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Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Dean Pomerleau

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Thanks for the digging on miR-196a2, and SNP rs11614913. I'm CT for that SNP according to 23andMe. Not as favorable as your CC, at least for converting white fat to brown.


On the other hand, being CC (or event CT like me) for that allele appears to have its downsides as well according to SNPedia - in the form of elevated risk of various forms of cancer, for example colorectal cancer (CRC) [1].


Expression analysis revealed that rs11614913 CC or carrying at least one C allele was associated with a significantly increased level of mature miR-196a (p = 0.010 or = 0.022).
Frequency of the CC genotype was higher in CRC patients than controls, implying that the subjects with the CC genotype or C allele containing genotypes (CT and CC) have a higher risk of CRC.

So you win some, you lose some I guess. But now that clever scientists have figured out a way to use CRISPR to edit single base pairs [2], all that may one day change... 


[1] Arch Med Res. 2011 Feb;42(2):144-8. doi: 10.1016/j.arcmed.2011.04.001.

A functional variant in microRNA-196a2 is associated with susceptibility of
colorectal cancer in a Chinese population.

Zhan JF(1), Chen LH, Chen ZX, Yuan YW, Xie GZ, Sun AM, Liu Y.

Author information:
(1)Department of Health Management Centre, Guangzhou First Municipal People's
Hospital Affiliated to Guangzhou Medical College, Guangzhou, Guangdong Province,
China. zhanjunfang@sina.cn

BACKGROUND AND AIMS: MicroRNAs (miRNA) can act as oncogenes or tumor suppressors.
Polymorphisms present in pri-, pre- and mature miRNAs can potentially modulate
the expression of hundreds of genes, broadly affecting miRNA function. Notably,
the rs11614913 SNP in miR-196a2 has been implicated in carcinogenesis, but its
association with colorectal cancer (CRC) remains unexplored. We performed a
case-control study to investigate the genetic association between this functional
SNP and CRC susceptibility and progression.
METHODS: We genotyped the rs11614913 SNP in 252 CRC patients and 543 healthy
controls by polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP). In addition, we examined miR-196a expression level in colorectal
cancer tissues (n = 50) obtained from the studied CRC patients.
RESULTS: Frequency of the CC genotype was higher in CRC patients than controls,
implying that the subjects with the CC genotype or C allele containing genotypes
(CT and CC) have a higher risk of CRC.
However, no significant association
between this polymorphism and CRC progression was observed. Expression analysis
revealed that rs11614913 CC or carrying at least one C allele was associated with
a significantly increased level of mature miR-196a (p = 0.010 or = 0.022).

CONCLUSIONS: The present study provides the first evidence that miR-196a2
polymorphism may contribute to CRC susceptibility in a Chinese population through
modulating mature miR-196a expression.

Copyright © 2011 IMSS. All rights reserved.

PMID: 21565628



[2] 1. Nature. 2016 Apr 20. doi: 10.1038/nature17946. [Epub ahead of print]

Programmable editing of a target base in genomic DNA without double-stranded DNA 
Komor AC(1,)(2), Kim YB(1,)(2), Packer MS(1,)(2), Zuris JA(1,)(2), Liu DR(1,)(2).
Author information: 
(1)Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, USA. (2)Howard Hughes Medical Institute, Harvard University,
Cambridge, Massachusetts 02138, USA.
Current genome-editing technologies introduce double-stranded (ds) DNA breaks at 
a target locus as the first step to gene correction. Although most genetic
diseases arise from point mutations, current approaches to point mutation
correction are inefficient and typically induce an abundance of random insertions
and deletions (indels) at the target locus resulting from the cellular response
to dsDNA breaks. Here we report the development of 'base editing', a new approach
to genome editing that enables the direct, irreversible conversion of one target 
DNA base into another in a programmable manner, without requiring dsDNA backbone 
cleavage or a donor template. We engineered fusions of CRISPR/Cas9 and a cytidine
deaminase enzyme that retain the ability to be programmed with a guide RNA, do
not induce dsDNA breaks, and mediate the direct conversion of cytidine to
uridine, thereby effecting a C→T (or G→A) substitution. The resulting 'base
editors' convert cytidines within a window of approximately five nucleotides, and
can efficiently correct a variety of point mutations relevant to human disease.
In four transformed human and murine cell lines, second- and third-generation
base editors that fuse uracil glycosylase inhibitor, and that use a Cas9 nickase 
targeting the non-edited strand, manipulate the cellular DNA repair response to
favour desired base-editing outcomes, resulting in permanent correction of
~15-75% of total cellular DNA with minimal (typically ≤1%) indel formation. Base 
editing expands the scope and efficiency of genome editing of point mutations.
PMID: 27096365  [PubMed - as supplied by publisher]
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Cold Exposure Turns Subcutaneous White Fat to Beige in Humans Too!


Strap on your cooling vests everyone, things are about to get interesting... I know you're waiting with bated (not baited) breath, but my promised rpWAT post is getting bumped once again...


Recall over the last few days I've built up a case that virtually all thermogenic fat in humans is not true BAT, but former white adipose tissue that has been turned to brown (beige) as a result of cold exposure, or in some experimental cases, via drugs. And we've seen that browning of white fat appears to occur in both visceral and subcutaneous fat.


But all that evidence was in mice. What about humans? Is there really evidence for conversion of WAT into thermogenic beige fat in parts of the human body away from the well-known 'BAT' pockets around the neck, upper chest, back and ribcage?




After reading my recent posts, my friend Eric from CoolFatBurner.com sent me a heads up about this paper [1]. It's actually two studies for the price of (reading) one.


In the first part, the researchers examined the abdominal (Group 1) and thigh (Group 2) subcutaneous (SC) fat from 71 people who were biopsied in either the summer or winter in Kentucky or Arkansas to see if the season influenced the degree of browning of their SC fat.


The average outdoor temperatures were ~6°C (43°F) in winter and ~22°C (72 °F) in summer.  None of the subjects had jobs that would subject them to extended outdoor exposure. All the subjects were "generally healthy", and were about evenly split between "obese" (BMI > 30, avg ~35) and simply "overweight" (BMI <30, avg ~27) - which the authors will refer to as the "obese" and "lean" <sic> groups.


What they found in this first part was pretty dramatic. UCP1 expression was about 3x higher, and mitochondria-proliferator PGC1α was almost 2x higher in abdominal fat from Group 1 subjects in winter compared with summer, as illustrated in the graph on the left. In the thigh fat biopsy folks (Group 2), the seasonal difference was even greater (right graph), with UPC1 about a factor of 7x higher (eyeballing the graph) in winter vs. summer biopsies.




Notice in the right graph the spike in TMEM26 expression in the winter? TMEM26 is a genetic marker of beige (rather than true brown) adipose tissue. In contrast, none of the known genetic markers of true BAT were elevated (data not shown). So it was definitely conversion of subcutaneous white fat cells to beige fat cells that was happening in these folks in wintertime, rather than de novo lipogenesis of true BAT cells.


Next they compared abdominal SC fat from "lean" (avg BMI ~27) vs "obese" (avg BMI ~35) to see how their respective browness compared, in summer and winter. Here is the graph:




As you can see, the "lean" subjects had browner abdominal SC fat than the obese subjects did at both times of year - an effect we've discussed previously, i.e. intermediate BMI folks like this "lean" <sic> group have the most BAT. And as you can see, it was only the "lean" subjects who saw a dramatic (and significant p < 0.05) increase in UCP-1 content in winter relative to summer. In other words, the browning of SC fat in general, and the browning induced by cooler winter temperatures, was blunted in the obese folks. 


So that's Part 1 of the study - representing pretty strong evidence that a cooler environment results in browning of subcutaneous fat, at least in non-obese folks.


But it only showed correlation of increased browning of SC fat with season/temperature, and not causation, and the biopsy data for winter and summer were from different groups of people, so the evidence wasn't definitive that cold causes browning of subcutaneous fat.


Moreover, their observation that "lean" (i.e. just overweight) subjects exhibited browner subcutaneous fat both in summer and winter, and gained more brown fat in association with the change in season, doesn't prove that having more BAT helps keep them leaner. It may be the result of better insulation that the obese people have need, and therefore develop, less BAT for thermogenic purposes.


That's where Part 2 of this study comes in, and where things get really cool.


They took the thigh biopsy folks from Part 1, did a further test to investigate the browning effects of acute and localized cold exposure. The tested 16 of the relatively "lean" folks (avg BMI ~26) from the thigh group who had their biopsy performed in the summer. In addition to a biopsy done on the "warm" thigh for the tests described in Part 1, the researchers also applied a 2 kg ice pack to the other thigh of these subjects for 30 minutes, waited 4 hours, and then took a biopsy of this "cold-exposed" thigh. So the subjects served as their own controls. During the cold stimulus, "subjects reported that the site felt numb, and there was a rewarming sensation, but no unpleasant side effects or shivering were observed." See it's not that bad.


They then did the obvious - they compared the degree of "browning" in the SC fat from the two thigh tissue samples - a control, warm "summer thigh" vs a summer thigh exposed to acute, localized cooling.


Since I'm telling you this, I bet you can guess what they found - increased browning in the SC thigh fat exposed to acute localized cooling. Here are the two graphs. Focus for now on the bars I've highlighted:




The top graph shows expression of PGC1α, a protein known to be involved in mitochondrial biogenesis, and the lack of which in adipose tissue is associated with insulin resistance [2]. The bottom graph shows expression of mitochondrial uncoupling protein 1, UCP1. The white bars are cells taken from the control thigh, and the black bars are from cells taken from the cold-exposed thigh. As you can see, the cold-exposed fat cells expressed twice as much PGC1α and 3.5 times more UCP1 relative to fat cells from the control thigh. After just half an hour of direct cold simulation. Pretty impressive!


The other bars in the two graphs represent tests to see if a pro-inflammatory environment (known to occur in the fat tissue of obese people) blunted the browning of SC fat tissue in response to cold.  They bathed the fat cells in a medium containing chemicals given off by macrophages of several types sometimes associated with an inflammatory response (named M1, M2a and M2c), or infused with the well-known marker of inflammation, TNFα at various concentrations. What you can see is that these inflammatory signals did indeed blunt the browning of SC fat.


This suggests that "better insulation" is not the only (or main) reason obese people have whiter (less thermogenic) subcutaneous fat than leaner people (as seen in Part 1). Instead or in addition, the systemic inflammation the obese exhibit likely suppresses the browning of SC fat, even when exposed to cold. This is another way of explaining part of the Ո-shaped relationship between BMI and BAT (beige fat) mass in humans. Really heavy people have increased systemic inflammation, suppression the conversion of white fat to beige.


Notice that this results in a vicious circle not unlike the one I described yesterday involving IL-33. In this one, obese people have increased inflammation, which suppresses SC fat browning, which results in their fat tissue burning fewer calories, which leads to weight gain, which leads to additional inflammation. Here again it would seem cold exposure has the potential to break the vicious cycle of weight gain begatting more weight gain in the obese, at least if done rigorously and consistently to overcome the initial "browning handicap" that obese people are saddled with.


Here are some other interesting tidbits from the discussion section of the paper (my emphasis):


In the abdominal SC WAT, other genes involved with lipolysis
and energy utilization (adiponectin, AMPK, HSL, and
ACC) were also elevated in the winter, as was the adipose
protein level of UCP1.


Recall from this post about CE and AMPK, and from this post about the synergy between the biochemical pathways of CR and CE, that adiponectin and AMPK are two of the enzymes the model points out as elevated by CE - so it makes sense they'd be observed to be elevated in winter relative to summer.


What they didn't observe was changes in gene expression in the thigh muscle tissue cells, despite the muscle receiving a similar degree of acute cooling as the thigh SC fat (the thigh fat on these folks wasn't very thick, according to the authors).  Although they didn't say explicitly which genes they tested, it was presumably the same UCP1 and Pgc1α they tested in the fat samples, which might not be involved in muscle non-shivering thermogenesis, as pointed out in this post about sarcolipin-induced thermogenesis in skeletal muscles. 


They also saw that signals of inflammation, in the form of either the presence of certain types of macrophages or the inflammatory cytokine TNFα, suppressed the browning of SC fat .


I can hear you saying, "But Dean, didn't you say two days ago in this post that macrophages were an important part of the SC fat browning pathway? Remember you said EOS → ↑ IL-4 → ↑ macrophages → ↑ norepinephrine → SC fat browning? Now you're saying macrophages suppress browning? What gives?"


It turns out that (not surprisingly), all macrophages are not created equal. There are all kinds of different macrophages that respond to different activators and that do different jobs. Notice in the above graph they tested three different macrophage types, M1, M2a and M2c, and it was M1 and M2c macrophages that really put the whammy on SC fat browning, while M2a macrophages had a relatively modest (although still negative) effect on browning. 


The M1 macrophages are the classic ones that get recruited to "seek and destroy" bacteria or viruses during acute infections - and are definitely pro-inflammatory. The M2c macrophages are activated by IL-10 and glucocorticoids, the latter of which we saw in this post suppressed brown fat and induced muscle wasting via reduced mTOR activity in people. So it's not surprising the M2c macrophages blunt the browning effect in SC fat.


That leaves the M2a macrophages, which recall weren't as bad for SC fat browning as the other two. Not surprisingly, it's these M2a macrophages that were the type involved in promoting SC fat browning - they are the ones recruited by IL-4 and IL-13, the two interleukins downstream of IL-33 shown to be responsible for the norepinephrine release so critical to turn white fat to beige in the diagrams in this post on IL-33 and this post on IL-4.


And in those two posts, we saw it wasn't just the presence of M2a macrophages that turned white fat to beige - the macrophages had to be induced to release norepinephrine by the presence of EOS cells and their release of IL-4. Since the in vitro experiment done with the thigh fat cells in this study didn't have either of these norepinephrine-inducing factors, it's not surprising that even the M2a macrophages caused a modest reduction in SC fat browning, rather than boosting the browning process as we saw previously. In other words, it takes cold to recruit EOS cells to release IL-4 to induce M2a macrophages to release the brown-inducing norepinephrine, and the SC fat cells in the petri dish in this study weren't exposed to cold, nor were there EOS cells around in the culture medium to help induce browning.


