooling for a little while at least with a damp t-shirt under the KewlTech vest. What I'm not sure about is how long that degree of cooling would last with the KewlTech.

I'll post an update if I notice anything else.

--Dean

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

[1] J Sports Med Phys Fitness. 2019 Feb 5. doi: 10.23736/S0022-4707.18.09010-2. [Epub

ahead of print]

Use of the "Cool Fat Burner" in conjunction with drinking of cold water is
associated with acute and minor increases in energy expenditure and fat
metabolism in overweight men and women.

Grove PE(1).

Author information: 
(1)Private Practictioner, Houstontown, PA, USA - CoolFatBurner@gmail.com.

BACKGROUND: Exposure to cold is associated with increased energy expenditure to
maintain thermal equilibrium. The Cool Fat Burner vest and Gut Buster are
chilling devices used to induce shivering and increase calorie use. Drinking
chilled water has a similar effect.                        ETHODS: Indirect calorimetry was performed on volunteers at rest with induced
shivering. VO2 (oxygen uptake), Rf (respiratory frequency), VT (tidal volume), VE
(minute ventilation), R (respiratory quotient, VCO2/VO2), energy expenditure (EE)
(kcal/min), and fuel source (% from carbohydrate and % from fat) during rest
(resting metabolic rate-RMR) were determined.
RESULTS: Eight men and 6 women with a mean age of 32.14 + 7.26 years were
evaluated while wearing the Cool Fat Burner Vest and Gut Buster and drinking
chilled water. Mean BMI was 27.58 + 2.11 (kg/m2).
CONCLUSIONS: Use of the chilling devices was associated with a significant
increase in VO2, VT, VE, R, and EE. An over 20% increase in fat use as a fuel
source was observed along with a 67% increase in EE. The energy expenditure
during the final 30 minutes of shiver chilling was 74.6% above that of the RMR.
Chilling induced significant increases in energy expenditure associated with a
shift in energy source towards more fat tissue use.

DOI: 10.23736/S0022-4707.18.09010-2 
PMID: 30722649 
 

 

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2 hours ago, TomBAvoider said:

this is such a long thread, it is difficult to remember where in the thread a specific mechanism is being discussed.

Tom. Yup, it is a pain to track down the posts in which various candidate BAT boosters are first discussed and added to the list. Here is the link to the Metformin post. They way I found it was via this search on the forum search page:

Screenshot_20190714-153759_Chrome.jpg

The "UCP2" in the "Search by Tags" box limits the search dramatically since the Cold Exposure thread is about the only one that has UCP2 as a tag. Then on the search results page I choose "sort by date" and then jump to the last page of results. Scanning up you can usually pretty easily find the post where the target factor (e.g. Metformin) is first mentioned in the thread and added to the list of BAT activators.

Obviously this isn't optimal and it would be nicer if the list was annotated with links to the original post where the factor is first discussed. But that would be a lot of work. I'll try to include a link from now on.

Regarding statins, I'm afraid this study [1] you pointed to is pretty clear, a wide range of statins appear to inhibit BAT and the browning of white fat in both mice and men. The statins they tested include Atorvastatin, Fuvastatin, Pravastatin, Rosuvastatin, and Simuvastatin. I'm adding "avoid statins" to the list of BAT (non-)activators, with a link to this post.

--Dean

Here is the latest full list of modifiable and [nonmodifiable] factors associated with increased brown/beige adipose tissue and/or thermogenesis, with the factors mentioned in this post highlighted in red:

  • Cold exposure - by far the best BAT inducer/activator
  • Spicy / pungent foods, herbs & supplements - capsaicin / chilli peppers, curcumin / turmeric root, menthol/mint/camphor, oregano, cloves, mustard, horseradish/wasabi, garlic, onions
  • Sulforaphane-rich foods - Broccoli, brussels sprouts, cabbage
  • Anthocyanin-rich foods - Blackberries, cherries, blueberries, raspberries, plums
  • Nitrate-rich foods - beets, celery, arugula, and spinach
  • Arginine-rich foods - Good vegan sources include seeds (esp. sesame, sunflower & pumpkin), nuts (esp. almonds and walnuts) and legumes (esp. soy, lupin & fava beans and peas)
  • Citrulline-rich foods - Highest by far in watermelon, but also some in onions, garlic, onions, cucumber, other melons & gourds, walnuts, peanuts, almonds, cocoa, chickpeas
  • Luteolin-rich foods - Herbs (thyme, parsley, oregano, peppermint, rosemary), hot peppers, citrus fruit, celery, beets, spinach, cruciferous veggies, olive oil, carrots. 
  • Rutin-rich foods - Buckwheat, apple peels, citrus fruit, mulberries, aronia berries, cranberries, peaches, rooibos tea, amaranth leaves, figs
  • Certain Fungi - Cordycepin but not shitake mushrooms
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • Healthy Gut Microbiome - Short chain fatty acids (e.g. Butyrate)
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • Other foods - Apples / apple peels / ursolic acid; Citrus fruit / citrus peels / limonene; Honey / chrysin
  • Beverages - green tea, roasted coffee, red wine, cacao beans / chocolate
  • Low gluten diet
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine, but also high in leucine.
  • Leucine restriction - Reduce animals protein. Leucine is highest in beef, fish, eggs, cheese and soy.
  • Low protein diet
  • Drugs / Supplements - metformin, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, melatonin, alpha-lipoic acid (ALA), CoQ10
  • Drugs / Supplements to avoid - statins
  • Medicinal Herbs - ginger root, ginseng, cannabidiol / hemp oil / medicinal marijuana, balloon flower root (Platycodon Grandiflorus)
  • Time Restricted Feeding - most calories at breakfast
  • Exercise & elevated lactate / lactic acid
  • Acupuncture - locations Zusanli (foot - ST36) and Neiting (lower leg - ST44) 
  • Whole body vibration therapy
  • Avoid obesity/overweight
  • Low testosterone / castration in mice (and men?)
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]
  • [being of genotype TT for rs1800592, TT for FTO SNP rs1421085 and AA for rs4994 as reported by 23andMe]

