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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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I missed these posts.  It is great to see you back.  If you are ever looking for a new hobby, you would make a great blogger.  

Have you found any sources that provide a summary ranking and quantifying  modifiable factors ( such as cold exposure, tea, etc from your list) the degree of brown / beige adipose tissue or thermogenesis?  You have collected an impressive list; it is just unclear besides CE - which  is most impactful as you state above  - which ones have in vivo clinical data supporting a material improvement in these parameters, and of those which are most impactful.  

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2 hours ago, Mechanism said:

Have you found any sources that provide a summary ranking and quantifying  modifiable factors ( such as cold exposure, tea, etc from your list) the degree of brown / beige adipose tissue or thermogenesis?  You have collected an impressive list; it is just unclear besides CE - which  is most impactful as you state above  - which ones have in vivo clinical data supporting a material improvement in these parameters, and of those which are most impactful.  

Hi Mechanism!

There have been quite a few review articles discussing other ways (besides cold) of boosting BAT. Here is the most recent such review [1] from January, which lists capsaicin, resveratrol, menthol, curcumin,  green tea polyphenols and fish oil as food ingredients that boost BAT activity. It has a nice diagram with the site of their action:

fphys-09-01954-g003.jpg

But it doesn't rank them, and I haven't seen such a ranking of efficacy anywhere else. Probably the most well-documented is capsaicin / spicy foods, but that doesn't necessary mean it is the most effective.

The best comparison I've seen of cold exposure vs another method of BAT stimulation is (not surprisingly) done with capsaicoids. It is study [2] which compared six weeks of CE (2h/day at 62F or 17C) with six weeks of daily capsaisoid supplementation (9mg/d of the capsasoids in the "CH-19 Sweet" variety of pepper that Gordo and I have grown) in men who previously had little or no BAT in a crossover design in which the men served as their own controls. What they found is shown in this diagram, with the two blue figures (D & E) being the most informative for our purposes:

pK6epc3.jpg

Figure D shows that "Cold Induced Thermogenesis" (CIT) went up by about 200kcal/day after six weeks of cold exposure. Figure E shows CIT went up by somewhat less, about 150kcal/day, as a result of the six weeks of capsaisoid supplements. But note that this BAT-mediated increase in energy expenditure was only measureable in response to cold exposure (i.e. after 2h at 62F). When measured at a warm temperature of 80F, there was no difference in energy expenditure after either six weeks of CE or six weeks of capsaisods. But this likely underestimates the calorie expenditure of simply having BAT, which is known to also increase calories burned after eating (diet-induced thermogenesis) too.

So in summary, it's hard to tell just how effective non-cold interventions are at boosting BAT. Pretty high daily doses of capsaicin/capsasoids may approach the same effectiveness ballpark as cold exposure. But ironically, in order to trigger (most of) the metabolic benefits of capsaicin/capsasoids-induced BAT (and presumably other BAT-boosting interventions as well) may require the addition of cold exposure,  in case you were hoping to wimp out and avoid CE :-).

--Dean

 

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[1] Front Physiol. 2019 Jan 11;9:1954. doi:10.3389/fphys.2018.01954.

Food Ingredients Involved in White-to-Brown Adipose Tissue Conversion and in Calorie Burning.

El Hadi H(1), Di Vincenzo A(1), Vettor R(1), Rossato M(1). 

Obesity is the consequence of chronic positive energy balance and considered a leading risk factor for cardiovascular and metabolic diseases. Due to its epidemic trends among children and adults, there is an increasing interest in implementing new therapeutic interventions to tackle overweight and obesity. Activation of brown adipose tissue (BAT) represents today a promising strategy to enhance energy expenditure (EE) through heat production. More recently, "browning" of white adipose tissue (WAT) has gained increasing attention in research area as an alternative method in stimulating energy dissipation. This minireview aims to summarize the current knowledge of some dietary compounds that have been shown to promote BAT activation and WAT browning with subsequent beneficial health effects.

DOI: 10.3389/fphys.2018.01954

PMID: 30687134

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

[2] J Clin Invest. 2013 Aug;123(8):3404-8. doi: 10.1172/JCI67803. Epub 2013 Jul 15. 

Recruited brown adipose tissue as an antiobesity agent in humans.

Yoneshiro T(1), Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M.

Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported that BAT decreases with age and thereby accelerates age-related accumulation of body fat in humans. Thus, the recruitment of BAT may be effective for body fat reduction. In this study, we examined the effects of repeated stimulation by cold and capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure (EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 weeks resulted in a parallel increase in BAT activity and CIT and a concomitant decrease in body fat mass. Changes in BAT activity and body fat mass were negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks increased CIT. These results demonstrate that human BAT can be recruited even in individuals with decreased BAT activity, thereby contributing to body fat reduction.

DOI: 10.1172/JCI67803

PMCID: PMC3726164

PMID: 23867622

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Alpha-lipoic Acid Supplements Boost BAT

Here is another one to add to the list of potential BAT inducers - the supplement alpha-lipoic acid (ALA).

Study [1] found that white fat cells cultured in a medium containing ALA for 24 hours turned brown. I.e. They generated more mitochondria and expressed a bunch of genes associated with browning and thermogenesis.

Granted it is in vitro, but this may explain at least in part why ALA has been shown to be beneficial for glucose metabolism and avoiding diabetes.

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
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • 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]

--Dean

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[1] Biochim Biophys Acta. 2015 Mar;1851(3):273-81. doi: 10.1016/j.bbalip.2014.12.013. 

α-Lipoic acid treatment increases mitochondrial biogenesis and promotes beige adipose features in subcutaneous adipocytes from overweight/obese subjects.

Fernández-Galilea M(1), Pérez-Matute P(2), Prieto-Hontoria PL(3), Houssier M(4), Burrell MA(5), Langin D(6), Martínez JA(7), Moreno-Aliaga MJ(8). 