In short, inflammation is bad for SC fat browning, or as the authors put it:


When cold exposed adipocytes were exposed to inflammatory products,
either macrophage conditioned medium or TNF,
the cold response was considerably blunted. This effect
was especially pronounced with M1 macrophage conditioned
medium, indicating that a proinflammatory environment
blunts the beiging effect of WAT in response to cold.


The authors cite Michael' jiggling pecs study (PMID 26993316), saying:


[C]old-induced thermogenesis in BAT [around the neck region - DP]
could only explain a small fraction of the
total increase in overall energy expenditure, leaving open
the possible contribution of other tissues, such as WAT.


Here is a cool statistic for you from the final paragraph of the paper (my emphasis):


In contrast to BAT mass, which in humans is small (ref),
SC WAT mass is at least 1000-fold greater than that of BAT,
and therefore even a small increase in UCP1-mediated
mitochondrial uncoupling in WAT could significantly increase
energy expenditure. These changes in energy expenditure
may occur naturally with seasons, and this effect could
potentially be manipulated through drug therapy [or cold exposure! - DP].


This statement, and the results of this study, are right in line with the hypothesis I've been developing ever since Michael's jiggling pecs challenge - namely that the tiny amount of "BAT" tissue (actually beige fat cells) observed in the neck, upper chest, back and ribcage region of people is just the "tip of the iceberg" when it comes to sources of non-shivering thermogenesis in humans. 


In summary, this study [1] shows that what was observed in mice holds for humans as well - namely that cold exposure turns white fat to beige in subcutaneous fat pockets (aka "love handles") all around the human body. And most excitingly of all, they go one step further than any rodent experiments I've seen, to show that acute, localized cold exposure (via application of cold packs) can very quickly kick off the process of turning white fat deposits to calorie-burning beige fat. 


Of course once again there is no free lunch. To maintain the cold-induced beige adipose tissue, and to get it to actually burn extra calories, you need to expose it to cold, either acutely or systemically. You can't just apply a cold pack for 30 minutes and expect to burn extra calories in warm ambient conditions and in perpetuity.


So if you are interested in boosting brown (= beige) fat, I suggest you buy and start wearing one of those stylish cooling vests reviewed in this post.





[1] J Clin Endocrinol Metab. 2014 Dec;99(12):E2772-9. doi: 10.1210/jc.2014-2440.

The effects of temperature and seasons on subcutaneous white adipose tissue in
humans: evidence for thermogenic gene induction.
Kern PA(1), Finlin BS, Zhu B, Rasouli N, McGehee RE Jr, Westgate PM,
Dupont-Versteegden EE.
CONTEXT: Although brown adipose tissue (BAT) activity is increased by a cold
environment, little is known of the response of human white adipose tissue (WAT) 
to the cold.
DESIGN: We examined both abdominal and thigh subcutaneous (SC) WAT from 71
subjects who were biopsied in the summer or winter, and adipose expression was
assessed after an acute cold stimulus applied to the thigh of physically active
young subjects.
RESULTS: In winter, UCP1 and PGC1α mRNA were increased 4 to 10-fold (p < 0.05)
and 1.5 to 2-fold, respectively, along with beige adipose markers, and UCP1
protein was 3-fold higher in the winter. The seasonal increase in abdominal SC
WAT UCP1 mRNA was considerably diminished in subjects with a BMI > 30 kg/m(2),
suggesting that dysfunctional WAT in obesity inhibits adipose thermogenesis.
After applying an acute cold stimulus to the thigh of subjects for 30 min, PGC1α 
and UCP1 mRNA was stimulated 2.7-fold (p < 0.05) and 1.9-fold (p = 0.07),
respectively. Acute cold also induced a 2 to 3-fold increase in PGC1α and UCP1
mRNA in human adipocytes in vitro, which was inhibited by macrophage-conditioned 
medium and by the addition of TNFα.
CONCLUSION: Human SC WAT increases thermogenic genes seasonally and acutely in
response to a cold stimulus and this response is inhibited by obesity and
PMCID: PMC4255113
PMID: 25299843 
[2] Kleiner S, Mepani RJ, Laznik D, et al. Development of insulin resistance
in mice lacking PGC-1alpha in adipose tissues. Proc. Natl.
Acad. Sci. USA. 2012;109:9635–9640.
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Very cool (forgive the lazy pun) science, Dean, thanks for all your hard work!


However, being a low down pleb, grubby and uncouth, when I read one of these cool science papers I always end up with "verrry interrestink! I tink I understand the vorld a bit better! BUT how can I apply this to MY life, mwahahaha!". Which is why I am much more excited to read about studies in humans, rather than in rodents. But the low down pleb that I am, I still end up: can I apply this to my life?


I hope that at some point there can be more focus on how a CRONie might apply CE in their life - supported by science insofar as one can. Now, since I'm a CRONie, that right there tells you that I'm willing to take a bit of a leap of faith (that CR works in humans, even a little), but I still cling to the hope that I can find some scientific backing to a lifestyle that already raises eyebrows and gets lots of eyes rolling. 


I'm talking about protocol based on science. It's all well and good to put on a cooling vest, turn down the thermostat, sleep without sheets in winter etc., but isn't this as serious as a CRON diet with a thousand considerations beyond just "cut calories!". What about initiation? Is it safe in late middle age (where many on this list find themselves), do we start exposure on a slope over time - 70° 6 months, 60° 4 months, 50° 3 months, 40° maintenance; how does the therapy look: ice vest at x temp for y amount of time z times a day... what are the x, y, z values? What are the contraindications which might inadvertently obviate CE bennies - the way there are plenty such in CR. All hopefully somewhat backed by science. Aren't we all pretty obsessive about our CR protocols, constantly tweaking them? Is CE different in that regard? Is it somehow a simpler intervention?


Again, not to take away from the intellectual aspect of this - no question very interesting. But there is also the grubby pleb side of me - how do I harness all this coolness?  

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All good points. I think the short answer is that we simply don't know what CE protocol is best for humans - i.e. we are in pretty much the same boat as we are in for CR. We don't know the best way to get cold, how cold is too cold, should we ease into cold exposure, can one be too old or frail for cold exposure, etc.


It's too new and unexplored even in rodents, to say nothing of people, to have answers to these questions.


Heck, we certainly don't know unequivocally that it will provide health & longevity benefits beyond weight loss (for those who need that...) although I would say improvements in glucose metabolism / insulin sensitivity / diabetes prevention seem extremely likely.


My hypothesis that "serious CR without CE will be futile" is just that - a hypothesis. But there is what I consider to be pretty compelling support for it from the rodent data (e.g. discussed here), from epidemiological data across species and in particularly long-lived small mammals (e.g. bats, grey squirrels and naked mole rats), and circumstantial and indirect support from the failure of "warm CR" to extend lifespan in monkeys as discussed here...


Regarding contraindications - that is the topic of my next post (yes, before rpWAT...), so stay tuned.



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I have been  tracking my body temp (trying to keep the average low) through the day the way one might track calories (trying to keep them low) throughout the day.  I tossed my FitBit and got a new fitness tracker band (after 1.5 days research) that tracks skin temperature (along with many other fancy sensors and software features like a "smart alarm" that does not wake me if I'm in the middle of a REM stage of sleep).  It's a "Microsoft Band 2."

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Thanks Kenton,


I didn't realize the Microsoft Band 2 tracks skin temperature. That's a pretty handy feature. How's it compare with your Fitbit in it's other features?




The Basis Peak also tracks skin temp, and its heart rate monitoring has consistently outperformed FitBit and beaten or tied all competitors in both independent and company-sponsored tests (more and less rigorous). I've been meaning to post about its many virtues in the Cool Tools thread (title in this context amusing) for some time ...

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So nice to see you're still monitoring this thread. I was beginning to wonder. Does your silence on other topics of discussion imply your agreement?


The Basis Peak also tracks skin temp, and its heart rate monitoring has consistently outperformed FitBit and beaten or tied all competitors in both independent and company-sponsored tests (more and less rigorous). I've been meaning to post about its many virtues in the Cool Tools thread (title in this context amusing) for some time ...


Thanks for the tip on the Basis Peak. I didn't realize it tracks skin temperature too. But it is one butt-ugly fitness tracker:




I initially read the word "Basic" at the bottom of the watch as "Casio" . Did you ever own one of these Casio calculator watches?




I loved mine, back in the '70s...


Looking over the reviews of the Basis Peak, it looks pretty mixed, with almost as many 1- and 2-star ratings as 4 and 5-star ratings. And the first, and longest video review in the product description is pretty mixed - which is surprising, given it's provided by the seller. I presume you own one and find it useful?


I came across an attribute of the Basic Peak that would pretty much makes it a non-starter for my usage pattern, if it's still the case. In this review, the Basis Peak owner says:


The most frustrating aspect of using the device is that data does not sync in real time and has to be uploaded to the cloud before it will show you anything on your mobile device. Syncing and uploading that data takes more than a minute.


But that review is from over a year ago. Has the software changed to continuously update the app? Continuous updates are one thing I really like and rely on with my Fitbit Charge HR. I have my phone on top of my bike desk and monitor at a glance how far I've gone, how many "steps" I've taken, my HR etc via the Fitbit app. Since I've got my Fitbit strapped around my lower quad for a lot of the day, which is moving and under my desk, I can't easily read it while pedaling. I guess I could manually trigger a sync sporadically to see the latest data, but it would be a bit of a hassle.


On the other hand, the Basis Peak's other features do look pretty cool - skin temperature, waterproof, text messages and notifications, connects to other HR monitoring software. Do you think it really can track REM sleep? I'd be curious to hear more about your experience with it. 



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Cold Exposure Downsides?




I'm surprised this news story, entitled Lab Mice Are Freezing Their Asses Off—and That’s Screwing Up Science hasn't already been posted by one of the CE detractors (I'm looking at you Al ). I've been meaning to post about it, and since Tom brought up the question of what contraindications there might be for CE, I figure now is a good time to discuss it. 


It basically focuses on the findings by a team of cancer researchers at the Roswell Park Cancer Institute, led by Elizabeth Repasky, that has been investigating the effects of temperature on cancer growth in mice. There body of work, which this new review paper [1] summarizes, boils down to the fact that mice at Standard Temperatures (ST = 20-24 °C) are cold-stressed relative to Thermoneutral Temperatures (TT = 30-32 °C), and must engage in much more calorie-burning thermogenesis to maintain their body temperature. As a result:


It is likely that with the burden of rapid tumor growth, expansion of immune cell populations would compete for energy needed for thermogenesis such that, ultimately, immunosuppression may protect the ability of the organism to maintain body temperature.


In other words, experiments conducted at ST require mice to burn a lot of calories to stay warm, and so they have less energy left over to mount an effective immune response to slow the rapid growth of tumors in cancer experiments.


So what's the deal Dean? I thought you said (and Michael even agreed! ) that one of the benefits of CE in mouse lifespan is reduced mortality from cancer relative to warmer housing conditions? E.g. in the famous Koizumi & Walford study (PMID 9032756) discussed  here and here, and in greater detail & more recently here.


Indeed, the authors of [1] cite Koizumi & Walford, acknowledging in that instance cancer rates were lower at ST than TT in the context of calorie restriction:


Interestingly, Koizumi and colleagues showed that the reported ability of dietary restriction to reduce the incidence of lymphoma in mice only occurred at ST, and that this effect was lost in mice housed at TT [ref], again demonstrating a dichotomy of experimental results at ST versus TT.


So overall, the authors of [1] aren't claiming "cold house is bad", but that "cold housing is different" from thermoneutral housing when it comes to cancer. They also acknowledge that TT housing is different, and potential worse, when it comes to inflammation and atherosclerosis:


Tian et al. [ref] found increased inflammation in mice at TT, which was associated with promoting atherosclerosis...


But focusing on their main point about cancer, the difference appears to be similar to what we see with CR and immunity, as we've recently discussed here, here and here. In fact, the CR & immunity story may be almost synonymous with the CE & immunity story, since CR rodent studies are almost invariably "CR + CE" rodent studies...


Both the CR science and our CR Society Poll on immunity suggest that CR increases one's ability to prevent infections and cancer. But once a foreign invader gains a foothold in the body, CR makes it more difficult to mount an effective immune response in order to fight it off. There just aren't enough calories available to "feed a fever". In fact, according to the latest science, the old saying should actually be "feed a cold, feed a fever":


Fever is part of the immune system’s attempt to beat the bugs. It raises body temperature, which increases metabolism and results in more calories burned; for each degree of temperature rise, the energy demand increases further. So taking in calories becomes important.


CR alone, or CR with CE to create a net calorie deficit (as I recommend), results in relatively less energy available to devote to an immune response. This is bad news if you've got an established illness or cancer, either naturally acquired, or in the case of rodents used in cancer research, as a result of being injected with a bolus of cancer cells.


The bottom line seems to be that both CR & CE, and especially the combination, are beneficial for preventing infections and cancer, but are contraindicated when/if you've already got an infection or cancer.


Tomorrow I hope to finally get to my post about CE and rpWAT.





[1] Trends In Cancer (59) http://dx.doi.org/10.1016/j.trecan.2016.03.005 1


Thermoneutrality, Mice, and Cancer: A Heated Opinion

Bonnie L. Hylander1 and Elizabeth A. Repasky1,*
The ‘mild’ cold stress caused by standard sub-thermoneutral housing temperatures
used for laboratory mice in research institutes is sufficient to significantly
bias conclusions drawn from murine models of several human diseases. We
review the data leading to this conclusion, discuss the implications for research
and suggest ways to reduce problems in reproducibility and experimental
transparency caused by this housing variable. We have found that these cool
temperatures suppress endogenous immune responses, skewing tumor growth
data and the severity of graft versus host disease, and also increase the
therapeutic resistance of tumors. Owing to the potential for ambient temperature
to affect energy homeostasis as well as adrenergic stress, both of which
could contribute to biased outcomes in murine cancer models, housing temperature
should be reported in all publications and considered as a potential
source of variability in results between laboratories. Researchers and regulatory
agencies should work together to determine whether changes in housing
parameters would enhance the use of mouse models in cancer research, as
well as for other diseases. Finally, for many years agencies such as the National
Cancer Institute (NCI) have encouraged the development of newer and more
sophisticated mouse models for cancer research, but we believe that, without
an appreciation of how basic murine physiology is affected by ambient temperature,
even data from these models is likely to be compromised.