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

[1] Cell Metab. 2019 Apr 2;29(4):901-916.e8. doi: 10.1016/j.cmet.2018.11.017. Epub

2018 Dec 20.

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by
Affecting Protein Prenylation.

Balaz M(1), Becker AS(2), Balazova L(1), Straub L(1), Müller J(3), Gashi G(4),
Maushart CI(4), Sun W(1), Dong H(1), Moser C(1), Horvath C(1), Efthymiou V(1),
Rachamin Y(1), Modica S(1), Zellweger C(3), Bacanovic S(3), Stefanicka P(5),
Varga L(6), Ukropcova B(7), Profant M(5), Opitz L(8), Amri EZ(9), Akula MK(10),
Bergo M(11), Ukropec J(12), Falk C(13), Zamboni N(14), Betz MJ(15), Burger
IA(16), Wolfrum C(17).

Recent research focusing on brown adipose tissue (BAT) function emphasizes its

importance in systemic metabolic homeostasis. We show here that genetic and
pharmacological inhibition of the mevalonate pathway leads to reduced human and
mouse brown adipocyte function in vitro and impaired adipose tissue browning
in vivo. A retrospective analysis of a large patient cohort suggests an inverse
correlation between statin use and active BAT in humans, while we show in a
prospective clinical trial that fluvastatin reduces thermogenic gene expression
in human BAT.
We identify geranylgeranyl pyrophosphate as the key mevalonate
pathway intermediate driving adipocyte browning in vitro and in vivo, whose
effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing 
geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ
signaling through F-actin modulation. Conversely, adipocyte-specific ablation of 
GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and
glucose intolerance under obesogenic conditions, highlighting the importance of
this pathway in modulating brown adipocyte functionality and systemic metabolism.

Copyright © 2018 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2018.11.017 
PMID: 30581121 
 

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On 7/12/2019 at 8:54 PM, Ron Put said:

Wow! How do you manage that?

(I saw that sundae photo you posted elsewhere.) 😄

I haven't done tracking in years, but since this is now relevant to BAT/CE curiosity got the better of me and I went back and looked at my data from when I did track everything.  I pulled out my most commonly eaten meals and calculated protein% and this was the result:

Protein%    
11.17%    
8.18%    
12.83%    
11.37%    
8.72%    
12.08%    
8.58%    
10.42%    Average

 

Based on some google searches it seems this is fairly typical of people who eat a mostly plant based whole food diet.  But I actually eat more nuts and beans these days compared to back then, so my protein % is likely a bit higher now.  I will eat dairy maybe a couple times a month, and meat every now and then, but neither are routine for me.  I'll eat some ice cream with my family a few times a year but I'd much rather indulge with one of my wife's strawberry or blueberry pies 😉

NOTE: The type of protein may be more important than just % or absolute grams of protein.  Fontana talked about this in his recent CR related lecture that keeps coming up in various threads:

53:40 Importance of low protein / methionine restriction for longevity independent of CR (blocks tumor development)

59:25 You should eat around 10% protein ("a calorie is not a calorie", "stay away from low carb or ketogenic diets")

1:04:20 Talks about the gut microbiome.  Diet reliably and rapidly changes the gut microbiome, protein intake and fiber are key, the more diversity of vegetables you eat the better your gut microbiome, which results in reduced inflamation (related to short chain fatty acids). Eat legumes, whole grains, and lots of vegetables.

1:10:50 Your gut microbiome impacts your physiologic response to CR

 

Dean - thanks for that circulating cooling vest review, looks pretty nice.  I think I might mess around with a homemade version just for fun (plus I already have pumps and a big coil of copper tubing and spare coolers).