α-Lipoic acid (α-Lip) is a natural occurring antioxidant with beneficial anti-obesity properties. The aim of this study was to investigate the putative effects of α-Lip on mitochondrial biogenesis and the acquirement of brown-like characteristics by subcutaneous adipocytes from overweight/obese subjects. Thus, fully differentiated human subcutaneous adipocytes were treated with α-Lip (100 and 250μM) for 24h for studies on mitochondrial content and morphology, mitochondrial DNA (mtDNA) copy number, fatty acid oxidation enzymes and brown/beige characteristic genes. The involvement of the Sirtuin1/Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (SIRT1/PGC-1α) pathway was also evaluated. Our results showed that α-Lip increased mitochondrial content in cultured human adipocytes as revealed by electron microscopy and by mitotracker green labeling. Moreover, an enhancement in mtDNA content was observed. This increase was accompanied by an up-regulation of SIRT1 protein levels, a decrease in PGC-1α acetylation and up-regulation of Nuclear respiratory factor 1 (Nrf1) and Mitochondrial transcription factor (Tfam) transcription factors. Enhanced oxygen consumption and fatty acid oxidation enzymes, Carnitine palmitoyl transferase 1 and Acyl-coenzyme A oxidase (CPT-1 and ACOX) were also observed. Mitochondria from α-Lip-treated adipocytes exhibited some morphological characteristics of brown mitochondria, and α-Lip also induced up-regulation of some brown/beige adipocytes markers such as cell death-inducing DFFA-like effector a (Cidea) and T-box 1 (Tbx1). Moreover, α-Lip up-regulated PR domain containing 16 (Prdm16) mRNA levels in treated adipocytes. Therefore, our study suggests the ability of α-Lip to promote mitochondrial biogenesis and brown-like remodeling in cultured white subcutaneous adipocytes from overweight/obese donors. Copyright © 2014 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.bbalip.2014.12.013

PMID: 25542506 [Indexed for MEDLINE]

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Vitamin E (Alpha-Tocopherol) Boosts BAT

One more way to promote the formation of BAT is vitamin E (alpha-tocopherol), per study [1], which looked at undifferentiated fat cells of mice in vitro and white adipose tissue of rats fed a diet supplemented with alpha-tocopherol diet for 8 weeks. Both interventions resulted in the fat cells turning brown/beige relative to controls.

The reason I checked was because Al Pater posted a study today that found lower all-cause mortality in people with higher vitamin E levels, and yesterday Ron Put posted a review article that mentions  how vitamin E is associated with lower rates of Alzheimer's disease. I figured with those benefits, vitamin E must also boost BAT. Sure enough. 

Correlation is not causation, but it is striking how many BAT-boosting interventions on the list below are also correlated with improved health and increased longevity.

--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
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • 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 / Vitamins - metformin, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, melatonin, alpha-lipoic acid (ALA), vitamin E (alpha-tocopherol)
  • 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]  J Oleo Sci. 2017;66(2):171-179. doi: 10.5650/jos.ess16137. 

Promoting Effect of α-Tocopherol on Beige Adipocyte Differentiation in 3T3-L1 Cells and Rat White Adipose Tissue.

Tanaka-Yachi R(1), Takahashi-Muto C, Adachi K, Tanimura Y, Aoki Y, Koike T, Kiyose C.

Thermogenic adipocytes that are distinct from classical brown adipocytes (beige adipocytes) were identified in 2012. Beige adipocytes are also called inducible brown adipocytes because their differentiation is induced by a number of physiological stimuli, including adrenaline or myokines. PPARγ is the master regulator of adipogenesis and promotes thermogenic adipocyte differentiation. A PPARγ agonist also promotes thermogenic adipocyte differentiation in mouse white adipose tissues. The vitamin E analog α-tocopherol promotes PPARγ expression and induces mRNA expression of target genes. This study investigated the effects of vitamin E analogs on thermogenic adipocyte differentiation in mouse preadipocytes and rat white adipose tissues. We determined the effects of vitamin E analogs (α-tocopherol and γ-tocopherol) on PPARγ, PGC-1α, and uncoupling protein 1 (UCP1) gene expression in 3T3-L1 cells. UCP1 expression and the mitochondrial contents were confirmed in the cells using immunofluorescence. In an in vivo study, male SD-IGS rats were fed a high-fat diet (HFD), α-tocopherol-enriched HFD, or γ-tocopherol-enriched HFD for 8 weeks before the analysis of PPARγ, PGC-1α, UCP1, and CD137 gene expression, and pathological examinations of white adipose tissues. The expression of PPARγ, PGC-1α, and UCP1 increased in 3T3-L1 cells following α-tocopherol treatment in a concentration-dependent manner. UCP1 expression and mitochondrial content also increased in α-tocopherol-treated cells. According to the histopathological examinations of rat white adipose tissues, multilocular cells were observed in the α-tocopherol intake group. Furthermore, the gene expression levels of PGC-1α, UCP1, and CD137 increased in the α-tocopherol intake group. Our results suggest that α-tocopherol promotes thermogenic adipocyte differentiation in mammalian white adipose tissues.

DOI: 10.5650/jos.ess16137

PMID: 28154348 [Indexed for MEDLINE]

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In the spirit of keeping this thread comprehensive on the topic of cold exposure benefits, I'm cross-posting the contents of my relevant post from a very interested exchange between Ron and I over on this thread about tau tangles and Alzheimer's disease. Please see that thread for more background, and sorry for the repetition.

--Dean

First off - I need to correct something I said yesterday in this post above. I said 6 of the 8anti-oxidant/anti-inflammatory agents that protect again Alzheimer's disease also boost BAT. It is actually 7 of 8, since Vitamin E was added to the list of interventions that boost BAT (see this post from earlier today). I've corrected the post above.

Now a few corrections to Ron's latest post.

Ron wrote:

I understand that many lab results indicate that cold may be beneficial in humans, temporarily (the effects appear to diminish with prolonged exposure, as far as I remember). 