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Along the lines of practical application and contraindications...

I think if CE is a detriment to your sleep, is causing any physical problems (cold burns/frost bite, certain hypothermia symptoms: irritability, combativeness, confusion, delirium, slow reflexes, seizures, stupor, coma) you are obviously going way overboard.  Remember, if you are doing this right, your body is going to produce its own heat, and lots of it, so that your core temperature remains steady instead of dropping (requiring extra calories in the process).  If you are seeing excessively low body temperatures I would speculate that you are either not eating enough calories, possibly not eating enough fat (I get 30-40% of my calories from fat), or do not have enough adipose (and possibly muscle) tissue to begin with to support thermogenesis (may require higher BMI).


Some studies have noted beneficial effects from as little as 2 hours a day at just 66 degrees F exposure.  The cooling vest I use has a phase change temp of 58 degrees and I think that is just about perfect honestly.


More tips on "how to stay cool when it's hot out"


Now that the temps are rising where I live, I've been experimenting with various ways to stay cooler without blasting air conditioning all the time.  These are also low cost things you can do if you don't own a cooling vest.


  • Take cold showers.  I can't believe it took me so long to discover this, but cold showers are amazing.  A good way to get started is by getting in with lukewarm water, then slowly make it colder taking it as far as you can handle until you can take 100% cold water.  The first couple times I did "full cold" it was a real shock to my system causing involuntary hyperventilation, discomfort, and probably spiking blood pressure, but it only took a few times before I got acclimated to it, now I can step directly into a full cold shower with no warm up and minimal shock factor.  There is nothing quite like the feeling you get after stepping out from a cold shower - I have come to really enjoy this now, the sense of invigoration and positive alertness is a wonderful way to start your day!  If you google: cold shower norepinephrine you will get a taste for the fascinating research that has been done with this.  Note: If for some reason your tap water isn't cold, a good alternative is to fill your bath with water and add ice, no reason to go below about 55 degrees though.  Research has shown that immersion in 57 degree water results in:
    "increased metabolic rate (by 350%), heart rate and systolic and diastolic blood pressure (by 5%, 7%, and 8%, respectively). Plasma noradrenaline and dopamine concentrations were increased by 530% and by 250% respectively, while diuresis increased by 163% (more than at 32 degrees C). Plasma aldosterone concentrations increased by 23%. Plasma renin activity was reduced as during immersion in water at the highest temperature. Cortisol concentrations tended to decrease. Plasma adrenaline concentrations remained unchanged." 


     As a bonus, it is nearly impossible to be or become depressed when you are following a cold shower protocol due to the boost it causes in endorphins, noradrenaline, and dopamine. 

TIP: Let the cold water hit your face alone at first, this activates your dive reflex which in turn prepares your body for full cold water immersion and less shock.


[Amusing anecdote of the day: I was taking my cold shower this morning while listening to the radio, when they decided to play the classic hip hop song Cool Like Dat  (Digable Planets) where the chorus repeats "I'm cool like dat" and later "I'm chill like that", thought that was great... ]



  • Drink ice water with crushed ice.  It is possible to be in a 75 degree room without a cooling vest, and still have goose bumps on your arms, just from drinking crushed ice.  Note: I also tried swallowing bigger ice cubes just to see if it was viable -- I do NOT recommend this, they sometimes get stuck "on the way down" resulting in intense pain, and sometimes brain freeze as you try to line it up just right, definitely not worth it.  One doctor has even been promoting what he calls "The Ice Diet" which is an interesting read.  Eating a liter of ice per day may burn over 100 extra calories although this is disputed.


  • Eat frozen superfoods.  Things like frozen berries not only taste great, but promote great health.  Frozen foods can even pack more nutrients than their fresh counterparts.  When I find the best tasting, in season, fresh produce that freezes well, I stock up the deep freezer.  I was really enjoying some amazing frozen Chilean blueberries yesterday.  I'm going to go get some more right now...
Edited by Gordo
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Aah, yes, lots of good tips on CE practice! For years now - decades - I've drunk my coffee and tea at room temperature; I hate to burn my mouth while drinking hot liquids, and some of my friends take pride in being able to drink piping hot liquids. And that was even before I read how drinking scalding hot tea results in elevated mouth/throat cancer. On the occasions that I go to some place like Starbucks, I always order my coffee with a side cup of ice which I use to rapidly lower the temp of the coffee. I have also been independently interested in cold brewed coffees and teas. And now with view to CE bennies, I wonder whether it would make sense to transition entirely to ice tea and ice coffee. However, that still leaves open the question: consuming cold coffee/tea is one thing - but what about the process of brewing? Is there a difference from the point of view of what you get in polyphenols, various substances from cold brewing tea/coffee/cacao versus hot brewing (and then chilling)?

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I second Tom - thanks for the good tips Gordo! 


Regarding cold brewing (vs. cold drinking) of tea and coffee - I do both, just to cover my bases. I cold brew overnight (on the countertop) and then hot brew the mix in order to maximum extraction. See this post and this post for the best info I've been able to find on cold vs. hot brewing.



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An "Enriched Environment" and Brain-Boosting BDNF Boosts Beige Fat Too!


Finally, here is my long-awaited, long-promised post about rpWAT.
Recall in this post we saw that adult humans have only "beige" fat, rather than true "brown" fat, and in recent posts we saw that chronic cold exposure can turn both white visceral and subcutaneous fat to beige, in both mice and people.
In this post, I focus on this study [1], which helps shed light on the conditions that stimulate the 'browning' of white fat, and its implications for human health and longevity. It's another one of those studies with a lot going on, but which I promise is worth the effort to understand.

Here is a pretty surprising (to me anyway) result. This study [1] divided standard C57Bl/6 mice into three groups, all of which were fed ad lib and housed at standard lab temperature (22 °C - chilly for mice):

  • Control Group - (CTR) standard, small, boring cages with 5 mice per cage.
  • Exercise Group - (EX) standard, small, boring cages with 5 mice per cage, augmented with a running wheel.
  • Enriched Environment Group - (EE) housed in the equivalent of a deluxe mouse resort, including:

[L]arge cages (63 cm x 49 cm x 44 cm, 5 mice per cage) supplemented with running wheels, tunnels, igloos, huts, retreats, wood toys, a maze, and nesting material in addition to standard lab chow and water. 


During 4 weeks of treatment, the EX and EE groups ate a bit more, and weighed a bit less than the controls. The EX and EE groups ate and weighed about the same, but the EE group had a lot less white fat than the EX group, despite running on their wheel an average of only 33% as far as the EX group. But here is where it really gets interesting...


They extracted different types of fat cells from the different groups and measured their oxygen consumption ex vivo. They found classic BAT cells from the EX group had a lot higher thermogenic activity than either the CTR or EE group (top graph), but the "RWAT" of the enriched mice consumed a lot more energy than either the runners or the controls (bottom graph):





So now you should be asking - what the heck is RWAT? RWAT, also known as rpWAT stands for "retroperitoneal white adipose tissue". It is a visceral, abdominal fat next to the kidneys, as illustrated in the mouse in the following graphic we saw in a much earlier posts from last week:



I've labelled the RWAT (= rpWAT) with the green box and arrow. As you can see it is just above and behind the kidney, and is "browner" as a result of cold exposure (right insert) vs. thermoneutral housing (left insert). In fact, while the above fat deposit pictures are from a completely different study [3], the pictures showing rpWAT in the severely cold-exposed vs. thermoneutral mice from [3] are likely very similar to the rpWAT (= RWAT) of the "enriched environment" mice relative to controls in [1]. How do I know? Because the RWAT in the EE mice in [1] was 73% smaller and 62% 'browner' (more thermogenic) than the RWAT of controls, which (eyeballing it) appears to be a pretty good match to the pictures above of the rpWAT difference between 30°C and 4°C.


In short, between [1] and [3], we see the following results in mice:

  • Ad lib food + bone-crushing CE    → skinnier mice with increased BAT activity & 'browner' WAT
  • Ad lib food + mild CE + EX          → skinnier mice with increased BAT activity
  • Ad lib food + mild CE + EX + EE  → skinnier mice with 'browner' WAT (at least rpWAT)

where 'bone crushing' CE = 4°C, 'mild' CE = 22°C, EX = exercise, and EE = enriched environment.


So do humans have this same retroperitoneal fat (i.e. RWAT = rpWAT) that mice have? Yup, it's behind our kidneys, just like in mice. Take a look at this diagram:




As noted in the caption, retroperitoneal fat is considered a "visceral" fat - the type of fat associated with all the major SAD diet-related health problems (high cholesterol, metabolic syndrome, diabetes, CVD etc.). 


So far so good. The enriched environment seems to be helping to turn white fat brown, particularly rpWAT. But how much of the effect is attributable to the enriched environment per se vs. the extra exercise that the mice in the enriched environment (which recall includes a running wheel) engage in?


To find out, the authors tested another group of mice housed in the enriched environment, but with the running wheel removed. Remarkably, it appears that it takes the combination of the enriched environment and the running wheel to get the change in rpWAT gene expression, as illustrated by this graph:




Look at the last set of bars representing UCP1 expression in rpWAT. The "enrich" environment, which included all the toys and the running wheel, had a hugely increased UPC1 expression (red bar) compared to the other conditions, including both a boring cage with a running wheel (green bars), or an enriched cage without the running wheel (blue bars).


They then put the EE and control mice on a high fat diet for four weeks to see if the EE would prevent obesity. It did. Here are the relevant graphics:




As you can see, the EE mice ate more, weighed less, has smaller amounts of various white fats (but no smaller liver), had greater expression of thermogenic genes in their white fat (including UCP1), and had significantly better markers of metabolic health, including lower serum insulin, IGF-1, glucose, and cholesterol.


Notice however the EWAT and RWAT (= rpWAT) is smaller but doesn't look much browner in the EE mice relative to controls. But that was after only four weeks of living in the EE environment. When they extended the EE exposure to three months and fed them a normal chow diet (rather than high fat chow), things got a lot browner. Take a look at these images of the BAT, EWAT and RWAT of EE mice vs. controls:




Pretty dramatic difference huh!?


The difference was evident in the gene expression data as well - UCP1 expression in rpWAT was boosted by 40x and the expression of the Elovl3 gene (responsible for elongating C16 fatty acids to C18 fatty acids in BAT to facilitate thermogenesis [2]) was upregulated in rpWAT by a factor of 118x (see full text for graphs).


Here is how the authors summarize the results up to this point:


EE consists of increased dynamic social interactions, frequent exposure to novel objects and enhanced physical activity. It is unlikely that a single variable accounts for all the effects of EE. Indeed several lines of evidence suggest exercise alone does not account for the EE-induced phenotype: 

  1. EE reduced adiposity more effectively than wheel running (Figure 1A, G).
  2. EE showed less physical activity than wheel running.
  3. EE with no wheel was able to decrease adiposity (Figure 1G).
  4. EE and wheel running mice displayed different behavioral adaption in CLAMS (Figure S1A).
  5. EE showed increased oxygen consumption in RWAT whereas wheel running showed an increase in BAT (Figure 1E).
  6. At the level of transcription, EE induced changes primarily in RWAT while wheel running influenced gene expression mainly in BAT (Figure 2A, B).
  7. EE and wheel running showed two qualitatively distinct gene expression profiles in PVH (Figure 1H) and whole hypothalamus (Figure S1B). However, the removal of running wheels attenuated WAT browning induced by EE suggesting that access to wheels is an important part of the complex environment provided in EE (Figure 2F).

They then did a bunch of genetic knockout experiments and determined that Brain-Derived Neurotrophic Factor (BDNF) was responsible for the EE-induced browning of WAT into beige fat. In support of BDNF's role in the browning of white fat in the enriched environment:

  1.  EE induced BDNF expression in the hypothalamus..
  2. Hypothalamic overexpression of BDNF mimicked EE-induced “browning” of WAT (Figure 5D).
  3.  Inhibition of hypothalamic BDNF function ... led to a complete reversal of the EE-associated molecular features in WAT (Figure 6B, 6D). 
  4. Inhibition of the EE-induced BDNF upregulation in hypothalamus by microRNA blocked the EE-induced brown fat molecular signature (Figure 6E). 
  5.  β-AR blockade attenuated EE- or hypothalamic BDNF overexpression-induced WAT browning (Figure S3C, S4E).

The authors summarize their results as follows:


In summary, our data demonstrate that EE decreases adiposity, increases energy expenditure, causes resistance to obesity, and induces a genetic, morphological and functional transformation from WAT to BAT through a central mechanism with hypothalamic BDNF as the key mediator linking environmental stimuli, sympathetic outflow and the “browning” of white fat and subsequent energy dissipation.


The takeaway for us humans appears to be that the combination of mild cold exposure, moderate sustained physical activity and keeping one's brain active through mental stimulation synergistically combine to turn white fat visceral fat to beige fat, and likely keep one's brain healthy, through increased expression of BDNF.


This is music to the ears of someone who spends a lot of his time in a cold basement pedaling continuously at his bike desk while researching health/longevity topics and reading voraciously. However I must acknowledge I come up a bit short on the "social interaction" that the EE mice enjoyed, unless engaging online discussions with friends count...





[1] Cell Metab. 2011 Sep 7;14(3):324-38. doi: 10.1016/j.cmet.2011.06.020.