Edited by Gordo

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By the way, this is obvious but we should always remind that protein ratio is a relative number. It is very arguable that it is a more important parameter rather than absolute protein quantity.

10% protein (by energy) in a 1800 kcal plan means 180 kcals of protein= 45 g protein

10% protein in a 3000 kcal plan means 300 kcals of protein= 75 g protein

More significant parameters would be g/kg/d or %RDA.

I know about the papers by Biot et al who affirm that this 10% ratio is the optimum for longevity, but conceptually it doesn't make much sense . In an hypocaloric diet this ratio might induce a deficit of essential amminoacids and in an hypercaloric one this ratio may provide an excess of protein.

Edited by mccoy

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Michael,

First of all. Great to hear from you! I hope life is treating you well.

23 hours ago, Michael R said:

This [i.e. The fact that subcutaneous white fat exhibited browning on 20% CR in one study, but not on 40% CR in another study] seems pretty strong evidence against BAT being an important driver of retardation of aging by CR, since (despite one odd one-off study) it's well-established that more severe (in some cases up to ≈55%) CR is dose-dependently more effective than less severe CR.

Nice try Michael, except you overlook a few things:

  1. The idea that CR is always longevity promoting up to 40% or even 55% restriction is not nearly as cut-n-dried as you suggest. The thread to which you point has a long discussion of the evidence, so I won't rehash all that here, except to point to the section of Luigi Fontana's recent video (thanks Gordo for the annotations!) where he briefly discusses the evidence that 40% CR in rodents isn't always beneficial, and can in fact result in shorten lifespan relative to a more moderate 20% CR. Quoting Luigi (at 46:00 in that video), he speculates:
    "The starvation [of 40% CR in certain strains of mice] was excessive and so there was not enough energy to promote longevity." 
  2. You seem to have conflated BAT with browning of subcutaneous white fat, despite the fact which you well know that they are two entirely separate tissues. In other words, the fact that 40% CR retards browning of scWAT says nothing about BAT activity, so your assertion "This [i.e. The fact that subcutaneous white fat exhibited browning on 20% CR in one study, but not on 40% CR in another study] seems pretty strong evidence against BAT being an important driver of retardation of aging by CR" is a complete non-sequitur.
  3. Fortunately, we have evidence (discussed here) that BAT is preferentially spared relative to other tissues and organs, to a similar degree that critical organs like the kidney are spared at all levels of CR up to 40%. Speakman found the same thing (i.e. CR-induced catabolism spares BAT), which you and I discussed here. Not only is BAT preferentially preserved at all levels of CR, so is the norepinephrine signaling that drives BAT to generate heat (discussed here). So you contention that BAT thermogenesis must be irrelevant for the longevity benefits of CR is again seriously undermined.
  4. My major longevity contention is not necessarily that BAT or BAT activity per se is beneficial, but that something downstream of cold exposure is beneficial when combined with CR. That "something" might involve BAT activity. It might involve beige fat activity. It might be improved immune response, less "inflamaging" and lower cancer rates. It might involve improved glucose metabolism even in the context of CR-induced low insulin levels. It might be lower mitochondrial damage due to greater uncoupling in various tissues. It might be a combination of any of these. So even if BAT (rather than scWAT browning) was minimal in severe CR (which it isn't, at least in rodents), it wouldn't prove cold exposure is irrelevant for CR-induced longevity benefits.
  5. Finally, and most directly, in trying to dismiss the potential relevance of CE for longevity benefits of CR you overlook the striking results (discussed here, here, here and here) that show the longevity benefits of CR are eliminated or at least greatly attenuated when CR rodents are housed at thermoneutrality, rather than the usual, chilly-for-mice room temperature. Despite eating more, CR mice housed at lower temperatures live longer than CR mice housed at thermoneutral temperature. Regardless of the mechanism (i.e. BAT or something else), this seems like the evidence that counts most in favor of CE being synergistic with CR, or perhaps as I've suggested, even obligatory for CR benefits.
23 hours ago, Michael R said:

It's also a reminder of something I've said before and should get more care in this thread: that mere induction of genes is an inadequate indicator of fat browning. There should be data on the target proteins, and preferably on the actual phenotype of the fat and/or experimental subject.

Agreed. It is the actual presence of the browning-related proteins (e.g. UCP-1 protein content) or increase in mitochondria content in a tissue rather than just browning-related gene induction that is the real indicator of fat browning. Which reminds me of an interesting study [1] with the cheeky title "UCP1 mRNA does not produce heat", that found indicators of increased in gene activity (e.g. 8-fold increased in UCP-1 messenger RNA!) may be misleading when it comes to gauging thermogenic capacity, especially in tissues like beige fat which has little UCP-1 activity to start with.