I challenge you to back up that recollection with actual evidence. I never seen any such evidence of attenuating benefits, despite rather extensive reading on the subject.

Speaking of (not) reading carefully, Ron wrote:

I also believe that if cold exposure was so dramatically beneficial, we would see some population-wide longevity differences, and to my knowledge, there are none (the opposite may be true).

Why do you keep bringing this up? I've addressed your misunderstanding repeatedly on the cold exposure thread (here and here).

And in a stunning example of more lack of careful reading/research/thinking, Ron wrote:

Drop in Body Temperature Linked to Dementia

It is normal for people to experience a drop in body temperature with age, but a new study has found that drops in temperature can lead to more than just a chill. A study from Canada found that by increasing body temperature, they could slow the production of beta-amyloid and improve the memory in mice.

First off, your link points to an article that is quoting another article in the UK Daily Mirror, a real trustworthy news source :-).

But more to the point, did you ever consider for a moment that this article may actually be evidence of the exact opposite of the conclusion you (and the writer) appear to draw from it?

Namely, that the body temperature drop in aged people and mice may be due to loss of brown adipose tissue with age, and that this loss may be casually responsible (at least in part) for the onset of dementia? Or put another way, did it occur to you that chronic cold exposure improves one's ability to maintain one's body temperature, thereby overcoming the age-associated drop that you and the writer appear to be worried about? Or that simply turning up the thermostat in the late stages of AD to reduce beta-amyloid formation may be a case of too little, too late? 

You probably didn't. But fortunately the Canadian research team of the original article on which your story is based did.

Here is a follow-up study by these same authors from April of this year [1], using the same AD-prone strain of mice used in the study your story obliquely references.

Rather than warming up aged animals to ameliorate the late stage symptoms of AD in these AD-prone mice, they subjected middle-aged mice of this strain to 4h of cold exposure (40F or 4C - ouch!) five days a week for four weeks, and compared them to similar mice house at regular room temperature.

Guess what. Chronic cold exposure completed prevented the harmful tau phosphorylation that occurred in the control mice when both groups were subject to a cold challenge.

In other words, cold exposure boosts BAT in these mice, which allows them to maintain their body temperature better, thereby preventing the phosphorylation to tau proteins implicated in the onset of Alzheimer's disease.

The researchers conclude:

These results suggest that improving thermogenesis could exert a therapeutic effect in AD. 

Your basic mistake Ron was to equate cold exposure with lower body temperature. Cold exposure (and the brown adipose tissue it induces) actually enables warm-blooded animals (including humans) to thermoregulate more effectively and avoid the age-related drop in body temperature (and loss of BAT) that may be (part of) the cause of Alzheimer's disease.

Thanks for making me look into this further. It's striking how many good things cold exposure and BAT does for the body.

--Dean

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

[1] Mol Metab. 2019 Apr;22:110-120. doi: 10.1016/j.molmet.2019.01.008. Epub 2019 Jan 26.

Repeated cold exposures protect a mouse model of Alzheimer's disease against cold-induced tau phosphorylation.

Tournissac M(1), Bourassa P(1), Martinez-Cano RD(2), Vu TM(2), Hébert SS(3), Planel E(3), Calon F(4). 

OBJECTIVE: Old age is associated with a rise in the incidence of Alzheimer's disease (AD) but also with thermoregulatory deficits. Indicative of a link between the two, hypothermia induces tau hyperphosphorylation. The 3xTg-AD mouse model not only develops tau and amyloid pathologies in the brain but also metabolic and thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals, and its stimulation counteracts metabolic deficits in rodents and humans. We thus investigated whether BAT stimulation impedes AD neuropathology. METHODS: 15-month-old 3xTg-AD mice were subjected to repeated short cold exposures (RSCE), consisting of 4-hour sessions of cold exposure (4 °C), five times per week for four weeks, compared to animals kept at housing temperature. RESULTS: First, we confirmed that 3xTg-AD RSCE-trained mice exhibited BAT thermogenesis and improved glucose tolerance. RSCE-trained mice were completely resistant to tau hyperphosphorylation in the hippocampus induced by a 24-hour cold challenge. Finally, RSCE increased plasma levels of fibroblast growth factor 21 (FGF21), a batokine, which inversely correlated with hippocampal tau phosphorylation. CONCLUSIONS: Overall, BAT stimulation through RSCE improved metabolic deficits and completely blocked cold-induced tau hyperphosphorylation in the 3xTg-AD mouse model of AD neuropathology. These results suggest that improving thermogenesis could exert a therapeutic effect in AD.

DOI: 10.1016/j.molmet.2019.01.008

PMCID: PMC6437631

PMID: 30770297

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Thank you Dean for the review and example.  I am still studying the subject of CE, and I will need to take more time to digest this excellent thread, and dig deeper in the literature.  One thing seems clear to me: that the extent benefit, if any, depends on context, and sometimes one variable can make the difference. 

For example, at room temperature, a low-protein diet may nevertheless increase the expression of UCP1.  However if you are practicing CE for its metabolic benefits, we may see less favorable ( lower) UCP1 with high dietary protein ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549346/ ).   

This is not too surprising; we have seen that lower protein and particularly BCAA & methionine diets promote FGF21 which along with other mechanisms mediates some of the beneficial effects in common between nutrient restriction and CE, and there are no doubt other common pathways.   But it does highlight that personalized medicine needs to incorporate multiple variables simulatneously.  There will never be an RCT incorporating all the pertinent ones lest of all for a particular individual profile with their own individual genotype, environment, epigenetics, etc.  We need better data and AI to help with this but it is a long wait. 

At a minimum, in lieu of this better data, I incorporate a combination of evidence-based practice ( akin to many of Michael's practices with some differences and some of my own ) which is the foundation of my practice, along with selective incorporation of tentative yet promising but less established interventions provided that they require acceptable cost and effort, and moreover low risk "low hanging fruit."  This includes the encouraging beiging/browning of adipose tissue at this time.  Since you can't do it all, quantifying the relative impact of different interventions for a given magnitude of expected benefit is vital for triage of effort. 