White to brown fat phenotypic switch induced by genetic and environmental
activation of a hypothalamic-adipocyte axis.
Cao L(1), Choi EY, Liu X, Martin A, Wang C, Xu X, During MJ.
Comment in
    Cell Metab. 2011 Sep 7;14(3):287-8.
Living in an enriched environment with complex physical and social stimulation
leads to improved cognitive and metabolic health. In white fat, enrichment
induced the upregulation of the brown fat cell fate determining gene Prdm16,
brown fat-specific markers, and genes involved in thermogenesis and β-adrenergic 
signaling. Moreover, pockets of cells with prototypical brown fat morphology and 
high UCP1 levels were observed in the white fat of enriched mice associated with 
resistance to diet-induced obesity. Hypothalamic overexpression of BDNF
reproduced the enrichment-associated activation of the brown fat gene program and
lean phenotype. Inhibition of BDNF signaling by genetic knockout or
dominant-negative trkB reversed this phenotype. Our genetic and pharmacologic
data suggest a mechanism whereby induction of hypothalamic BDNF expression in
response to environmental stimuli leads to selective sympathoneural modulation of
white fat to induce "browning" and increased energy dissipation.
Copyright © 2011 Elsevier Inc. All rights reserved.
PMCID: PMC3172615
PMID: 21907139



[2] Cell Rep. 2015 Dec 15;13(10):2039-47. doi: 10.1016/j.celrep.2015.11.004. Epub

2015 Nov 25.
Brown Adipose Tissue Thermogenic Capacity Is Regulated by Elovl6.
Tan CY(1), Virtue S(2), Bidault G(1), Dale M(1), Hagen R(1), Griffin JL(3),
Vidal-Puig A(4).
Although many transcriptional pathways regulating BAT have been identified, the
role of lipid biosynthetic enzymes in thermogenesis has been less investigated.
Whereas cold exposure causes changes in the fatty acid composition of BAT, the
functional consequences of this remains relatively unexplored. In this study, we 
demonstrate that the enzyme Elongation of Very Long Chain fatty acids 6 (Elovl6) 
is necessary for the thermogenic action of BAT. Elovl6 is responsible for
converting C16 non-essential fatty acids into C18 species. Loss of Elovl6 does
not modulate traditional BAT markers; instead, it causes reduced expression of
mitochondrial electron transport chain components and lower BAT thermogenic
capacity. The reduction in BAT activity appears to be counteracted by increased
beiging of scWAT. When beige fat is disabled by thermoneutrality or aging, Elovl6
KO mice gain weight and have increased scWAT mass and impaired carbohydrate
metabolism. Overall, our study suggests fatty acid chain length is important for 
BAT function.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
PMCID: PMC4688035
PMID: 26628376
[3] Am J Physiol Endocrinol Metab. 2015 Jun 15;308(12):E1085-105. doi:
10.1152/ajpendo.00023.2015. Epub 2015 Apr 21.
A stringent validation of mouse adipose tissue identity markers.
de Jong JM(1), Larsson O(2), Cannon B(1), Nedergaard J(3).
The nature of brown adipose tissue in humans is presently debated: whether it is 
classical brown or of brite/beige nature. The dissimilar developmental origins
and proposed distinct functions of the brown and brite/beige tissues make it
essential to ascertain the identity of human depots with the perspective of
recruiting and activating them for the treatment of obesity and type 2 diabetes. 
For identification of the tissues, a number of marker genes have been proposed,
but the validity of the markers has not been well documented. We used established
brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose
tissues and corresponding primary cell cultures as validators and examined the
informative value of a series of suggested markers earlier used in the discussion
considering the nature of human brown adipose tissue. Most of these markers
unexpectedly turned out to be noninformative concerning tissue classification
(Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1
(brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be
informative in these three tissues. However, the expression of the brite markers 
was not maintained in cell culture. In a more extensive set of adipose depots,
these validated markers provide new information about depot identity. Principal
component analysis supported our single-gene conclusions. Furthermore, Zic1,
Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating
a relationship between anatomic localization and adipose tissue identity (and
possibly function). Together, the observed expression patterns of these validated
marker genes necessitates reconsideration of adipose depot identity in mice and
Copyright © 2015 the American Physiological Society.
PMID: 25898951
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But focusing on their main point about cancer, the difference appears to be similar to what we see with CR and immunity, as we've recently discussed here, here and here. In fact, the CR & immunity story may be almost synonymous with the CE & immunity story, since CR rodent studies are almost invariably "CR + CE" rodent studies...


Both the CR science and our CR Society Poll on immunity suggest that CR increases one's ability to prevent infections and cancer. But once a foreign invader gains a foothold in the body, CR makes it more difficult to mount an effective immune response in order to fight it off. There just aren't enough calories available to "feed a fever". In fact, according to the latest science, the old saying should actually be "feed a cold, feed a fever":


Fever is part of the immune system’s attempt to beat the bugs. It raises body temperature, which increases metabolism and results in more calories burned; for each degree of temperature rise, the energy demand increases further. So taking in calories becomes important.


CR alone, or CR with CE to create a net calorie deficit (as I recommend), results in relatively less energy available to devote to an immune response. This is bad news if you've got an established illness or cancer, either naturally acquired, or in the case of rodents used in cancer research, as a result of being injected with a bolus of cancer cells.


The bottom line seems to be that both CR & CE, and especially the combination, are beneficial for preventing infections and cancer, but are contraindicated when/if you've already got an infection or cancer.



Hello Dean, thanks for all the reported analysis .

I have some doubts on the finals. I remember that Luigi fontana in the lecture i linked some months ago ( link at about 33:40) recalled some studies on the inibitory effects of protein restrictions on prostate cancer models on mice [1] and of protein restrictions and intermittent fasting in breast cancer [2] (open issue: relationship between CR and protein restrictions)


If then we consider the new view on cancer seen like a failure of the body's immune defense system, for convenience I cite the text regarding that from Josh Mitteldorf's blog here :

<< The old view was that there are random mutations in a particular cell line, a series of unfortunate accidents that cause the cells to disregard regulating signals from the body and just continue replicating and growing out of control.  Now we realize that cancer is a failure of the body’s immune defense system.  When we are young, our white blood cells search and destroy incipient cancers, but as we get older the immune early warning system is gradually shut down.>>  

the difference between prevention and inhibition becomes more smooth, could not be so? In other words if CR is effective in preventing infections and cancer and the reason is  the reinforced immunitary system (isn't it so?), then should be effective also if you have got an infection or cancer (with the inhibiting effects reported by Fontana).  What do you think?




[1] Fontana, Oncotarget, 2013 PMID 24353195

[2] Lamming, Oncotarget, 2015  PMI 26378060

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CR and protein restriction like in the two paper you cite downregulates the pro-growth Insulin/IGF-1/AKT/MTOR pathway, and that should be a good thing for preventing cancer and for slowing the growth of slow-growing cancers like prostate cancer in your Fontana (PMID 24353195) reference. I've heard it said the IGF-1 is like rocket fuel for cancer cells - encouraging them to grow and divide. So elevated IGF-1 fans the flames of the cancer flame, and CR & PR avoids this.


But at the same time, it's becoming increasingly evident that immunotherapy, where the body's own immune system is revved up to kill cancer cells, is probably the best way to combat cancer once established - as opposed to poorly-targeted, often toxic chemotherapy and/or radiation. But to mount an effective immune response to cancer requires synthesizing new immune system cells, and that requires energy and the right anabolic hormonal milieu to turn immature progenitor cells into the various types of leukocytes. And this is seems to be dependent on MTOR activation. 


So CR / protein restriction may have good effects and bad effects on cancer proliferation via it's downregulation of IGF-1 & MTOR. 


The other good thing that CR / protein restriction (or cold exposure) seems to do is prevent the immune system from constantly being in a hyperactive state by reducing obesity and systemic inflammation. This had two salutary effects. It requires the immune system to produce fewer leukocytes, and therefore avoids depleting the reserve of stem cells, thereby preserving immunocompetence into old age. And with lower systemic inflammation, the (fewer) immune cells that are produced can focus their energy on hunting down and eliminating the real bad guys (e.g. cancer cells, viruses or bacteria), rather than wasting their time trying to clean up gunk and killing off cells that have been damaged by the toxic environment that has triggered the viscous circle of inflammation - e.g. macrophages mopping up oxidized cholesterol in the bloodstream, turning into harmful foam cells themselves and creating plaques in the arteries.


In short, it seems the interaction between CR, PR and CE on the one hand and the immune system, cancer and infections on the other is a complicated balance. It's not easy to say what their effects will be and it's almost certainly dependent on the type of cancer/infection and its stage. It appears from the evidence that CR, PR and CE are on beneficial on balance for preventing cancer. But once cancer has gotten a foothold, it's gets pretty confusing.


If I got cancer today (heaven forbid), and I wanted some kind of adjunctive therapy on top of whatever standard treatment my oncologist and I agree is best, I'd probably try to adopt a plant-based ketogenic diet (high fat, low protein, low carb) diet that was pretty replete with calories. That way my body would get the calories it needs to mount an effective immune response (and avoid sarcopenia), but at the same time avoid fanning the cancer flame with elevated Insulin, IGF-1 or glucose, the favored energy source for cancer cells. Note - I would not eschew traditional treatments in favor of diet & lifestyle cancer treatments alone, but use diet & lifestyle to boost the effectiveness of standard treatments.


Sorry for the lack of references...



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I like to peruse papers published on Gerotarget: Aging, and coincidentally, I was just reading about dopamine gene expression in mice results in prolonged lifespan in an enriched environment combined with exercise, which is an interesting addition to your EE mice because it found that LE was present in an EE only when combined with exercise (full paper):




DOI: 10.18632/oncotarget.8088



Panayotis K. Thanos1, John Hamilton1, Joseph R. O’Rourke1, Anthony Napoli2, Marcelo Febo3, Nora D. Volkow4, Kenneth Blum3 and Mark Gold3

1 Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA

2 Department of Psychology, Suffolk Community College, Riverhead, NY, USA

3 Department of Psychiatry, University of Florida, Gainesville, FL, USA

4 NIDA, Bethesda, MD, USA

Correspondence to:

Panayotis K. Thanos, email: pthanos@ria.buffalo.edu

Keywords: aging, D2, environmental enrichment, exercise, cognition, Gerotarget

Received: January 08, 2016 Accepted: February 23, 2016 Published: March 15, 2016




Aging produces cellular, molecular, and behavioral changes affecting many areas of the brain. The dopamine (DA) system is known to be vulnerable to the effects of aging, which regulate behavioral functions such as locomotor activity, body weight, and reward and cognition. In particular, age-related DA D2 receptor (D2R) changes have been of particular interest given its relationship with addiction and other rewarding behavioral properties. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.

Edited by TomBAvoider
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Cold Exposure, Calorie Restriction and BDNF


Recall we saw in yesterday's post that the combination of mild cold exposure (CE), exercise (EX) and an enriched environment (EE) resulted in browning of white visceral fat, along with a host of metabolic improvements including reduced diet-induced obesity, and lower glucose, insulin, and cholesterol. We also saw that the release of Brain-Derived Neurotrophic Factor (BDNF) was critical for this process to occur. 


But in the interest of keeping that post relatively brief, I left out a couple important pieces of the story. In particular, there were (at least) three question I didn't address, that I'll follow-up on in this post:

  • Does CE play any role in BDNF-mediated visceral fat browning effect?

We saw that with exercise and enriched environment, one without the other didn't have the same BDNF-browning effect. But mild cold-exposure (i.e. standard lab temperature) was a common feature of all the conditions in the study I analyzed. So what about CE? Is it obligatory? Does it alone increase BDNF?

  • What about the CR & BDNF connection? 

All the experiments I described yesterday were done with ad lib feeding. What if anything does CR have to do with BDNF, and what can we learn from it in this context?

  • What good is BDNF anyway?

 I left out of yesterday's discussion any reason for why we should care about BDNF, apart from its role in the browning of visceral fat and improving metabolic health. 



Does CE play any role in BDNF-mediated visceral fat browning effect? 


Apparently the answer is yes. I didn't mention this much in my discussion yesterday, but the researchers found the hypothalamus to the source of the BDNF that signalled the browning of white visceral fat by the combination of CE, EE & EX. For those who don't remember, the hypothalamus is the body's 'thermostat' (i.e. it is the central controller for thermogenesis), as illustrated in this rather amusing schematic diagram. Follow the yellow pathway from the upper left "Start Here!" at cold exposure through the hypothalamus and sympathetic nervous system to epinephrine release and brown fat activation:



The important role that the hypothalamus plays in thermogenesis via BAT activation is supported by [1], and in particular, [2] found that CE alone (no EE or EX required) triggers BDNF expression in the hypothalamus. So while yesterday's study (PMID: 21907139) didn't explicitly acknowledge the role that CE was likely to be playing (in combination with EX and EE) in the browning of visceral fat via hypothalamic BDNF-signalling, it seems quite likely that CE was playing an important (perhaps obligatory) role in the process.
What about the CR & BDNF connection?
As everyone may already be aware, CR is well known for its BDNF-boosting effects, either alone [3][4][5] or especially in combination with exercise [6][7]. Those studies were in rodents, but CR in humans also appears to increase BDNF, at least peripherally in serum [8].
What good is BDNF anyway?
Finally, I didn't discuss in yesterday's post why we should care about BDNF levels. People probably already know this as well, but BDNF serves lots of important cognition-related functions in the brain, including neurogenesis, synaptogenesis, memory formation, and is thought to play a role in many brain-related diseases & conditions, ranging from schizophrenia to depression to Alzheimer's disease. See the wikipedia page on BDNF for all it's functions, with references. 
Given that we've seen BDNF is responsible at least in part for the browning of visceral fat, it should come as no surprise that BDNF expression is associated with reduced obesity in mice [9] and humans [10].
Finally, relevant to the discussion Mechanism and I just had on immunity and cancer, the same researchers who did the enriched environments study in yesterday's post found that housing mice in an enriched environment (i.e. CE + EE + EX) not only browns visceral fat, but also reduces tumor grown and cancer proliferation [11]:
We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic BDNF was selectively upregulated by EE, its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE.
In summary, it's not just the cocktail of CE + EE + EX that increases BDNF. CR or CE alone, or in combination with exercise can also increase BDNF expression both in the brain and periphery. And increased expression of BDNF keeps you from getting fat, and appears to cure what ails ya', especially when it comes to the brain, and possibly cancer. 
[1] Front Syst Neurosci. 2015 Nov 3;9:150. doi: 10.3389/fnsys.2015.00150. eCollection
Hypothalamic control of brown adipose tissue thermogenesis.
Labbé SM(1), Caron A(1), Lanfray D(1), Monge-Rofarello B(1), Bartness TJ(2),
Richard D(1).
Author information: 
(1)Centre de Recherche de l'Institut Universitaire de Cardiologie et de
Pneumologie de Québec, Department of Medicine, Université Laval Québec, QC,
Canada. (2)Department of Biology, Center for Obesity Reversal (COR), Georgia
State University Atlanta, GA, USA.
It has long been known, in large part from animal studies, that the control of
brown adipose tissue (BAT) thermogenesis is insured by the central nervous system
(CNS), which integrates several stimuli in order to control BAT activation
through the sympathetic nervous system (SNS). SNS-mediated BAT activity is
governed by diverse neurons found in brain structures involved in homeostatic
regulations and whose activity is modulated by various factors including
oscillations of energy fluxes. The characterization of these neurons has always
represented a challenging issue. The available literature suggests that the
neuronal circuits controlling BAT thermogenesis are largely part of an autonomic 
circuitry involving the hypothalamus, brainstem and the SNS efferent neurons. In 
the present review, we recapitulate the latest progresses in regards to the
hypothalamic regulation of BAT metabolism. We briefly addressed the role of the
thermoregulatory pathway and its interactions with the energy balance systems in 
the control of thermogenesis. We also reviewed the involvement of the brain
melanocortin and endocannabinoid systems as well as the emerging role of
steroidogenic factor 1 (SF1) neurons in BAT thermogenesis. Finally, we examined
the link existing between these systems and the homeostatic factors that modulate
their activities.
PMCID: PMC4630288
PMID: 26578907
[2] Cell Metab. 2015 Jul 7;22(1):175-88. doi: 10.1016/j.cmet.2015.05.008. Epub 2015
Jun 11.