Then again, mitochondrial leakage orchestrated by UCPs is only one thermogenic pathway up-regulated by CE. Study [2] suggests that beige fat may generate heat via futile calcium ion cycling across the sarcoplasmic reticulum (i.e. the sarcolipin story we've discussed several times before (e.g. here) in the context of non-shivering thermogenesis in muscles), in addition to via UCP-1 mediated proton leakage across the mitochondrial inner membrane.

--Dean

Update: After writing the above, I rediscovered [3] (originally discussed here), which found that 5 weeks of 40% CR does result in browning of subcutaneous white fat in mice. It does so even at thermoneutrality, just to a much lesser extent than if the CR mice are house at normal room temperature. The white fat browning was also lower at 40% CR than at 20% CR. Interestingly though, the size of the BAT deposits in the 40% CR mice was the same as AL-fed mice, unlike many other tissues which shrank on CR. Once again demonstrating the sparing of BAT but also the browning of WAT on severe CR.

Michael, per your suggestion, here is the graph and actual histology of BAT and other tissues from controls and 40% CR mice from [3]. As you can see, the weight of white fat (SAT and VAT) and even the liver dropped significantly after 5 weeks of 40% CR, but BAT weight didn't drop. The photos show the two white fat deposits (ingSAT and pgVAT) shrunk but got a lot browner, and BAT deposits were virtually unchanged in size or darkness in the CR mice relative to AL-fed controls:

Screenshot_20190715-132931_Foxit PDF.jpg

 

----------

[1] Biochim Biophys Acta. 2013 May;1831(5):943-9. doi: 10.1016/j.bbalip.2013.01.009. 

Epub 2013 Jan 22.

UCP1 mRNA does not produce heat.

Nedergaard J(1), Cannon B.

Author information: 
(1)Dept. of Molecular Biosciences, The Wenner-Gren Institute, Stockholm
University, Stockholm, Sweden. jan@metabol.su.se

Because of the possible role of brown adipose tissue and UCP1 in metabolic
regulation, even in adult humans, there is presently considerable interest in
quantifying, from in-vitro data, the thermogenic capacities of brown and
brite/beige adipose tissues. An important issue is therefore to establish which
parameters are the most adequate for this. A particularly important issue is the 
relevance of UCP1 mRNA levels as estimates of the degree of recruitment and of
the thermogenic capacity resulting from differences in physiological conditions
and from experimental manipulations. By solely following UCP1 mRNA levels in
brown adipose tissue, the conclusion would be made that the tissue's highest
activation occurs after only 6h in the cold and then successively decreases to
being only some 50% elevated after 1month in the cold. However, measurement of
total UCP1 protein levels per depot ("mouse") reveals that the maximal
thermogenic capacity estimated in this way is reached first after 1month but
represents an approx. 10-fold increase in thermogenic capacity. Since this
in-vitro measure correlates quantitatively and temporally with the acquisition of
nonshivering thermogenesis, this must be considered the most physiologically
relevant parameter. Similarly, observations that cold acclimation barely
increases UCP1 mRNA levels in classical brown adipose tissue but leads to a
200-fold increase in UCP1 mRNA levels in brite/beige adipose tissue depots may
overemphasise the physiological significance of these depots, as the high
fold-increases are due to very low initial levels, and the UCP1 mRNA levels
reached are at least an order of magnitude lower than in brown adipose tissue;
furthermore, based on total UCP1 protein amounts, the brite/beige depots attain
only about 10% of the thermogenic capacity of the classical brown adipose tissue 
depots.
Consequently, inadequate conclusions may be reached if UCP1 mRNA levels
are used as a proxy for the metabolic significance of recruited versus
non-recruited brown adipose tissue and for estimating the metabolic significance 
of brown versus brite/beige adipose tissues. This article is part of a Special
Issue entitled Brown and White Fat: From Signaling to Disease.

Copyright © 2013 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.bbalip.2013.01.009 
PMID: 23353596  [Indexed for MEDLINE]
 

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

[2]  Nat Med. 2017 Dec;23(12):1454-1465. doi: 10.1038/nm.4429. Epub 2017 Nov 13.

UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates
beige fat thermogenesis and systemic glucose homeostasis.

Ikeda K(1)(2)(3), Kang Q(1)(2)(3), Yoneshiro T(1)(2)(3), Camporez JP(4), Maki
H(5), Homma M(5), Shinoda K(1)(2)(3), Chen Y(1)(2)(3), Lu X(1)(2)(3), Maretich
P(1)(2)(3), Tajima K(1)(2)(3), Ajuwon KM(6), Soga T(5), Kajimura S(1)(2)(3).

Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in

brown fat; however, its role in beige fat remains unclear. Here we report a
robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced
ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b
(SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs
UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a
species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling
by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway
stimulates UCP1-independent thermogenesis in beige adipocytes.
In the absence of 
UCP1, beige fat dynamically expends glucose through enhanced glycolysis,
tricarboxylic acid metabolism and pyruvate dehydrogenase activity for
ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby
functions as a 'glucose sink' and improves glucose tolerance independently of
body weight loss. Our study uncovers a noncanonical thermogenic mechanism through
which beige fat controls whole-body energy homeostasis via Ca2+ cycling.

DOI: 10.1038/nm.4429 
PMCID: PMC5727902
PMID: 29131158  [Indexed for MEDLINE]
 

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

[3] 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).

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  [Indexed for MEDLINE]
 

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I am pleased to see the Dean-Michael debate rekindled.  A great way to test all our assumptions.

I insert only a few thoughts here - meant to be respectful and in the spirit science and positive peer-review; I hope  they are helpful and clear.

Based on my review of the evidence  I agree with Dean's statement "My main argument is that once you're doing everything right, including moderate CR, CE is likely to help you age successfully, via improved metabolic health (e.g. glucose tolerance), avoiding bone loss, improving immune response and potentially maintaining brain health."  What remains to be shown is how significant this incremental benefit it is, and whether or not it is material for someone very slim or practicing a substantial degree of CR.  The benefit of CE is best established in animal models fed ad libitum and/or with metabolic syndrome and related pathology at baseline.  

Also, reviewing the data, for any given adipose tissue, there is clear benefit having BAT or beige fat over WAT for a wide variety of reasons - from immunosensnce to mitochondrial function, to relation to nutrient sensing pathways, etc.  The net effect of all of these seems to depend on the model and degree to which other health markers are optimized.

Having said that, there is yet insufficient data to conclusively confirm nor definitively repudiate the hypothesis that a formal CE practice is strictly required for CR benefits.   I am talking nothing extreme here with regard to CR, but modest benefits ranging from what we are seeing here: https://www.thelancet.com/journals/landia/issue/current on the lower scale, to super-centenarians living in the Blue Zones on the upper scale). 

I appreciate that the Blue Zones have been discussed several times in this thread.  Whether or not we can pick up overall differences in populations due to variable health practices, the high degree of extreme longevity among the traditional Okinawa elders represents population data that makes me particularly skeptical that a deliberate stark CE practice is required to achieve Blue-zone like longevity.  But the argument here is different from the "picking up a signal in a population with diverse practices" debate discussed previously.

It is simply that the exception breaks the rule.  Despite some well-described genetic factors among the Okinawans, their longevity does not appear to be primarily due to genetic advantage given the results of migration studies and the decline of health in the latest Okinawan cohorts.  Okinawans presumably had fewer modern amenities than the modern Western lifestyle, but based on this heat map, even if they regularly were shirtless throughout the day, bathed in cool lakes, etc., we are still observing nothing extreme with respect to their degree of cold immersion.   This suggests that if some CE is necessary, a very high degree of cold exposure does not appear to be required.  Temperature data here: https://weatherspark.com/y/142278/Average-Weather-in-Okinawa-Japan-Year-Round .

I try to be skeptical of everything yet open-minded, and certainly can appreciate the counter-argument that as low as high 50s for part of the day for part of the year is still CE and that in the West, a more formal practice is required to make up for building temperatures in the workplace and perhaps more effective clothing.  Either way though, it does set an upper limit how to just much cold would hypothetically be needed, if at all.  The example of Costa Rica ( acknowledged: not clear at all that they are CR with if anything data to the contrary, so a less apt population to compare with and hence less robust argument to make, but nevertheless highlight that within the spectrum of evidence a degree of lifestyle-based relative health & longevity can be achieved at a population level without the stark cold; indeed in downright tropical conditions most of the time):. https://www.holiday-weather.com/costa_rica_oaxaca_mx/averages/ 

I think it is important not to lose our perspective.  CE is one tool, and its value depends on the individual and everything else they are doing.  For the vast majority the highest yield priority and yield is arguably more likely to be targeting better adherence to the foundations of sound health practices such as reducing calories / calorie restriction, following a minimally processed plant-rich diet based on on whole foods with optimal micro & macronutrients, watching glycemic load and the impact on glucose disposal, following exercise guidelines, moderating methionine / EAA , etc.

Having said that, particularly in the case Dean noted already doing everything else right, this does not mean that it is not possible that even greater benefits could be seen with more extreme CE practice.  This is an open and unresolved question and a common argument for CR practice too.  It also requires additional data.

In particular, unresolved is: (1) How much CE - if any - is required to achieve most of the benefits and (2) for humans optimized on other fronts in particular, what degree of additional benefit CE may confer and whether or not this is material.