This is why your highlight that capsaicin intake may be a higher yield nutritional intervention relative to some of others for beige/brown adipose tissue activation along with CE practice was particularly helpful I thought.  Without a dose-response curve for a hard outcome for my situation; namely  already optimizing health as I see it: e.g., the extent to which I practice nutrient restriction, exercise and activity pattern, etc, it is hard to justify rigorous CE beyond what I dub as "convenience CE" - by exposing myself to cold whenever I have the opportunity and inclination as opposed to following a specific ritual.  I certainly can do this easily enough when I shower, outdoors, swimming, etc., but this is not robust and it is hard to say how much of an impact it has.  I would go further if there was better data in metabolically healthy skinny optimized people -- While the animal data you presented in this thread making the case that CR may not work without CE is interesting and has compelled me to study it further -- it may be a moot point for myself if I am adequately happy with the results of having an overall lifestyle more closely resembling a traditional Okinawan or Seventh Day Adventist.

So where does that leave me given no RCT with my profile is likely to come on the horizon?  Above and beyond convenience CE, adjusting my *dietary*  practices to increase some of the browning/beiging   takes only seconds and is also low hanging fruit not to mention very enjoyable.  The cost/risk is low even if I appreciate it may not represent a material benefit to my healthspan with all my other variables optimized AFAIK.  Having said that, It is affirming when there is evidence - such as for capsaicin as you cited - that the impact at least on hypothesized surrogates of health such as browning of fat is present.  Unfortunately that is not always the case, so now, I just have the quick and easy task now of carefully going citation-by-citation through your entire extensive thread and then naturally follow with my own more extensive comprehensive literature search  - Thank you for inspiring me to dig deeper 😉 

 

 

Edited by Mechanism

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Nice find Sibiriak, one of the many benefits of my daily lemon peel 🙂  I noticed Dean already has "citrus peel" and this adds to the stack of evidence in its favor.

The list of BAT promoting and enhancing compounds appears endless, for example quercetin  ( https://www.ncbi.nlm.nih.gov/pubmed/31224085 ) appears to act in part through sympathetic stimulation mediated UCP1 activation ( https://www.ncbi.nlm.nih.gov/pubmed/31089549 ) and is found at different levels in a very wide array of foods, and also no doubt is influenced by a plethora of identified and unidentified compounds ingested with it .  It seems on a weekly if not daily basis less well characterized compounds such as  Platycodin D (https://www.ncbi.nlm.nih.gov/pubmed/30599906) and Liraglutide ( https://www.ncbi.nlm.nih.gov/pubmed/30535743 ) are characterized with similar effects.

Perhaps one approach approach to addressing the enormity and rapid pace of the literature is to classifying BAT promoters by mechanism of action.  For example sympathetic stimulation was noted above, and Berberine promotes BAT an an AMPK dependent manner( https://www.ncbi.nlm.nih.gov/pubmed/31197160 ).   I should caveat here that berberine's overall impact on glucose homeostasis extends far beyond BAT, and is also fundamentally disparate from metformin despite it frequently carrying "metformin mimetic" moniker along the lines of mutual AMPK activity: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839379/

However even  focusing strictly on BAT activation, taking a classification approach seems inept  to adequately address the complexity of biologic health and regulation .  For example in the case of exercise listed by Dean above ( both aerobic and anerobic: https://www.ncbi.nlm.nih.gov/pubmed/30712161) a wide variety of mechanisms including both mitochondrial biogenesis proteins (PGC-1α, SIRT1, and pAMPK) and respiratory chain activity (complexes I, II/III, III, and IV) coordinate to generate the overall affect ( https://www.ncbi.nlm.nih.gov/pubmed/30174613).  We are not so much scrutinizing a note from a musical instrument as observing an orchestra the size of an army with dynamic ever adjusting evolutionary honed feedback loops. 

I think this pickle underscores the value of, in lieu of trials, quantifying at least in relative if not absolute terms which interventions on the whole appear to be highest yield, allowing us to triage our efforts and get the biggest health bang for the buck so to speak.

Edited by Mechanism

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Thanks for the additions to the list Sibiriak and Mechanism! I've added them below except for platycodin d, which was included previously under "balloon flower root (Platycodon Grandiflorus)".

I've also added carotenoids, per extensive discussion in [1] of the BAT-boosting effects of several of them, including beta-carotene, astaxanthin (red seafood and algae), fucoxanthin (brown seaweeds) but surprisingly not lycopene. 

You could easily eat a very healthy (vegan) diet exclusively eating foods which have been shown to boost BAT!

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
  • Carotenoid-rich foods - Beta-carotene (orange fruits and veggies, leafy greens esp kale and spinach),  astaxanthin (red seafood and algae), fucoxanthin (brown seaweeds)
  • 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)
  • Citrus Flavenoid-rich foods - linonene and naringenin. Citrus fruit, peal and juice
  • 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
  • Quercetin-rich foods - capers, onions, elderberries, kale, okra, apple peals, aronia berries, cranberries, asparagus, goji berries
  • Healthy Fats - DHA / EPA / fish-oil, MUFA-rich diet,  Extra Virgin Olive Oil
  • Fiber - Especially cereal fiber (wheat and oat fiber)
  • Olive Polyphenols - Extra Virgin Olive Oil / Olive Leaf Extract / Olive Leaf Tea
  • Other foods - Apples / apple peels / ursolic acid; 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 / Vitamins - metformin, liraglutide, berberine, caffeine, creatine, nicotinamide riboside (NAD), resveratrol, melatonin, alpha-lipoic acid (ALA), vitamin E (alpha-tocopherol)
  • 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]  Arch Biochem Biophys. 2015 Apr 15;572:112-125. doi: 10.1016/j.abb.2015.02.022. Epub 2015 Feb 23. 