Discrete BDNF Neurons in the Paraventricular Hypothalamus Control Feeding and
Energy Expenditure.

An JJ(1), Liao GY(1), Kinney CE(2), Sahibzada N(3), Xu B(4).

Author information:
(1)Department of Neuroscience, The Scripps Research Institute Florida, Jupiter,
FL 33458, USA. (2)Department of Neuroscience, The Scripps Research Institute
Florida, Jupiter, FL 33458, USA; Department of Pharmacology and Physiology,
Georgetown University Medical Center, Washington, DC 20057, USA. (3)Department of
Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC
20057, USA. (4)Department of Neuroscience, The Scripps Research Institute
Florida, Jupiter, FL 33458, USA. Electronic address: bxu@scripps.edu.

Brain-derived neurotrophic factor (BDNF) is a key regulator of energy balance;
however, its underlying mechanism remains unknown. By analyzing BDNF-expressing
neurons in paraventricular hypothalamus (PVH), we have uncovered neural circuits
that control energy balance. The Bdnf gene in the PVH was mostly expressed in
previously undefined neurons, and its deletion caused hyperphagia, reduced
locomotor activity, impaired thermogenesis, and severe obesity. Hyperphagia and
reduced locomotor activity were associated with Bdnf deletion in anterior PVH,
whereas BDNF neurons in medial and posterior PVH drive thermogenesis by
projecting to spinal cord and forming polysynaptic connections to brown adipose
tissues. Furthermore, BDNF expression in the PVH was increased in response to
cold exposure,
and its ablation caused atrophy of sympathetic preganglionic
neurons. Thus, BDNF neurons in anterior PVH control energy intake and locomotor
activity, whereas those in medial and posterior PVH promote thermogenesis by
releasing BDNF into spinal cord to boost sympathetic outflow.

Copyright © 2015 Elsevier Inc. All rights reserved.

PMCID: PMC4497865 [Available on 2016-07-07]
PMID: 26073495
[3] J Neurochem. 2002 Sep;82(6):1367-75.
Evidence that brain-derived neurotrophic factor is required for basal
neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary
restriction in the hippocampus of adult mice.
Lee J(1), Duan W, Mattson MP.
Author information: 
(1)Laboratory of Neurosciences, National Institute on Aging Gerontology Research 
Center, Baltimore, Maryland 21224, USA.
To determine the role of brain-derived neurotrophic factor (BDNF) in the
enhancement of hippocampal neurogenesis resulting from dietary restriction (DR), 
heterozygous BDNF knockout (BDNF +/-) mice and wild-type mice were maintained for
3 months on DR or ad libitum (AL) diets. Mice were then injected with
bromodeoxyuridine (BrdU) and killed either 1 day or 4 weeks later. Levels of BDNF
protein in neurons throughout the hippocampus were decreased in BDNF +/- mice,
but were increased by DR in wild-type mice and to a lesser amount in BDNF +/-
mice. One day after BrdU injection the number of BrdU-labeled cells in the
dentate gyrus of the hippocampus was significantly decreased in BDNF +/- mice
maintained on the AL diet, suggesting that BDNF signaling is important for
proliferation of neural stem cells. DR had no effect on the proliferation of
neural stem cells in wild-type or BDNF +/- mice. Four weeks after BrdU injection,
numbers of surviving labeled cells were decreased in BDNF +/- mice maintained on 
either AL or DR diets. DR significantly improved survival of newly generated
cells in wild-type mice, and also improved their survival in BDNF +/- mice,
albeit to a lesser extent. The majority of BrdU-labeled cells in the dentate
gyrus exhibited a neuronal phenotype at the 4-week time point. The reduced
neurogenesis in BDNF +/- mice was associated with a significant reduction in the 
volume of the dentate gyrus. These findings suggest that BDNF plays an important 
role in the regulation of the basal level of neurogenesis in dentate gyrus of
adult mice, and that by promoting the survival of newly generated neurons BDNF
contributes to the enhancement of neurogenesis induced by DR.
PMID: 12354284
[4] J Mol Neurosci. 2000 Oct;15(2):99-108.
Dietary restriction increases the number of newly generated neural cells, and
induces BDNF expression, in the dentate gyrus of rats.
Lee J(1), Duan W, Long JM, Ingram DK, Mattson MP.
Author information: 
(1)Laboratory of Neurosciences, Gerontology Research Center, National Institute
on Aging, Baltimore, MD 21224, USA.
The adult brain contains neural stem cells that are capable of proliferating,
differentiating into neurons or glia, and then either surviving or dying. This
process of neural-cell production (neurogenesis) in the dentate gyrus of the
hippocampus is responsive to brain injury, and both mental and physical activity.
We now report that neurogenesis in the dentate gyrus can also be modified by
diet. Previous studies have shown that dietary restriction (DR) can suppress
age-related deficits in learning and memory, and can increase resistance of
neurons to degeneration in experimental models of neurodegenerative disorders. We
found that maintenance of adult rats on a DR regimen results in a significant
increase in the numbers of newly produced neural cells in the dentate gyrus of
the hippocampus, as determined by stereologic analysis of cells labeled with the 
DNA precursor analog bromodeoxyuridine. The increase in neurogenesis in rats
maintained on DR appears to result from decreased death of newly produced cells, 
rather than from increased cell proliferation. We further show that the
expression of brain-derived neurotrophic factor, a trophic factor recently
associated with neurogenesis, is increased in hippocampal cells of rats
maintained on DR. Our data are the first evidence that diet can affect the
process of neurogenesis, as well as the first evidence that diet can affect
neurotrophic factor production. These findings provide insight into the
mechanisms whereby diet impacts on brain plasticity, aging and neurodegenerative 
PMID: 11220789
[5] J Mol Neurosci. 2001 Feb;16(1):1-12.
Dietary restriction stimulates BDNF production in the brain and thereby protects 
neurons against excitotoxic injury.
Duan W(1), Lee J, Guo Z, Mattson MP.
Author information: 
(1)Laboratory of Neurosciences, National Institute on Aging Gerontology Research 
Center, Baltimore, MD 21224, USA.
Dietary restriction (DR) increases the lifespan of rodents and increases their
resistance to several different age-related diseases including cancer and
diabetes. Beneficial effects of DR on brain plasticity and neuronal vulnerability
to injury have recently been reported, but the underlying mechanisms are unknown.
We report that levels of brain-derived neurotrophic factor (BDNF) are
significantly increased in the hippocampus, cerebral cortex, and striatum of rats
maintained on a DR regimen compared to animals fed ad libitum (AL).
Seizure-induced damage to hippocampal neurons was significantly reduced in rats
maintained on DR, and this beneficial effect was attenuated by intraventricular
administration of a BDNF-blocking antibody. These findings provide the first
evidence that diet can effect expression of a neurotrophic factor, demonstrate
that BDNF signaling plays a central role in the neuroprotective effect of DR, and
proffer DR as an approach for reducing neuronal damage in neurodegenerative
PMID: 11345515
[6] Conf Proc IEEE Eng Med Biol Soc. 2012;2012:6764-7. doi:
Exercise training plus calorie restriction causes synergistic protection against 
cognitive decline via up-regulation of BDNF in hippocampus of stroke-prone
hypertensive rats.
Kishi T(1), Sunagawa K.
Author information: 
(1)Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu
University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
One of the important organ damage of hypertension is cognitive decline. Cognitive
function is determined by the function of hippocampus, and previous studies have 
suggested that the decrease in brain-derived neurotrophic factor (BDNF) in the
hippocampus causes cognitive decline. Protection against cognitive decline is
reported not only in pharmacological therapy but also in exercise training or
calorie restriction. The aim of the present study was to determine whether
exercise training plus calorie restriction cause synergistic protection against
cognitive decline via BDNF in the hippocampus or not. Exercise training for 28
days improved cognitive decline determined by Morris water maze test via
up-regulation of BDNF in the hippocampus of stroke-prone spontaneously
hypertensive rats, whereas calorie restriction for 28 days did not. However,
exercise training plus calorie restriction causes the protection against
cognitive decline to a greater extent than exercise training alone. In
conclusion, exercise training plus calorie restriction causes synergistic
protection against cognitive decline via up-regulation of BDNF in the hippocampus
of stroke-prone hypertensive rats.
PMID: 23367482
[7] Hippocampus. 2009 Oct;19(10):951-61. doi: 10.1002/hipo.20577.
Voluntary exercise and caloric restriction enhance hippocampal dendritic spine
density and BDNF levels in diabetic mice.
Stranahan AM(1), Lee K, Martin B, Maudsley S, Golden E, Cutler RG, Mattson MP.
Author information: 
(1)Psychology department, Princeton University, Princeton, New Jersey, USA.
Erratum in
    Hippocampus. 2009 Nov;19(11):1151.
Diabetes may adversely affect cognitive function, but the underlying mechanisms
are unknown. To investigate whether manipulations that enhance neurotrophin
levels will also restore neuronal structure and function in diabetes, we examined
the effects of wheel running and dietary energy restriction on hippocampal neuron
morphology and brain-derived neurotrophic factor (BDNF) levels in db/db mice, a
model of insulin resistant diabetes. Running wheel activity, caloric restriction,
or the combination of the two treatments increased levels of BDNF in the
hippocampus of db/db mice. Enhancement of hippocampal BDNF was accompanied by
increases in dendritic spine density on the secondary and tertiary dendrites of
dentate granule neurons. These studies suggest that diabetes exerts detrimental
effects on hippocampal structure, and that this state can be attenuated by
increasing energy expenditure and decreasing energy intake.
Copyright 2008 Wiley-Liss, Inc.
PMCID: PMC2755651
PMID: 19280661
[8] Endocrine. 2008 Jun;33(3):300-4. doi: 10.1007/s12020-008-9090-x.
Evaluation of the effect of caloric restriction on serum BDNF in overweight and
obese subjects: preliminary evidences.
Araya AV(1), Orellana X, Espinoza J.
Author information: 
(1)Endocrinology Section, Department of Internal Medicine, University of Chile
Clinical Hospital, Santos Dumont 999, Independencia, Santiago, Chile.
Brain-derived neurotrophic factor (BDNF) has emerged as a new element related
with insulin resistance and obesity.OBJECTIVE: To evaluate the effect of a
3-month reduced-calorie diet (RCD) on serum BDNF concentrations in overweight and
obese subjects.
SUBJECTS: Seventeen healthy overweight and obese subjects of both sexes (24 - 48 
years, BMI 34.6 +/- 1.1 kg/m2).
METHODS: Anthropometry, oral glucose tolerance test (OGTT), lipid levels, and
serum BDNF were measured at baseline and at the end of the third month.
Reduced-calorie diet was defined as a 25% reduction in energy intake composed of:
55% carbohydrates, 20% proteins, and 25% fat (less than 10% saturated fat and
over 10% nonsaturated fat). Refined sugar was not allowed.
RESULTS: There was a significant decrease in BMI, waist circumference, body fat
percentage, fasting glucose, post-OGTT glucose levels, area under the curve of
glucose, and HOMA2-IR after 3 months of RCD. Serum BDNF showed a significant
increase (3.97 +/- 0.87 to 6.75 +/- 1.62 ng/ml, P = 0.02). Final serum BDNF
correlated negatively with weight (r = -0.51, P = 0.03), and basal post-OGTT
insulin correlated positively with final serum BDNF (r = 0.48, P = 0.04).
CONCLUSIONS: Serum BDNF increases in insulin-resistant overweight and obese
subjects after three months on a RCD. This observation could indicate that BDNF
may be modulated in humans through diet composition.
PMID: 19012000


[9] Nat Neurosci. 2003 Jul;6(7):736-42.