And on that note yes, I do hedge my bets with a little bit of mild CE myself, primarily via opportunistic less insulation from the elements.  When the data landscape changes, I have my cool vest ready 🙂  

Edited by Mechanism

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Mechanism - that temperature data for Costa Rica doesn't seem correct to me.  Don't get me wrong, its not like its an arctic cold place, but I was actually surprised when I went there by how cold it gets, especially at night, for such a tropical location.  In fact I would guess that the people of Costa Rica get more cold exposure than a typical North American (and they have MUCH BETTER DIETS - fresh fruit and rice with beans are the typical meal there).  It is precisely because they are in a tropical zone that I'm guessing few people use any sort of heating systems.  For example, its the middle of July right now, I just pulled up the forecast from TODAY:

image.png.7fac3e452d46535a17f784810ab36389.png

60's at night every single night for the next 10 days, that's significantly cooler than where I live (Pennsylvania), those temps are substantically lower than were I set my air conditioner thermostat as well - I'd much rather have their temps.  Many of the hotels in costa rica that we stayed at had fireplaces and heavy blankets for guests (but I was loving the cool night air, it was 50's at night in the mountain areas).  

My theory is that men benefit from cold exposure more than women - possibly because women naturally have more BAT than men so they don't need as much CE to see the same level of benefit (this may also be a contributing factor to women living longer than men).  Here are the rankings by country based on male life expectancy:

image.png.32bc91314ae43d054a6dc23235a83f20.png 

And here is a heat map of countries by life expectancy (men and women combined):

image.png.9a824413d3e66ba3d68cd730a294951d.png

This pictorial would be more remarkable if the Russians didn't drink so much vodka:

https://www.nytimes.com/2014/02/18/science/why-russian-men-dont-live-as-long.html

 

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Hi Gordo, thank you for the great visual 🙂

As beautiful as the color-coded life expectancy data ( thank you for sharing),  I am not at all persuaded by the epidemiology for the same reasons that Dean has rightfully dismissed similar data for other examples in this thread - lifestyle and local factors tend to dominate and confound ecological analyses like these - for example industrialization, sanitation, poverty, and access to healthcare.

I hope I made my point clear above that my Blue Zones example  was not to re-invoke rather weak arguments on both sides of the discussion -- ie, citing trends by country or latitude as strong evidence either way.  Rather, instead the emphasis is that optimal life extension and health extension is possible in environments with less extreme temperature zones ( ie stark CE protocol equivalent).

Moreover, migrant data, longitudinal cohort population-based data, and genetic data all suggest that while genetics certainly have played some role in some of the longevity seen in the Blue Zones including in Okinawa, the preponderance of scientific evidence is that these are not the dominant factor.  Rather, environmental and lifestyle factors - and in apparent absence of a strong CE stimulus with only more modest CE exposures being available in these regions ( cool bathing, exposure to the elements all day, etc.). 

To make clear, the argument is not that CE can't help - and it indeed appears helpful for a variety of populations and circumstances, especially in the context of suboptimal metabolism and glucose disposal, as discussed above. 

Rather the degree of CE, if required, is more likely to be of relatively modest dose ( not of the Wim Hof variety ).  And any incremental hypothetical benefits, if any,  beyond those obtained maintaining a baseline of other healthy practices, is as of yet still poorly defined.  

 

Edited by Mechanism

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On 7/15/2019 at 7:02 AM, mccoy said:

By the way, this is obvious but we should always remind that protein ratio is a relative number. It is very arguable that it is a more important parameter rather than absolute protein quantity....

True. Although as CR appears to be related to energy expenditure deficits, relative protein ratio numbers are still of some value.

As to the map above, it appears to correlate more with the level and accessibility of healthcare, than with temperatures. Which is precisely my point: there is no population study I am aware of, which makes a claim that cold weather is beneficial to lifespan in humans (and if CE was beneficial, I would expect to see such a pattern, as we see it in other areas such as diet, lifestyle and physical activity). In fact, most population studies show that cold weather results in higher mortality (for various reasons, but it is important to remember that cold exposure significantly reduces arterial blood flow).

Thus, while I am aware of the lab results, I am not convinced that long-term CE exposure has longevity benefits. I don't want to beat a dead horse, but until I see some better long-term evidence in support of CE, I am chalking up the stellar numbers of Dean and Gordo to their CR practice, extremely healthy lifestyle and low protein, plant-based diets. And their genes must help a bit, of course.

Edited by Ron Put

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Quote

Ron Put:  there is no population study I am aware of, which makes a claim that cold weather is beneficial to lifespan in humans (and if CE was beneficial.  I would expect to see such a pattern.

 

1) "Cold weather" is NOT the same as cold exposure (CE).    Your argument depends on falsely conflating the two.

2) The issue  under discussion is whether  CR + [good nutrition, exercise etc.] needs to be coupled with CE to be fully effective.

 As Dean said:

Quote

 

It seems virtually certain that there no significant population anywhere in the world that practices significant CR with good nutrition and cold exposure, not to mention having access to good medical care, and engaging in exercise to maintain CV health, etc to test this hypothesis. 