Carotenoids and their conversion products in the control of adipocyte function, adiposity and obesity.

Bonet ML(1), Canas JA(2), Ribot J(3), Palou A(3). 

A novel perspective of the function of carotenoids and carotenoid-derived products - including, but not restricted to, the retinoids - is emerging in recent years which connects these compounds to the control of adipocyte biology and body fat accumulation, with implications for the management of obesity, diabetes and cardiovascular disease. Cell and animal studies indicate that carotenoids and carotenoids derivatives can reduce adiposity and impact key aspects of adipose tissue biology including adipocyte differentiation, hypertrophy, capacity for fatty acid oxidation and thermogenesis (including browning of white adipose tissue) and secretory function. Epidemiological studies in humans associate higher dietary intakes and serum levels of carotenoids with decreased adiposity. Specifically designed human intervention studies, though still sparse, indicate a beneficial effect of carotenoid supplementation in the accrual of abdominal adiposity. The objective of this review is to summarize recent findings in this area, place them in physiological contexts, and provide likely regulatory schemes whenever possible. The focus will be on the effects of carotenoids as nutritional regulators of adipose tissue biology and both animal and human studies, which support a role of carotenoids and retinoids in the prevention of abdominal adiposity. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.abb.2015.02.022

PMID: 25721497 [Indexed for MEDLINE]

 

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In my opinion none of the above methods will not give you full effect like example testosterone injection purchased on https://steroids-evolution.com. There will be both strength and muscle mass gain. All that remains to secure the result is right PCT.

Edited by JohnBrown

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1 hour ago, JohnBrown said:

In my opinion none of the above methods will not give you full effect like example testosterone injection. There will be both strength and muscle mass gain. All that remains to secure the result is right PCT.

If you spend a moment looking at the thread subject and the line of discussion, you'll see that these interventions are intended to increase brown adipose tissue mass and/or activity, "for increased health and longevity" — not strength and muscle mass gain.strength and muscle mass gain. I'm aware of no evidence that testosterone injection will affect any of this. Can you point to any? Indeed, barring any other changes, effective interventions on this front might well modestly decrease strength and muscle mass, simply because of energy balance.

Your post might giv epeople the impression that you're here to sell steroids; if so, you need to revise your marketing analysis 😉 .

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3 hours ago, JohnBrown said:

In my opinion none of the above methods will not give you full effect like example testosterone injection. There will be both strength and muscle mass gain. All that remains to secure the result is right PCT.

JB, perhaps you should post in the 'exercise optimization' thread..., or maybe create a 'pharamacological intervention against myopenia' thread.

TRTs may actually be part of a longevity strategy, in cases of infraphysiological concentrations of the hormone.

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5 hours ago, JohnBrown said:

In my opinion none of the above methods will not give you full effect like example testosterone injection.

John,

As Michael points out, the "full effect" you are looking for isn't the same as what we're discussing. But you made me wonder, "how does testosterone treatment impact brown adipose tissue?"  I was actually worried. Given the strongly anabolic nature of testosterone and its tendency to trigger weight loss, I half expected testosterone to boost the conversion of white adipose tissue into metabolically active brown adipose tissue (BAT), which would have been sad as it would have broken the streak in which BAT appears to be boosted only by interventions that are known to be health promoting.

I shouldn't have been worried. Partly because I've presented evidence previously that the opposite of testosterone injections (i.e. castration) actually does boost BAT, so you wouldn't expect increasing testosterone to also boost BAT. Sure enough. In fact, not only do testosterone treatment not appear to boost BAT, it actually tended to blunt some of the markers of increased BAT activity that normally accompanies cold exposure [1].

Given the evidence that testosterone injections aren't likely to promote long-term health and longevity (while castration just might), I count this as more evidence in favor of BAT and interventions that appear able to boost it.

--Dean

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

[1] Acta Endocrinol (Copenh). 1992 May;126(5):434-7.

Brown adipose tissue thermogenesis in testosterone-treated rats.

Abelenda M(1), Nava MP, Fernández A, Puerta ML.

The participation of sexual hormones in body weight regulation is partly accomplished by altering food intake. Nonetheless, female sexual hormones also alter brown adipose tissue thermogenesis in females. This study was aimed to find out if male hormones could alter brown adipose tissue thermogenesis in male rats. Testosterone was administered by means of Silastic capsules in adult male rats acclimated either at 28 degrees C (thermoneutrality) or at 6 degrees C (cold), treatment lasting 15 days. Food intake and body weight gain were reduced by hormonal treatment. However, brown adipose tissue mass, protein content, mitochondrial mass and GDP-binding were unchanged at both environmental temperatures. Accordingly, testosterone participation in body weight regulation is thought to be carried out without altering brown adipose tissue thermogenesis. A reduction in the weight of the sex accessory glands was also observed after cold acclimation. PMID: 1621488 [Indexed for MEDLINE]

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Dean, you are  prescient in many ways, and a trend-setter BAT is all over the news ( recency bias on my part ?): (a) https://www.sciencedaily.com/releases/2019/06/190624111622.htm ,

(b) https://www.sciencedaily.com/releases/2019/06/190620164634.htm which should be interesting since you do brew your own chocolate after all ( while I enjoy them in modest portions brewed in olive leaf, matcha, etc. mostly herbal medley tea along with my cacao nibs, extra cadmium notwithstanding), and perhaps my favorite of the three, on the evolution of human obesity contributing to our moniker as "the fat primate" along with the SAD and lifestyle of modernity.

(c) https://www.sciencedaily.com/releases/2019/06/190626160337.htm

(links with references to the original work).