Brain-derived neurotrophic factor regulates energy balance downstream of
melanocortin-4 receptor.
Xu B(1), Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt
Author information: 
(1)Howard Hughes Medical Institute, University of California, San Francisco,
California 94143, USA. bx3@georgetown.edu
Comment in
    Nat Neurosci. 2003 Jul;6(7):655-6.
The melanocortin-4 receptor (MC4R) is critically involved in regulating energy
balance, and obesity has been observed in mice with mutations in the gene for
brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed
at high levels in the ventromedial hypothalamus (VMH) where its expression is
regulated by nutritional state and by MC4R signaling. In addition, similar to
MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of
the normal amount showed hyperphagia and excessive weight gain on higher-fat
diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and
excessive weight gain observed on higher-fat diets in mice with deficient MC4R
signaling. These results show that MC4R signaling controls BDNF expression in the
VMH and support the hypothesis that BDNF is an important effector through which
MC4R signaling controls energy balance.
PMCID: PMC2710100
PMID: 12796784
[10] Front Neurosci. 2013 Mar 21;7:37. doi: 10.3389/fnins.2013.00037. eCollection
Molecular and neural bases underlying roles of BDNF in the control of body
Vanevski F(1), Xu B.
Author information: 
(1)Department of Pharmacology and Physiology, Georgetown University Medical
Center Washington, DC, USA.
Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal
development and synaptic plasticity that is fundamental to neural circuit
formation and cognition. It is also involved in the control of appetite and body 
weight, with mutations in the genes for BDNF and its receptor, TrkB, resulting in
remarkable hyperphagia and severe obesity in humans and mice. Recent studies have
made significant progress in elucidating the source, action sites, and regulatory
pathways of BDNF with regard to its role in the control of energy homeostasis,
and have shed light on the relationships between BDNF and other molecules
involved in the control of body weight. Here we provide a comprehensive review of
evidence from pharmacological, genetic, and mechanistic studies, linking BDNF to 
the control of body weight. This review also aims to organize the main findings
on this subject into a more refined framework and to discuss the future research 
directions necessary to advance the field.
PMCID: PMC3604627
PMID: 23519010
[11] Cell. 2010 Jul 9;142(1):52-64. doi: 10.1016/j.cell.2010.05.029.
Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes
cancer remission and inhibition.
Cao L(1), Liu X, Lin EJ, Wang C, Choi EY, Riban V, Lin B, During MJ.
Cancer is influenced by its microenvironment, yet broader, environmental effects 
also play a role but remain poorly defined. We report here that mice living in an
enriched housing environment show reduced tumor growth and increased remission.
We found this effect in melanoma and colon cancer models, and that it was not
caused by physical activity alone. Serum from animals held in an enriched
environment (EE) inhibited cancer proliferation in vitro and was markedly lower
in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively 
upregulated by EE, and its genetic overexpression reduced tumor burden, whereas
BDNF knockdown blocked the effect of EE. Mechanistically, we show that
hypothalamic BDNF downregulated leptin production in adipocytes via
sympathoneural beta-adrenergic signaling. These results suggest that genetic or
environmental activation of this BDNF/leptin axis may have therapeutic
significance for cancer.
Copyright 2010 Elsevier Inc. All rights reserved.
PMCID: PMC3784009
PMID: 20603014
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BAT May Increase Conversion of Omega-3 ALA to DHA


The long-chain, highly-unsaturated fatty acid DHA, found most abundantly in fatty fish (but also available in vegan supplement form), is pretty controversial around here. Michael thinks it's probably healthy (or at least not harmful) for the general public, but potentially deleterious for CR folks based on his DHA-accelerated Aging Hypothesis (DHA-AAH), which postulates that the many double bonds in DHA results in more peroxidizable (damage-prone) membranes, a claim which several people (including me) have criticized in that thread.


DHA is not without controversy in the mainstream either, where it is frequently claimed that DHA supplements or fatty fish consumption can improve cardiovascular and/or brain health - the evidence for which is pretty equivocal. In fact, just got done bashing on a study that purported to show DHA reverses alleged fructose-induce impairment to metabolic health and gene expression in the brain. Adding to the controversy, DHA is easily oxidized, and so supplements can sometimes become rancid, and DHA in "fresh" form (i.e. as fatty fish) comes packages with nasties like mercury, arsenic, and PCBs as discussed here and elsewhere on these forums. So it's not clear that fish is the best way to go either.


But there are two things about DHA that virtually nobody disputes:

  1. Adequate DHA is important in the brain, where it comprises upwards of 50% of the weight of neuronal membranes [2].
  2. The conversion of shorter-chain Omega-3 fatty acids, like ALA in flaxseeds, walnuts, chia seeds etc is quite limited and inefficient [3]:

 tudies in humans have shown that whereas a certain, though restricted, conversion of high doses of ALA to EPA occurs, conversion to DHA is severely restricted. The use of ALA labelled with radioisotopes suggested that with a background diet high in saturated fat conversion to long-chain metabolites is approximately 6% for EPA and 3.8% for DHA. With a diet rich in n-6 PUFA, conversion is reduced by 40 to 50%.


This results in some degree of consternation for non-fish eaters who want to maintain brain health, but would prefer not to take supplements, or for any CR folks who buy Michael's DHA-AAH.


Fortunately, it appears that once again brown adipose tissue (and hence cold exposure) may come to the rescue. Is there anything CE can't do?!


In this recent study [1], researcher incubated isolated mouse white (WAT) and brown (BAT) adipose cells in a standard medium supplemented with short-chain omega-3 ALA at the standard cell culturing temperature. They measured the amount of various fatty acids the cells synthesized on day 0 (before they fully differentiated into WAT or BAT cells) and after 8 days, when the cells had completed differentiation. What they found was:


[O]ur results show that both WAT and BAT synthesize omega-3 LCPUFA. Differentiated BAT synthesizes more
DHA than WAT, supporting the hypothesis that it may serve as a source of DHA for the developing brain.
BAT is most abundance during the intense period of the human brain growth spurt, suggesting BAT may be
a net producer of DHA during the period of most intense DHA requirements.



That last part about "human brain growth spurt" is in reference to the fact that native BAT cells like they tested in this study (as opposed to beige fat cells) are abundant in human infants, when the brain is rapidly developing, and when non-shivering thermogenesis is important for infant survival.


So before we get too excited about these results, we should recognize several caveats. As alluded to in the previous paragraph, this was a result in true BAT cells, from mice cultured in vitro. This is quite a ways from showing the beige fat most abundant in adult humans synthesizes significant amounts of DHA in vivo.


So despite eating a "stupid high"amount of PUFA and short-chain Omega-3 ALA, I'm not counting on it to get converted into all the DHA my body and especially my brain requires, despite the results of this study which suggest I may potentially benefit from increased ALA→DHA conversion as a result of cold exposure and increased expression of beige/brown fat. Instead, at least for now I'm continuing with my two capsules weekly of Ovega-3 vegan DHA/EPA, which contain a total of ~600mg of pre-formed DHA, equivalent to about one fatty fish meal per week. 





[1] Prostaglandins Leukot Essent Fatty Acids. 2016 Jan;104:19-24. doi:
10.1016/j.plefa.2015.11.001. Epub 2015 Nov 28.
Brown but not white adipose cells synthesize omega-3 docosahexaenoic acid in
Qin X(1), Park HG(2), Zhang JY(2), Lawrence P(2), Liu G(1), Subramanian N(2),
Kothapalli KS(2), Brenna JT(2).
Adipose tissue is a complex endocrine organ which coordinates several crucial
biological functions including fatty acid metabolism, glucose metabolism, energy 
homeostasis, and immune function. Brown adipose tissue (BAT) is most abundant in 
young infants during the brain growth spurt when demands for omega-3
docosahexaenoic acid (DHA, 22:6n-3) is greatest for brain structure. Our aim was 
to characterize relative biosynthesis of omega-3 long chain polyunsaturated fatty
acids (LCPUFA) from precursors in cultured white (WAT) and brown (BAT) cells and 
study relevant gene expression. Mouse WAT and BAT cells were grown in regular
DMEM media to confluence, and differentiation was induced. At days 0 and 8 cells 
were treated with albumin bound d5-18:3n-3 (d5-ALA) and analyzed 24h later.
d5-ALA increased cellular eicosapentaenoic acid (EPA, 20:5n-3) and
docosapentaenoic acid (DPA, 22:5n-3) in undifferentiated BAT cells, whereas
differentiated BAT cells accumulated 20:4n-3, EPA and DPA. DHA as a fraction of
total omega-3 LCPUFA was greatest in differentiated BAT cells compared to
undifferentiated cells. Undifferentiated WAT cells accumulated EPA, whereas
differentiated cells accumulated DPA. WAT accumulated trace newly synthesized
DHA. Zic1 a classical brown marker and Prdm16 a key driver of brown fat cell fate
are expressed only in BAT cells. Ppargc1a is 15 fold higher in differentiated BAT
cells. We conclude that in differentiated adipose cells accumulating fat, BAT
cells but not WAT cells synthesize DHA, supporting the hypothesis that 
BAT is a net producer of DHA.
Copyright © 2015 Elsevier Ltd. All rights reserved.
PMCID: PMC4724391 [Available on 2017-01-01]
PMID: 26802938
[2] Meharban Singh (March 2005). "Essential Fatty Acids, DHA and the Human Brain from the Indian Journal of Pediatrics, Volume 72" (PDF). Retrieved October 8, 2007.
[3] Int J Vitam Nutr Res. 1998;68(3):159-73.

Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic
acid (20:5n-3) and docosahexaenoic acid (22:6n-3)?

Gerster H(1).

Author information:
(1)Vitamin Research Department, F. Hoffman-Roche Ltd, Basel, Switzerland.

A diet including 2-3 portions of fatty fish per week, which corresponds to the
intake of 1.25 g EPA (20:5n-3) + DHA (22:6n-3) per day, has been officially
recommended on the basis of epidemiological findings showing a beneficial role of
these n-3 long-chain PUFA in the prevention of cardiovascular and inflammatory
diseases. The parent fatty acid ALA (18:3n-3), found in vegetable oils such as
flaxseed or rapeseed oil, is used by the human organism partly as a source of
energy, partly as a precursor of the metabolites, but the degree of conversion
appears to be unreliable and restricted. More specifically, most studies in
humans have shown that whereas a certain, though restricted, conversion of high
doses of ALA to EPA occurs, conversion to DHA is severely restricted. The use of
ALA labelled with radioisotopes suggested that with a background diet high in
saturated fat conversion to long-chain metabolites is approximately 6% for EPA
and 3.8% for DHA. With a diet rich in n-6 PUFA, conversion is reduced by 40 to
It is thus reasonable to observe an n-6/n-3 PUFA ratio not exceeding 4-6.
Restricted conversion to DHA may be critical since evidence has been increasing
that this long-chain metabolite has an autonomous function, e.g. in the brain,
retina and spermatozoa where it is the most prominent fatty acid. In neonates
deficiency is associated with visual impairment, abnormalities in the
electroretinogram and delayed cognitive development. In adults the potential role
of DHA in neurological function still needs to be investigated in depth.
Regarding cardiovascular risk factors DHA has been shown to reduce triglyceride
concentrations. These findings indicate that future attention will have to focus
on the adequate provision of DHA which can reliably be achieved only with the
supply of the preformed long-chain metabolite.

PMID: 9637947

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Turning Things Around - DHA Increases BAT Too!


In my last post, I reviewed a study which suggested BAT → ↑ DHA. It appears there is even more evidence that the inverse is the case too, namely that ↑ DHA → ↑ BAT. In fact, it's better than that. This new1 study [1] found that dietary DHA results in the browning of inguinal (subcutaneous) white fat, so it's likely to be relevant for human adults who as we saw recently in this post, have beige subcutaneous fat but little if an true BAT.


I'm happy to say the experimental design of [1] was much less insane in terms of the amount of fish-oil/DHA fed to mice than the study Michael used to claim has DHA-accelerated Aging Hypothesis had been "validated" (PMID 25313149) and the recent study of fructose & DHA (ref) which I bashed on hereIn Michael's study and the fructose/DHA study the rodents were fed the human equivalent of 10 and 20 fatty fish meals per day, respectively.


In contrast, researchers in [1], fed standard C57BL/6 male mice a diet high in fat (45% of calories) mostly from Lard (20.9% of food weight) and corn oil (2.9%). That's all the control group got, while the fish oil group ate the same thing, except a relatively small amount of the lard was replaced by fish oil at two different dosage levels, 1.2% or 2.4% of food weight, equivalent to approximately 2.5 or 5 fatty fish meals per day for six weeks. That is still a lot of fish oil, but not nearly as unrealistic as those other two studies. In addition, unlike the fructose/DHA study, "the energy intake of all the mice was equalized by pair feeding", so we don't have to worry about differences in calorie intake, which was one of the Achilles heel of the fructose/DHA study.  The mice were housed singly at standard (cold for mice) lab temperature (23°F). 


So what did they find? There are a lot of details and graphs in the full text of the paper, involving wild-type and genetic mutant mice. To summarize, the authors found that DHA and EPA increased BAT expression and WAT browning through what is by now a familiar pathway, that the authors were kind enough to show in graphical form:




Not only did the fish oil group gain less weight while eating the same number of calories, and same percent total fat as the controls, they also had lower serum triglycerides, glucose, insulin and higher adiponectin. In short, substituting fish oil in place of some dietary lard resulted in a reversal of all the obesity-related metabolic derangements induced by an ad lib, high (saturated) fat diet. Note this is exactly the same metabolic pattern observed in the fructose/DHA study, which attempted to vilify fructose but which didn't even control for (or even reporting) body weight or food intake.


This study isn't the only one to find the combination of DHA & EPA to reduce obesity & fat mass via increase BAT thermogenesis. Study [2] found:


[DHA & EPA] induce a marked stimulation of BAT thermogenic activity without changes in the UCP content compared to a high-fat diet without n-3 PUFA. The mixture of EPA and DHA has the more pronounced effect while EPA and DHA seem to act in synergy on BAT thermogenesis via different mechanisms.


Update 5/13/2016: Note that [1] was in mice and [2] was in rats. What about people? Study [3] helps fill in that gap, at least in vitro. It found that human white adipose cells treated for 12 days with omega-3 EPA (but not with omega-6 arachidonic acid AA), "increased expression of the brown adipocyte-related genes UCP1 and CPT1B, and improved mitochondrial function of adipocytes."


These results are interesting for several reasons. First, they add yet another non-CE approach for boosting BAT and for browning of WAT - I've added DHA / EPA / Fish oil to the 'master list' at the bottom. Interestingly, we see that once again the pattern holds, namely that treatments which increase BAT level are also consistently among the category of treatments that have long been thought to be "good for you", independent of the realization that they increase BAT. It may be a coincidence, but this is seeming more and more unlikely as the healthy, BAT-inducing treatments continue to be discovered / uncovered.


But note, the mice in this study were housed at normal lab temperatures, and hence were cold-exposed. It's not clear that a diet supplemented with fish oil will induce BAT, brown WAT, or improve metabolic health in the absence of cold exposure. And as we say yesterday, CE on it's own appears to increase conversion of ALA to DHA. So there appears to be a virtuous circle illustrated thusly:


↑ BAT   ⇄  ↑ DHA


Here is the latest full list of modifiable and [non-modifiable] factors associated with increased BAT quantity and/or activity:
  • 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
  • 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)
  • Other foods - green tea, roasted coffee, cacao beans / chocolate
  • Drugs - metformin, caffeine
  • Avoiding gluten
  • Olive Oil / MUFA-rich diet
  • DHA / EPA / fish-oil
  • Methionine restriction - Reduce animal protein. Soy is low in methionine and high in arginine (see below).
  • Low protein diet
  • Fasting
  • Exercise
  • Avoid obesity/overweight
  • [being naturally thin - high metabolic rate]
  • [being younger]
  • [being female]
  • [Ethnicity - having cold-climate ancestors]



1Has anyone else been struck by how recent all the research on cold exposure and BAT is? Virtually every paper of significance seems to be from 2013 - present. It's an exciting time with lots of CE research going on. This seems quite unlike CR research, which at least subjectively seems to have died down somewhat in recent years. Perhaps it reflects the fact that CE mimetics seem much more feasible and potentially beneficial for weight loss (given the obesity epidemic) than do CR mimetics for human life extension.