In summary, expecting to see support of the longevity benefits of CE (or CR, or CR+CE) in country-wide or "Blue Zone" epidemiological data is a fool's errand

 

 

image.png.4fa045b5f5d2e99509ac324a36c26a89.png

 

Edited by Sibiriak

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4 hours ago, Sibiriak said:

 

1) "Cold weather" is NOT the same as cold exposure (CE).    Your argument depends on falsely conflating the two.

1. Common sense tells us that "cold weather" strongly correlates with "cold exposure." I will repeat, until the last few decades, central heating was not commonplace even in developed countries. Most rooms and especially bedrooms in colder climates were not heated 24/7 and homes were not nearly as well insulated. Average room temperatures were likely to be lower than in modern climate controlled homes. Thus cold exposure would have been much more significant.

Similarly, many people work outdoors during the winter months in cold areas. They are exposed to temperatures close to, or below what the ice vests above provide, for probably longer periods, often over decades. As I mentioned earlier, if long-term cold exposure was correlated with longevity we would see a patter, as we see if most everything else. But we don't.

Based on the CE arguments, construction workers in Siberia should live longer than their counterparts in warmer areas of Russia. The opposite is true.

Someone living in the Dominican Republic can go around naked year around and still will not get the cold exposure of a construction worker in Siberia. Yet that Dominican is much likely to outlive the Russian by a decade or more, even with the marginally worse healthcare access and healthcare level in the DR.

2. There are a number of studies (I don't need to repost, as per your cartoon above) which clearly indicate significantly higher mortality (predominantly due to cardiovascular events) during and shortly after cold periods, even after adjusting for infectious diseases and other causes. The cold is not your friend, particularly if you are older.

Edited by Ron Put

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1 hour ago, Ron Put said:

Common sense tells us that "cold weather" strongly correlates with "cold exposure."

Fortunately we don't have to rely on your "common sense". As I discussed recently here (in response to you I might add), cold weather is correlated with cold exposure, but the relationship is very flat. In other words, as I said in that post:

The  researchers found that for ever 1 degree changed in outdoor temperature, there was on average a 0.08 degree change  in the temperature the person actually experienced.

From the graph I included in that post, when it was at the freezing point outside (32F/0C) in the UK, the average temperature people actually experienced during the day on their skin (wrist) was 82degF/27.75C down only 4degF/1.8C from the wrist temperature they experienced when the outside temperature was a balmy 72F/21C.

The authors acknowledge that the wrist temperture was likely influenced by their body temperature, since at lower outdoor temperatures the subjects wore insulating gloves. But it shows how toasty even people's hands are in industrial societies even when the temperatures outdoors are quite chilly. The surface of more central, better covered parts of their body would undoubtedly be much warmer.

1 hour ago, Ron Put said:

 Similarly , many people work outdoors during the winter months in cold areas. They are exposed to temperatures close to, or below what the ice vests above provide, for probably longer periods, often over decades.

You really don't get it Ron.

As I'm sitting here with my cold vest on, the temperature at the contact point between my vest and my skin (chest) is 55F/13C. It is the equivalent of sitting outside on 55F day with a damp shirt on. I have goosebumps and am on the threshold of shivering, despite the fact that I'm well-adapted to cold. Go try it for yourself if you don't think it is chilly.

Like Gordo, I live in Pennsylvania, where winter temperatures drop to 10F/-12C or lower, and I spend a lot of time outdoors in wintertime, shoveling snow, walking the dog, etc. I can assure you that I'm never close to shivering outdoors even when it is that cold. Why? Because I dress appropriately with a heavy winter coat, gloves, long pants and a hat. Plus I'm active when I'm outside in those temperatures.

The same will be true for the type of outdoor workers you reference. I guarantee you that even construction workers in Siberia aren't seriously cold exposed to the point of shivering when on the job - their bodies beneath their heavy clothes are just not that cold.

But I don't expect you'll understand or accept any of this based on your track record on this thread...

--Dean

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Dean, I do get it. I get that you are see nothing but BAT and that your confirmation biases make you ignore anything that contradicts them. But trust me, if I really felt that there was good evidence, I'd don the cold vest too (I don't get cold easily).

But with all due respect, you have provided only rather weak arguments in defense of your position.

Again, you are perfectly happy to accept and advance population studies in other areas, including CR, exercise and plant-based diets, but twist yourself into a pretzel trying to come up with an explanation why no population study supports your "cold exposure" conviction.

And it's not just my "common sense," it a host of studies which correlate increased deaths from cardiovascular events due to cold exposure in regular folks, including studies done in the UK where supposedly people don't get cold exposure when it's cold outside (I posted one earlier here).