When your thread on CE collides with this one on heat and heat therapy and HSPs therapy  ( https://www.longecity.org/forum/topic/102741-an-ancient-heat-shocknrf2pluripotency-related-epigenetic-turn-accelerates-human-aging-and-these-can-be-modulated/ ), will it be like antimater and mater touching - Neo and Smith together and arrival of the Singularity?  😁  In all seriousness, beyond impassioned elaborate arguments with corresponding literature documentation in piecing together a narrative, they do share in common heat shock proteins ( released in CE too) and norepinephrine among other mechanisms.   This is not equating evidence, you had me at UCP1 😉

The risk of any theory among many is being led astray by confirmation bias and other foibles, yet creativity and innovation behind model development have brought forth some of the most valuable insights: I admire the research and energy you have put behind this thread.   While I  remain agnostic with regard to some of the details of your CE theory, your persistent energy has motivated me to go through this thread in detail, starting from the beginning.  I was not "ready" to study it in the earlier version iteration of Mechanism when this was last active.

As you know I maintain skepticism regarding the necessity of this intervention for metabolically healthy lean otherwise optimal lifestyle humans seeking primarily a Blue-Zone like healthy longevity with compression of morbidity ( animal model data and human observational data from this thread duly noted along with the inter-species longitudinal studies albeit we can entertain other hypotheses and explanatory narratives consistent with the data), until I study this further I consider it premature to come to definitive assessment there.  In the intervening period ( as that will take some time, and likely more studies), since this is a low cost and low risk intervention, I wonder whether you have any updates or links on these -- if it is buried deep in the thread, feel free to defer responding here, and just let me know - please don't go to the trouble of finding the links again since I will eventually encounter it as & I plan on slowly and thoroughly going through the evidence you have amassed over the next several months:

1) Is there evidence immediate cold immersion is superior to slow cold immersion for a given session ( ie, jumping into a cold shower or pool rather than slowly lowering the temperature)?

2) What top classic papers do you recommend describing beiging of WAT ( and/or beige fat activation) in humans that either have major health state outcomes or else quantify the translation between dose ( duration, temperature and frequency of cold exposure) and beiging?

3) Have you come across any new data that alternating sauna and CE abrogates some of the impact of CE?

4) Exercise and CE - exercising in the same cold room makes the room temperature seem warmer though it is not.  Are you aware of evidence this negates beiging of WAT.

Edited by Mechanism

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On 6/27/2019 at 3:43 AM, JohnBrown said:

Hmm. Guys just relax. that's just my opinion and observation!

My opinion is that testosterone injections might actually halt the aging process entirely.

This occurs via the ‘death’ pathway.  This is only my observation of individuals that have possibly done this (opinion, no evidence).  Such as

https://watchotc.com/dead-bodybuilders/

 

 

Edited by Clinton

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As a follow-up to my previous post, here is a very interesting review article [1] on the effects of exercise (without simultaneous cold exposure) on beige and brown adipose tissue.

The summary is that exercise pretty clearly causes the beneficial "beiging" of white adipose tissue, in both rodents and humans. But as for the response of BAT to exercise, it appears in rodents that exercise (without CE) may boost BAT activity, but in humans, exercise (without CE) may actually reduce BAT activity.

It is unclear the relative importance of beige vs. (true) brown adipose tissue in humans in terms of metabolic benefits. To be safe I think it wise to combine exercise with cold exposure, by exercising in cold conditions or as, I've taken to doing again, wearing a cold vest while exercising.

--Dean

[1] J Exp Biol. 2018 Mar 7;221(Pt Suppl 1). pii: jeb161570. doi: 10.1242/jeb.161570.

Exercise-induced adaptations to white and brown adipose tissue.

Lehnig AC(1), Stanford KI(2).

The beneficial effects of exercise on skeletal muscle and the cardiovascular system have long been known. Recent studies have focused on investigating the effects of exercise on adipose tissue and the effects that these exercise-induced adaptations have on overall metabolic health. Examination of exercise-induced adaptations in both white adipose tissue (WAT) and brown adipose tissue (BAT) has revealed marked differences in each tissue with exercise. In WAT, there are changes to both subcutaneous WAT (scWAT) and visceral WAT (vWAT), including decreased adipocyte size and lipid content, increased expression of metabolic genes, altered secretion of adipokines and increased mitochondrial activity. Adaptations specific to scWAT include lipidomic remodeling of phospholipids and, in rodents, the beiging of scWAT. The changes to BAT are less clear: studies evaluating the effect of exercise on the BAT of humans and rodents have revealed contradictory data, making this an important area of current investigation. In this Review, we discuss the exercise-induced changes to WAT and BAT that have been reported by different studies and highlight the current questions in this field.

DOI: 10.1242/jeb.161570

PMCID: PMC6524684

PMID: 29514893 

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The Downsides of Thermoneutrality (Warm Exposure)

These two studies in mice [1][2] found that housing mice that thermoneutral (TNtemperature as opposed to standard housing temperature (TS) results in higher levels of inflammation, greater susceptibility to diet-induced fatty liver disease and increased rates of atherosclerosis.

This was one of the most interesting paragraphs from the full text of [1]:  

The thermoneutral zone (TN), or temperature of metabolic homeostasis, for Mus musculus is 30–32°C15. However, the standard temperature (TS) range that mice are usually housed is between 20–23°C, a range chosen primarily for human comfort14. Housing mice at TS, as opposed to TN, conditions leads to remarkable physiological changes, including a heart rate increase of over 200 beats per minute, a 30% increase in mean arterial blood pressure16, an overall increase in energy expenditure (50–60%)16,17 and sustained upregulation of catecholamine and corticosteroid production18. Alleviating cold stress, through TN housing, alters immune function in a variety of mouse models, including basal cytokine production19, responses to bacterial20 and viral21,22 infection and tumor immunity14,23. Further, mice housed at TS fail to develop fever after LPS challenge, while TN housing promotes febrile responses following LPS challenge20. In context of metabolic diseases, TN housing is required for modeling obesity in nude mice17, exacerbates adipose tissue inflammation24 and induces atherosclerosis in C57BL/6 WT mice19. 

With the usual caveat about results from rodents, these two studies enumerate quite the laundry list of deleterious side effects of thermoneutral temperature. It is no wonder that thermoneutral housing appears to negate life extending effects of CR, as I've discussed previously.