[1] Sci Rep. 2015 Dec 17;5:18013. doi: 10.1038/srep18013.

Fish oil intake induces UCP1 upregulation in brown and white adipose tissue via
the sympathetic nervous system.
Kim M(1), Goto T(1,)(2), Yu R(3), Uchida K(4,)(5), Tominaga M(4,)(5), Kano Y(6), 
Takahashi N(1,)(2), Kawada T(1,)(2).
Brown adipose tissue (BAT) plays a central role in regulating energy homeostasis,
and may provide novel strategies for the treatment of human obesity. BAT-mediated
thermogenesis is regulated by mitochondrial uncoupling protein 1 (UCP1) in
classical brown and ectopic beige adipocytes, and is controlled by sympathetic
nervous system (SNS). Previous work indicated that fish oil intake reduces fat
accumulation and induces UCP1 expression in BAT; however, the detailed mechanism 
of this effect remains unclear. In this study, we investigated the effect of fish
oil on energy expenditure and the SNS. Fish oil intake increased oxygen
consumption and rectal temperature, with concomitant upregulation of UCP1 and the
β3 adrenergic receptor (β3AR), two markers of beige adipocytes, in the
interscapular BAT and inguinal white adipose tissue (WAT). Additionally, fish oil
intake increased the elimination of urinary catecholamines and the noradrenaline 
(NA) turnover rate in interscapular BAT and inguinal WAT. Furthermore, the
effects of fish oil on SNS-mediated energy expenditure were abolished in
transient receptor potential vanilloid 1 (TRPV1) knockout mice. In conclusion,
fish oil intake can induce UCP1 expression in classical brown and beige
adipocytes via the SNS, thereby attenuating fat accumulation and ameliorating
lipid metabolism.
PMCID: PMC4682086
PMID: 26673120
[2] Int J Obes Relat Metab Disord. 1997 Nov;21(11):955-62.
Brown fat thermogenesis in rats fed high-fat diets enriched with n-3
polyunsaturated fatty acids.
Oudart H(1), Groscolas R, Calgari C, Nibbelink M, Leray C, Le Maho Y, Malan A.
Author information: 
(1)Centre d'Ecologie et Physiologie Energétiques, associé à l'Université Louis
Pasteur, CNRS UPR 9010, Strasbourg, France.
OBJECTIVE: To examine the possible involvement of an increase in diet-induced
thermogenesis from brown adipose tissue (BAT) in the n-3 polyunsaturated fatty
acids (n-3 PUFA) induced limitation of the development of white fat pads during
high-fat feeding.
DESIGN: Rats fed for four weeks on a low-fat/high-carbohydrate diet (C group) or 
high-fat diet without n-3 PUFA (REF group), with eicosapentaenoic acid (EPA
group), with docosahexaenoic acid (DHA group) or with a mixture of these two
fatty acids (MIX group).
MEASUREMENTS: Epididymal and retroperitoneal fat pad mass, BAT composition,
Guanosine 5'-diphosphate (GDP) binding and uncoupling protein (UCP) content were 
measured in the five groups of rats.
RESULTS: The masses of retroperitoneal and epididymal white fat pads were lower
in the groups fed n-3 PUFA than in the C and REF groups. The total BAT GDP
binding was 1.6 times higher in the MIX and EPA groups than in the REF group. The
BAT from the EPA group presented an enrichment in mitochondria compared to the C 
and REF groups whereas the BAT from the DHA and REF groups presented a
hyperplasia and an increase in thermogenic activity of the mitochondria compared 
to the C group. The higher thermogenic activity of BAT was observed in the MIX
group and is due to hyperplasia and to an increase in thermogenic activity of
CONCLUSIONS: n-3 PUFA induce a marked stimulation of BAT thermogenic activity
without changes in the UCP content compared to a high-fat diet without n-3 PUFA. 
The mixture of EPA and DHA has the more pronounced effect while EPA and DHA seem 
to act in synergy on BAT thermogenesis via different mechanisms.
PMID: 9368817
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Cold Exposure WON'T Rot Your Membranes via DHA Enrichment


After all this talk the last couple days about DHA, I bet I know what you're thinking, especially if you are Michael. I'll channel him since it seems unlikely he'll respond ☹:


Sure, dietary DHA might boost BA Synthesis and I might even buy the idea that BAT could increase conversion of ALA to DHA, but per my DHA-accelerated Aging Hypothesis (DHA-AAH), increasing DHA is likely to be bad at least for CR folks, since DHA gets incorporated into membranes (incl. & esp. mitochondrial membranes). With all those double bounds, DHA makes membrane more peroxidizable (i.e. prone to damage), and therefore more likely to undermine rather than improve health & longevity.


Good point (virtual) Michael. Thanks for raising it.


Despite my skepticism about Michael's DHA-AAH, as expressed in my analysis of the study that Michael says "validates" his theory, in this and the subsequent four posts in that thread, I too have thought about this issue of DHA-induced increased peroxidizability as a result of cold-induced membrane enrichment with DHA.


It's natural to expect cold exposure to cause an increase in the unsaturation of cellular (and mitochondrial) membranes by incorporating more double-bond-rich fatty acids (FAs) like DHA. Why? In order to keep membranes more fluid. Why?  In order to facilitate continued metabolic activity in membrane-embedded receptors, pumps etc despite things naturally slowing down due to cold, and to allow more protons to (passively) leak through mitochondrial membrane to increase thermogenesis.


It's like in your car - you use oil that is less viscous (more fluid) the winter to prevent it from "gumming up" your engine when the oil gets thicker due to cold. By the way, here is a good graphical representation of what a more unsaturated, and therefore more fluid and leakier, membrane looks like (left) relative to a more saturated membrane (right):




BTW - the tighter packing of the straighter carbon chains of saturated fatty acids is why oils with lots of saturated fat (like coconut oil) are solid at room temperature, while more highly unsaturated fats (like olive oil) are liquid at room temperature. Other vegetable oils (like flax oil) with even more double bounds remain liquid in the fridge, while mostly-MUFA extra virgin olive oil becomes solid when refrigerated. In short, fatty acids are more fluid at a given temperature if they have more double bonds.


That sort of adaptation is likely to be a good thing - you'd hate for your metabolism to freeze up when you go out in the cold. But all those extra double bond in more unsaturated membranes has the potential to make them more vulnerable to peroxidation damage as mentioned above, which is not so good.


So is this something people practicing cold exposure should be concerned about? In other words, will elevated levels of DHA in BAT membranes turn BAT cells into miniature free-radical factories, undermining health and longevity?


To find out, the researchers in [1] tested the fatty acid content and unsaturation index of BAT and plasma phospholipids (membranes) of rats subjected to serious cold exposure (four weeks and 5 °C), and fed an ad lib diet with a normal (i.e. tiny) amount of DHA, ~0.15% of calories. They also tested the effects of intermittent immobilization on rat BAT and plasma membranes, but I'll ignore that part of the study.


What they found wrt CE was fascinating and unexpected. Compared with controls housed at a relatively balmy 25°C, the cold-adapted rats had less DHA in both their BAT and plasma membranes, not more! And the effect was quite large and highly significant. The DHA content of cold-acclimated rats was 46% lower in BAT membranes and 30% lower in plasma membranes than controls.


Further, the degree of unsaturation of the BAT and plasma membranes in the cold-acclimated rats did not change relative to rats housed at the warmer temperature. What happened was that the cold-acclimated rats decreased the DHA content of their membranes, and increased the membrane levels of other, less unsaturated omega-6 fatty acids - specifically linoleic acid (18:2) and arachidonic acid (20:4), so the net effect was a wash in terms of the total number of double bonds (i.e. the unsaturation index).


While this shift from a membrane enrichment in DHA to a membrane enrichment in LA and AA left the overall unsaturation index (# of double bonds) unchanged, as Michael points out in this post, degree of unsaturation and peroxidizability are two different animals. In particular, a membrane enriched with DHA will be much more peroxidizable that an equivalently unsaturated membrane with less DHA but more LA and AA, because the peroxidizability of a fatty acid (roughly) doubles with each additional double bond. Since DHA has six double bonds, while LA and AA have only 2 and 4 double bonds respectively, a membrane with less DHA and more LA & AA will be less peroxidizable, even if the total number of double bonds (hence the unsaturation index) remains constant. In fact, this is the whole reason Michael postulates that DHA is so toxic - because it is so much more peroxidizable than other fatty acids when incorporated into membranes - especially mitochondrial membranes.


Teleologically, this shift to less peroxidizable membranes as a result of cold exposure makes sense, particularly in BAT. Why? Because in order to generate enough heat to keep warm at 5°C, metabolic activity in BAT has to be cranked up to 11 (hat tip to Spinal Tap). Increased metabolic activity means greater potential for free radical generation. So reducing membrane DHA content (and hence lower peroxidizability) will counteract this effect - basically making BAT more "bulletproof" to damage. The authors of [1] put it this way:


It is inferred that BAT from cold-acclimated animals is endowed with some mechanism(s) as an adaptive strategy to protect tissue with high thermogenic capacity against excessive heat production in cold and consequent cell destruction.


In other words, since BAT is such an energy furnace during cold exposure (via active proton transport across the mitochondrial membrane through UCP1), the body has to take pains to prevent it from self-immolating & self-destructing. One of these mechanisms appears to be reducing the DHA content of its membranes to make them less peroxidizable. It never ceases to amaze me just how incredibly tuned the body is - yes we eventually fall to pieces, but in the meantime we're an incredible machine.


Here is another interesting quote from [1]:


The present study confirmed the previous study that cold acclimation decreases the plasma triglyceride level, but did not change the phospholipid level (ref), possibly due to an accelerated utilization of triglycerides as an energy substrate for nonshivering thermogenesis in cold.


In other words, even if you're eating PUFA-rich fat during cold exposure, the body doesn't shove the PUFA into membranes thereby making them more peroxidizable, but instead burns the PUFA as fuel to support thermogenesis.


So on the one hand, as we saw yesterday, large amounts of dietary DHA boosts thermogenesis by upregulating UCP1 in BAT tissue. And eating truly excessive amounts of DHA (equivalent of 10 fatty fish meals a day) does result in DHA getting incorporated into membranes, thereby increasing peroxidizability of mitochondrial membranes in liver and skeletal muscles as I point out here - although with only very modest shortening of lifespan in CR mice, and no lifespan shortening in AL mice, I might add.


In contrast to these effect of large and excessive amounts of dietary DHA, we see in [1] that CE coupled with a diet containing only modest amounts of DHA increases UCP1-mediated BAT thermogenesis, but actually decreases DHA content (and hence peroxidizability) in BAT and plasma membranes.


Of course it should be noted that this study didn't look specifically at mitochondrial membranes nor at other cell types besides BAT and plasma. Nevertheless it is encouraging to see that in response to cold, the body appears smart enough not to simply increase thermogenesis the "easy way", by increasing the DHA content of membranes and thereby making them produce more heat via passive proton leakage, but which would also make them more prone to damage.


In summary, it appears we don't have to worry that cold exposure will cause our membranes to become peroxidation-prone via incorporation of extra DHA. In fact, at least in BAT and plasma, quite the opposite appears to be the case - cold exposure results in membranes that are less packed with DHA and hence less peroxidation-prone, not more. So we got that goin' for us, which is nice.




[1]  Jpn J Physiol. 1996 Jun;46(3):265-70.
Fatty acid profiles of phospholipids in brown adipose tissue from rats during
cold acclimation and repetitive intermittent immobilization: with special
reference to docosahexaenoic acid.
Ohno T(1), Ohinata H, Ogawa K, Kuroshima A.
Author information: 
(1)Medical Sciences Laboratory, Hokkaido University of Education, Asahikawa,
The effects of cold acclimation and repetitive intermittent immobilization were
examined on fatty acid (FA) compositions in phospholipids of rat interscapular
brown adipose tissue (BAT) and plasma. As previously reported, cold acclimation
and intermittent immobilization increased the degree of unsaturation as a whole
in FAs of BAT but not in plasma. N-3 polyunsaturated docosahexaenoic acid (22-6; 
DHA) decreased in cold acclimation but increased in intermittent immobilization
in phospholipids of BAT. DHA was decreased in phospholipids of plasma in both
groups. Considering our previous findings that the in vitro thermogenic response 
of BAT was suppressed in cold acclimation and enhanced in intermittent
immobilization, it was inferred that DHA in BAT is involved in the regulation of 
thermogenic function of this tissue.
PMID: 8899494
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I wonder how closely medical science has studied populations from arctic regions - First Peoples, Inuits, Eskimos etc.; here we have populations that consume highly lopsided macronutrients (in favor of protein and fats), where the consumption of meat is high while vegetables/fruit is low to none, where the DHA & EPA intake is high and vegetable oils is low to none, where exertion levels (exercise) is high, where cold exposure is year round. Now, of course, I mean in more original state, before the comforts/distortions of civilization completely upended traditional lifestyles/diets. 


Here it seems the effects of "high DHA diet + CE + Exercise" could be seen in actual humans rather than rodents, because while I appreciate all the science, I always get depressed when I see "in rodents" in the title of any study. As they say every time we find a great treatment for cancer in mice "well, great for the mice!". 

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I wonder how closely medical science has studied populations from arctic regions - First Peoples, Inuits, Eskimos etc


My answer hasn't really changed since the last time you posed a similar question about the evidence for cold exposure in different human populations, including people of the north. 


Regarding the Inuits and Greenland natives, they do have increased thermogenesis relative to people of African descent, as discussed here. And as we've seen here, folks from southeast Asia have less BAT that folks of caucasian descent. So there is some variation in BAT between populations, probably as a result of genetics, at least in part.