Here is another study, in youngish, healthy men, which also supports and provides a possible explanation why people die more often in the cold:

Acute Effects of Exposure to Cold on Blood Pressure, Platelet Function and Sympathetic Nervous Activity in Humans
To clarify the mechanism for cold-related thrombosis, we evaluated responses of blood pressure, platelet function, and sympathetic nervous activity after cold exposure in ten healthy male volunteers (33 ± 2 years old). Mean blood pressure, β-thromboglobulin, platelet factor 4, and plasma noradrenaline were increased after cold exposure associated with significant falls in skin, oral, and urine temperature. The increase in plasma noradrenaline significantly correlated with the change in platelet aggregation (3 μΜ ADP: r = 0.73, P < .02, 3.0 μg/mL epinephrine: r = 0.65, P < .05), and with mean blood pressure in the warn environment (r = 0.76, P < .02). These results suggest that the cold-related increase in sympathetic nervous activity may contribute to enhancement of platelet function. This provides a possible explanation for the risk of thrombosis in cold weather in essential hypertension.
https://academic.oup.com/ajh/article-abstract/2/9/724/201779


Here is another one, which also helps explain why more people die in cold weather:
 

Cold Weather Hikes Blood Pressure, UF Scientist Warns

How much will your blood pressure increase in cold? The answer depends on variables such as the current temperature and wind chill, the temperatures you’re accustomed to, how long you’re exposed and your health, dress and activity level, Sun said. But it doesn’t take much; a previous study by Sun and his colleagues showed just five minutes’ exposure to a temperature of 52 degrees Fahrenheit can cause pressure to rise substantially. And a common medical evaluation known as the cold pressor test shows that a person who plunges one hand into freezing water for one minute will experience a rise in blood pressure lasting up to two hours.

People — and their furry mammalian counterparts — living in warmer climates aren’t immune to cold-induced blood-pressure change, either, he said. UF researchers found that a control group of 12 healthy mice kept at a constant 41 degrees Fahrenheit around the clock experienced a 50 percent increase in blood pressure after five weeks, he said.
...

Wearing a hat, scarf and gloves will minimize the amount of skin exposed, important because blood pressure increases don’t require full-body exposure, he said.

People whose jobs require prolonged or repeated exposure to cold, such as farmers, construction workers, meat cutters and law enforcement officers, should be particularly mindful of precautions, he said.
https://www.sciencedaily.com/releases/2005/02/050205124018.htm

 

But hey, what do I know...?

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OK, so I did a search to find life expectancy heat maps from further back in time when there was less push button convenince for 24/7 heating.  This is one that came up:

http://users.erols.com/mwhite28/life-exp.htm

Am I just a victim of my own confirmation bias, or does it look like the closer to the frozen poles you live, the longer you live?  This is even more remarkable considering its way easier to grow abundant, nutritious food year round near the tropical equator.

lifespan.gif

1930-lif.gif

lifespan.gif

1960-lif.gif

lifespan.gif

1996-lif.gif

OK - how about when we look at species that don't use ANY external heating?

Quote

 

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.

 


 

Cooler environments → increased lifespan across a huge range of land, freshwater and marine species. 

Humans in cooler environments -> better biomarkers of health.

 

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

[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.
 

 

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34 minutes ago, Dean Pomerleau said:

Ron, 

Ignoring all the repetitive stuff I've addressed repeatedly, you say:

I challenge you to identify a population study that I've advanced or endorsed, except for the Adventists where they are compared against each other (e.g. vegetarian vs. non-vegetarian Adventists).

--Dean

Dean, I am not ignoring it. I just don't find it convincing and I have repeatedly explained why. Which is the point you are ignoring.

As to what you've endorsed, you know better than me. You've already identified one :) My guess is, there are more, as I seem to have that impression (the Mediterranean Study which is basically a population study, with all of its problems, comes to mind for some reason).

But that's only part of the point. The main point is, population studies consistently show trends in the impact of stuff which is harder to verify, like CR, or dietary and lifestyle habits. For cold exposure, which is easy to verify based on recorded temperatures, the ONLY consistent trend is that more people die when it's cold. Do you get it?

And speaking of ignoring, you have completely ignored the two studies I posted above, which clearly contribute to the discussion by providing an explanation for the correlation of cold and increased human deaths. Instead, you are challenging me to search through you past comments.

Peace.

Edited by Ron Put

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1 minute ago, Gordo said:

... Am I just a victim of my own confirmation bias, or does it look like the closer to the frozen poles you live, the longer you live?  This is even more remarkable considering its way easier to grow abundant, nutritious food year round near the tropical equator.

lifespan.gif

1930-lif.gif

 

LOL. To me it looks like the better access you have to advanced medicine, the longer you live.

I don't know if you've been to Australia, but it's kind of like California, just a little bit hotter in the summer in most places. I always thought Russia and Finland were colder.... But what do I know :)

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