--Dean

--------

[1] Nat Med. 2017 Jul;23(7):829-838. doi: 10.1038/nm.4346. Epub 2017 Jun 12. 

Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling.

Giles DA(1)(2), Moreno-Fernandez ME(1), Stankiewicz TE(1), Graspeuntner S(3), Cappelletti M(1), Wu D(4), Mukherjee R(1), Chan CC(1)(2), Lawson MJ(1), Klarquist J(1)(2), Sünderhauf A(5), Softic S(6), Kahn CR(6), Stemmer K(7), Iwakura Y(8), Aronow BJ(9), Karns R(10), Steinbrecher KA(10), Karp CL(11), Sheridan R(12), Shanmukhappa SK(12), Reynaud D(13), Haslam DB(14), Sina C(5), Rupp J(3), Hogan SP(4), Divanovic S(1). 

Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis. 

DOI: 10.1038/nm.4346

PMCID: PMC5596511

PMID: 28604704

 

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

[2]  Mol Metab. 2016 Sep 21;5(11):1121-1130. doi: 10.1016/j.molmet.2016.09.008. eCollection 2016 Nov.

Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice.

Giles DA(1), Ramkhelawon B(2), Donelan EM(3), Stankiewicz TE(3), Hutchison SB(4), Mukherjee R(3), Cappelletti M(3), Karns R(5), Karp CL(6), Moore KJ(4), Divanovic S(7). 

OBJECTIVES: Obesity and obesity-associated inflammation is central to a variety of end-organ sequelae including atherosclerosis, a leading cause of death worldwide. Although mouse models have provided important insights into the immunopathogenesis of various diseases, modeling atherosclerosis in mice has proven difficult. Specifically, wild-type (WT) mice are resistant to developing atherosclerosis, while commonly used genetically modified mouse models of atherosclerosis are poor mimics of human disease. The lack of a physiologically relevant experimental model of atherosclerosis has hindered the understanding of mechanisms regulating disease development and progression as well as the development of translational therapies. Recent evidence suggests that housing mice within their thermoneutral zone profoundly alters murine physiology, including both metabolic and immune processes. We hypothesized that thermoneutral housing would allow for augmentation of atherosclerosis induction and progression in mice. METHODS: ApoE-/- and WT mice were housed at either standard (TS) or thermoneutral (TN) temperatures and fed either a chow or obesogenic "Western" diet. Analysis included quantification of (i) obesity and obesity-associated downstream sequelae, (ii) the development and progression of atherosclerosis, and (iii) inflammatory gene expression pathways related to atherosclerosis. RESULTS: Housing mice at TN, in combination with an obesogenic "Western" diet, profoundly augmented obesity development, exacerbated atherosclerosis in ApoE-/- mice, and initiated atherosclerosis development in WT mice. This increased disease burden was associated with altered lipid profiles, including cholesterol levels and fractions, and increased aortic plaque size. In addition to the mild induction of atherosclerosis, we similarly observed increased levels of aortic and white adipose tissue inflammation and increased circulating immune cell expression of pathways related to adverse cardiovascular outcome. CONCLUSIONS: In sum, our novel data in WT C57Bl/6 mice suggest that modulation of a single environmental variable, temperature, dramatically alters mouse physiology, metabolism, and inflammation, allowing for an improved mouse model of atherosclerosis. Thus, thermoneutral housing of mice shows promise in yielding a better understanding of the cellular and molecular pathways underlying the pathogenesis of diverse diseases.

DOI: 10.1016/j.molmet.2016.09.008

PMCID: PMC5081423

PMID: 27818938

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Cool mice live longer:

https://www.nature.com/news/2006/061030/full/061030-11.html

Body temperature of C57BL/6J mice with age:

https://www.ncbi.nlm.nih.gov/pubmed/6723816

As Dean mentioned, the studies he linked to were in mice. It is important to note that thermoregulation in mice and humans is very different, including impact on BAT - for one, mice enter regulated hypothermia states, and humans do not:

Of Mice and Men

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13070

So we have to exercise some caution here, as these various findings may not translate from mice to men. Always be careful wrt. animal results (my perennial warning!).

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Tom,

13 hours ago, TomBAvoider said:

I discussed that study [1] in my "Cold Exposure Albatross" post under the section enumerating all the benefits of CE. Here is what I said there:

Quote

Study [1] found that reducing core body temperature of ad lib fed mice via genetic mutation that modulates hypothalamus temperature (the body's thermostat) and thereby reduces core body temperature, increases lifespan without changes in calorie intake. Depending on its severity, CE can easily reduces core body temperature even more than CR, and so is likely to extend lifespan along this same pathway.

And yes, the usual caveats about rodent study certainly applies here.

--Dean

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

[1] Science. 2006 Nov 3;314(5800):825-8.

Transgenic mice with a reduced core body temperature have an increased life span.

Conti B(1), Sanchez-Alavez M, Winsky-Sommerer R, Morale MC, Lucero J, Brownell S,
Fabre V, Huitron-Resendiz S, Henriksen S, Zorrilla EP, de Lecea L, Bartfai T.

Author information:
(1)Harold L. Dorris Neurological Research Center, Scripps Research Institute, La
Jolla, CA 92037, USA. bconti@scripps.edu

Comment in
Science. 2006 Nov 3;314(5800):773-4.

Reduction of core body temperature has been proposed to contribute to the
increased life span and the antiaging effects conferred by calorie restriction
(CR). Validation of this hypothesis has been difficult in homeotherms, primarily
due to a lack of experimental models. We report that transgenic mice engineered
to overexpress the uncoupling protein 2 in hypocretin neurons (Hcrt-UCP2) have
elevated hypothalamic temperature. The effects of local temperature elevation on
the central thermostat resulted in a 0.3 degrees to 0.5 degrees C reduction of
the core body temperature. Fed ad libitum, Hcrt-UCP2 transgenic mice had the same
caloric intake as their wild-type littermates but had increased energy efficiency
and a greater median life span (12% increase in males; 20% increase in females).
Thus, modest, sustained reduction of core body temperature prolonged life span
independent of altered diet or CR.

PMID: 17082459

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"Rats with Cold Feet" Replication

Holloszy's famous 1985 "Rats with Cold Feet" experiment [1] was the reason I kicked off this thread 3.5 years ago with this post. Holloszy found that rats who spent 5h/day for their entire adult life standing in a cold puddle of water ate 44% more than normally-housed rats, but nonetheless stayed thin and didn't live any shorter lives than the normally-housed rats. In fact they lived slightly longer and got less cancer.

Somehow I've never discussed what turns out to be a nice replication of Holloszy's study. In this 2009 study [2], researchers housed mice (rather than rats) at either "normal" temperature (72F/22C which is still pretty chilly for mice) or a very chilly 50F/10C for their entire adult lives. 

The cold mice at 48% more food, weighed slightly less, and lived just as long as the warm-house mice. The authors conclude:

This result demonstrates that increased energy expenditure does not shorten life span and adds evidence to the intraspecific refutation of the rate-of-living theory.

It is nice to see a replication of an important study like Holloszy's, especially when it is in a different species, even if in this case they are both rodents.

--Dean

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

[1] J Appl Physiol (1985). 1986 Nov;61(5):1656-60.

Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory".

Holloszy JO, Smith EK.

It has been postulated that increased energy expenditure results in shortened
survival. To test this "rate-of-living theory" we examined the effect of raising
energy expenditure by means of cold exposure on the longevity of rats. Male
6-mo-old SPF Long-Evans rats were gradually accustomed to immersion in cool water
(23 degrees C). After 3 mo they were standing in the cool water for 4 h/day, 5
days/wk. They were maintained on this program until age 32 mo. The cold exposure
resulted in a 44% increase in food intake (P less than 0.001). Despite their
greater food intake, the cold-exposed rats' body weights were significantly lower
than those of control animals from age 11 to 32 mo. The average age at death of
the cold-exposed rats was 968 +/- 141 days compared with 923 +/- 159 days for the
controls. The cold exposure appeared to protect against neoplasia, particularly
sarcomas; only 24% of the necropsied cold-exposed rats had malignancies compared
with 57% for the controls. The results of this study provide no support for the
concept that increased energy expenditure decreases longevity.

PMID: 3781978

----------

[2] Physiol Biochem Zool. 2009 Jul-Aug;82(4):314-24. doi: 10.1086/589727.

Metabolism and aging: effects of cold exposure on metabolic rate, body
composition, and longevity in mice.

Vaanholt LM(1), Daan S, Schubert KA, Visser GH.

The proposition that increased energy expenditure shortens life has a long

history. The rate-of-living theory (Pearl 1928 ) states that life span and
average mass-specific metabolic rate are inversely proportional. Originally based
on interspecific allometric comparisons between species of mammals, the theory
was later rejected on the basis of comparisons between taxa (e.g., birds have
higher metabolic rates than mammals of the same size and yet live longer). It has
rarely been experimentally tested within species. Here, we investigated the
effects of increased energy expenditure, induced by cold exposure, on longevity
in mice. Longevity was measured in groups of 60 male mice maintained at either 22
degrees C (WW) or 10 degrees C (CC) throughout adult life. Forty additional mice 
were maintained at both of these temperatures to determine metabolic rate (by
stable isotope turnover, gas exchange, and food intake) as well as the mass of
body and organs of subsets of animals at four different ages. Because energy
expenditure might affect longevity by either accumulating damage or by
instantaneously affecting mortality rate, we included a third group of mice
exposed to 10 degrees C early in life and to 22 degrees C afterward (CW).
Exposure to cold increased mean daily energy expenditure by ca. 48% (from 47.8 kJ
d(-1) in WW to 70.6 kJ d(-1) in CC mice, with CW intermediate at 59.9 kJ d(-1)). 
However, we observed no significant differences in median life span among the
groups (WW, 832 d; CC, 834 d; CW, 751 d). CC mice had reduced body mass (lifetime
mean 30.7 g) compared with WW mice (33.8 g), and hence their lifetime energy
potential (LEP) per gram whole-body mass had an even larger excess than per
individual. Greenberg ( 1999 ) has pointed out that the size of the energetically
costly organs, rather than that of the whole body, may be relevant for the
rate-of-living idea. We therefore expressed LEP also in terms of energy
expenditure per gram dry lean mass or per gram "metabolic" organ mass (i.e.,
heart, liver, kidneys, and brain). No matter how it was expressed, LEP in CC mice
significantly exceeded that of WW mice. This result demonstrates that increased
energy expenditure does not shorten life span and adds evidence to the
intraspecific refutation of the rate-of-living theory.
We suggest that increased 
energy expenditure has both positive and negative effects on different factors
determining life span and that the relationship between energy turnover and
longevity is fundamentally nonmonotonic.

DOI: 10.1086/589727 
PMID: 19115965  [Indexed for MEDLINE]
 

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Dean,

your contribution with this thread is significant .

BAT and ‘good fat’ is (apparently?) common enough now to be discussed on my local radio channel (morning show).  Due to recent headlines in the news radio show hosts here got excited.  It was painful to listen to with allot of confusion and misleading comments- including asking the drive through worker at the coffee shop to add cream to their coffee with brown fat or good fat - they had completely taken out of context fat tissue in the body to fat that they consume.

Regardless- I believe CE will be found to be as significant or required to go with CR for optimal results- thank you,

Clinton 

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1 hour ago, Clinton said:

including asking the drive through worker at the coffee shop to add cream to their coffee with brown fat or good fat

Smells like a winner to me, wait a bit and maybe you'll be able to order it from Dave Asprey - Bomb Proof coffee made with 100% wild caught baby seal brown fat.

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