But as for longevity, as I pointed out when I last answered your question:


Epidemiological studies in humans based on geography are notoriously difficult, given all the other aspects of diet & lifestyle, not to mention genetics, that vary dramatically among people from one region of the globe to another.
Much better evidence comes from studies of a wide variety of species with a wide latitudinal range of habitats, which clearly show that within a species, individuals living in colder latitudes live longer, as discussed here
As for the Inuits/Greenlanders specifically, they are a sad and controversial case. There has long been thought to be an "Inuit Paradox", in which the Inuit were thought to be relatively free from heart disease despite a very heavily meat-based diet with little plant foods. Researchers attributed it to the richness of the Inuit diet in long-chain omega-3 fatty acids [1]. In fact, this apparent paradox was part of what kicked off the whole "fish oil for heart disease" excitement.
But since then, the very existence of Inuit paradox has been called into question, as has been well documented by one of my favorite plant-based diet proponents, Plant Positive, in this blog post and accompanying video. And we all should know by now that fish and fish oil consumption have been a big disappointment when it comes to primary prevention of cardiovascular disease in most controlled intervention trials [4], as discussed here, and evidence from prospective cohort studies have been mixed at best, potentially because of the contamination of fatty fish and fish oil with heavy metals and pesticides [2].
That issue of contamination is one reason it is though that the Inuit and Greenlanders may not do as well as they otherwise might [3]:
The level of methyl mercury in organs [of Inuits - DP] is generally high. PCB concentrations found in organs of Greenlanders are higher than among other populations. 
Plus, the Inuit pick up a lot of parasites from eating raw fish and marine mammals, which may explain both their low cholesterol and their less-than-stellar longevity - a topic that Plant Positive covers in the link above. Other confounders are the fact that Inuits eating their traditional diet eat very few plants, and hence miss out on many of the healthy phytochemicals in a plant-rich diet. Not to mention the fact that the traditional Inuit live in a very harsh and dangerous environment, far from state-of-the-art medical care. 
In short, the Inuit are not a very good model of anything except the incredible tenacity of human beings, and our ability to live in the most extreme of environments. They also illustrate my point about how hard it is to tease apart the effects of one particularly nutrient (in this case, long-chain omega-3s) from the plethora of other effects of diet and lifestyle on health and longevity that vary from one culture to another. Humans are just too damn heterogeneous in diet, lifestyle and genetics to learn much from epidemiological studies.
Finally, you say:

Here [in the Inuit - DP] it seems the effects of "high DHA diet + CE + Exercise" could be seen in actual humans rather than rodents,


You may not be under this impression - but to be clear I'm not advocating a diet high in DHA, fish oil, or whole fish like the Inuit. There is evidence that a diet very high in DHA will boost metabolism in part but upregulating BAT and BAT activity, at least in rodents as discussed here. But a diet like that (i.e. with the DHA-equivalent of many servings of fatty fish per day) also results in a lot of highly peroxidizable-DHA getting stuffed into your cellular and mitochondrial membranes, which may have deleterious effects on health and longevity, especially if you put stock in Michael's DHA-AAH. Plus all the risk of heavy metal & pesticides unless your source of DHA is very pure.
As we've seen, there are many ways to boost BAT and thermogenesis. I don't consider DHA to be one of the better ones, both due to it's lack of proven effectiveness in humans, and it's potential negative side effects.
[1] Am J Clin Nutr. 2001 Oct;74(4):464-73.
n-3 Fatty acids and cardiovascular disease risk factors among the Inuit of
Dewailly E(1), Blanchet C, Lemieux S, Sauvé L, Gingras S, Ayotte P, Holub BJ.
Author information: 
(1)Public Health Research Unit, CHUL Research Center, Centre Hospitalier
Universitaire de Quebec, Ste-Foy, Canada. eric.dewailly@crchul.ulaval.ca
Comment in
    Am J Clin Nutr. 2002 May;75(5):951-3; author reply 953-4.
    Am J Clin Nutr. 2001 Oct;74(4):415-6.
BACKGROUND: Inuit traditionally consume large amounts of marine foods rich in n-3
fatty acids. Evidence exists that n-3 fatty acids have beneficial effects on key 
risk factors for cardiovascular disease.
OBJECTIVE: Our goal was to verify the relation between plasma phospholipid
concentrations of the n-3 fatty acids eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) and various cardiovascular disease risk factors among 
the Inuit of Nunavik, Canada.
DESIGN: The study population consisted of 426 Inuit aged 18-74 y who participated
in a 1992 health survey. Data were obtained through home interviews and clinical 
visits. Plasma samples were analyzed for phospholipid fatty acid composition.
RESULTS: Expressed as the percentage of total fatty acids, geometric mean
concentrations of EPA, DHA, and their combination in plasma phospholipids were
1.99%, 4.52%, and 6.83%, respectively. n-3 Fatty acids were positively associated
with HDL-cholesterol concentrations and inversely associated with triacylglycerol
concentrations and the ratio of total to HDL cholesterol. In contrast,
concentrations of total cholesterol, LDL cholesterol, and plasma glucose
increased as n-3 fatty acid concentrations increased. There were no significant
associations between n-3 fatty acids and diastolic and systolic blood pressure
and plasma insulin.
CONCLUSIONS: Consumption of marine products, the main source of EPA and DHA,
appears to beneficially affect some cardiovascular disease risk factors. The
traditional Inuit diet, which is rich in n-3 fatty acids, is probably responsible
for the low mortality rate from ischemic heart disease in this population.
PMID: 11566644 
[2] BMJ. 2012 Oct 30;345:e6698. doi: 10.1136/bmj.e6698.
Association between fish consumption, long chain omega 3 fatty acids, and risk of
cerebrovascular disease: systematic review and meta-analysis.
Chowdhury R(1), Stevens S, Gorman D, Pan A, Warnakula S, Chowdhury S, Ward H,
Johnson L, Crowe F, Hu FB, Franco OH.
Author information: 
(1)Department of Public Health and Primary Care, University of Cambridge, UK.
Comment in
    Dtsch Med Wochenschr. 2013 Feb;138(6):250.
    BMJ. 2012;345:e7219.
OBJECTIVE: To clarify associations of fish consumption and long chain omega 3
fatty acids with risk of cerebrovascular disease for primary and secondary
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Studies published before September 2012 identified through
electronic searches using Medline, Embase, BIOSIS, and Science Citation Index
ELIGIBILITY CRITERIA: Prospective cohort studies and randomised controlled trials
reporting on associations of fish consumption and long chain omega 3 fatty acids 
(based on dietary self report), omega 3 fatty acids biomarkers, or
supplementations with cerebrovascular disease (defined as any fatal or non-fatal 
ischaemic stroke, haemorrhagic stroke, cerebrovascular accident, or transient
ischaemic attack). Both primary and secondary prevention studies (comprising
participants with or without cardiovascular disease at baseline) were eligible.
RESULTS: 26 prospective cohort studies and 12 randomised controlled trials with
aggregate data on 794,000 non-overlapping people and 34,817 cerebrovascular
outcomes were included. In cohort studies comparing categories of fish intake the
pooled relative risk for cerebrovascular disease for 2-4 servings a week versus ≤
1 servings a week was 0.94 (95% confidence intervals 0.90 to 0.98) and for ≥ 5
servings a week versus 1 serving a week was 0.88 (0.81 to 0.96). The relative
risk for cerebrovascular disease comparing the top thirds of baseline long chain 
omega 3 fatty acids with the bottom thirds for circulating biomarkers was 1.04
(0.90 to 1.20) and for dietary exposures was 0.90 (0.80 to 1.01). In the
randomised controlled trials the relative risk for cerebrovascular disease in the
long chain omega 3 supplement compared with the control group in primary
prevention trials was 0.98 (0.89 to 1.08) and in secondary prevention trials was 
1.17 (0.99 to 1.38). For fish or omega 3 fatty acids the estimates for ischaemic 
and haemorrhagic cerebrovascular events were broadly similar. Evidence was
lacking of heterogeneity and publication bias across studies or within subgroups.
CONCLUSIONS: Available observational data indicate moderate, inverse associations
of fish consumption and long chain omega 3 fatty acids with cerebrovascular risk.
Long chain omega 3 fatty acids measured as circulating biomarkers in
observational studies or supplements in primary and secondary prevention trials
were not associated with cerebrovascular disease. The beneficial effect of fish
intake on cerebrovascular risk is likely to be mediated through the interplay of 
a wide range of nutrients abundant in fish.
PMCID: PMC3484317
PMID: 23112118
[3] Arctic Medical Research [1996, 55 Suppl 1:20-24]
The Inuit diet. Fatty acids and antioxidants, their role in ischemic heart disease, and exposure to organochlorines and heavy metals. An international study.
Mulvad G , Pedersen HS , Hansen JC , Dewailly E , Jul E , Pedersen M , Deguchi Y , Newman WP , Malcom GT , Tracy RE , Middaugh JP , Bjerregaard P
Traditional food is culturally, economically and nutritionally important for the Greenlandic Inuit people. In the 1970s the preventive effect of marine fat on cardiovascular disease, thrombosis and atherosclerosis was described. The low incidence of ischemic heart disease among Greenlanders has been related to the high intake of marine food. Since 1990 routine autopsies have taken place in two towns in Greenland, Nuuk and Ilulissat. The autopsies represent 26% of the total number of deaths in these two towns. Samples have been collected from 104 autopsies. International cooperative studies have analysed specimens in relation to ischemic heart disease as a benefit related to diet, as well as the level of heavy metals and organochlorine in organs as a risk related to diet. High amounts of mono-unsaturated and Omega-3 poly-unsaturated fatty acid were found in adipose tissue. Liver analyses of selenium have confirmed the expected high intake among Greenlanders. Reduced atherosclerotic lesions were found in the coronary arteries. Blood pressure levels calculated from renovascholopathia of hypertension indicate prevailing levels similar to those in industrialized countries. Some factors in Greenland may be protecting the coronary arteries, thereby of setting the expected effect of hypertension. The level of methyl mercury in organs is generally high. PCB concentrations found in organs of Greenlanders are higher than among other populations. Health and risk effects of the traditional foods need further investigation.
[4] Circ Cardiovasc Qual Outcomes. 2012 Nov;5(6):808-18. doi:
10.1161/CIRCOUTCOMES.112.966168. Epub 2012 Oct 30.
Omega 3 Fatty acids and cardiovascular outcomes: systematic review and
Kotwal S(1), Jun M, Sullivan D, Perkovic V, Neal B.
Author information: 
(1)George Institute for Global Health, University of Sydney, Sydney, Australia.
BACKGROUND: Early trials evaluating the effect of omega 3 fatty acids (ω-3 FA)
reported benefits for mortality and cardiovascular events but recent larger
studies trials have variable findings. We assessed the effects of ω-3 FA on
cardiovascular and other important clinical outcomes.
METHODS AND RESULTS: We searched MEDLINE, EMBASE, and the Cochrane Central
Register of Controlled Trials for all randomized studies using dietary
supplements, dietary interventions, or both. The primary outcome was a composite 
of cardiovascular events (mostly myocardial infarction, stroke, and
cardiovascular death). Secondary outcomes were arrhythmia, cerebrovascular
events, hemorrhagic stroke, ischemic stroke, coronary revascularization, heart
failure, total mortality, nonvascular mortality, and end-stage kidney disease.
Twenty studies including 63030 participants were included. There was no overall
effect of ω-3 FA on composite cardiovascular events (relative risk [RR]=0.96; 95%
confidence interval [CI], 0.90-1.03; P=0.24) or on total mortality (RR=0.95; 95% 
CI, 0.86-1.04; P=0.28). ω-3 FA did protect against vascular death (RR=0.86; 95%
CI, 0.75-0.99; P=0.03) but not coronary events (RR=0.86; 95% CI, 0.67-1.11;
P=0.24). There was no effect on arrhythmia (RR=0.99; 95% CI, 0.85-1.16; P=0.92)
or cerebrovascular events (RR=1.03; 95% CI, 0.92-1.16; P=0.59). Adverse events
were more common in the treatment group than the placebo group (RR=1.18, 95% CI, 
1.02-1.37; P=0.03), predominantly because of an excess of gastrointestinal side
CONCLUSIONS: ω-3 FA may protect against vascular disease, but the evidence is not
clear-cut, and any benefits are almost certainly not as great as previously
PMID: 23110790
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I wonder how closely medical science has studied populations from arctic regions - First Peoples, Inuits, Eskimos etc


My answer hasn't really changed since the last time you posed a similar question about the evidence for cold exposure in different human populations, including people of the north.


Sheesh, Tom :) .


By the way, in addition to using your memory and making more skilled use of Google, folks really ought to make use of the Advanced Search on the CR Forums, which let you do Boolean searches, searches restricted by authors and date ranges, etc.



But as for longevity, as I pointed out when I last answered your question:


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



As for the Inuits/Greenlanders specifically, they are a sad and controversial case. There has long been thought to be an "Inuit Paradox", in which the Inuit were thought to be relatively free from heart disease despite a very heavily meat-based diet with little plant foods. Researchers attributed it to the richness of the Inuit diet in long-chain omega-3 fatty acids [1]. In fact, this apparent paradox was part of what kicked off the whole "fish oil for heart disease" excitement.


But since then, the very existence of Inuit paradox has been called into question ...

That issue of contamination is one reason it is though that the Inuit and Greenlanders may not do as well as they otherwise might [3]:


The level of methyl mercury in organs [of Inuits - DP] is generally high. PCB concentrations found in organs of Greenlanders are higher than among other populations. 


Plus, the Inuit pick up a lot of parasites from eating raw fish and marine mammals, which may explain both their low cholesterol and their less-than-stellar longevity


I don't think you need to look at anything as exotic, recent, or long-acting as mercury contamination of seal blubber. The Inuit have never, ever lived long enough for their allegedly low CVD mortality rates to mean anything: if you're a dead block of ice at age 40, you're not going to die of a heart attack. Plus, they're avoiding outright obesity and metabolic disease by working on the ice day in and day out, and there's no question that higher thermogenesis is good for you if it's burning energy that would otherwise go to excess fat. The issue that's in question is whether it's good for a person who already is slim and has reasonable metabolic health.


Today, the Icelanders and Greenlanders generally, and Inuit especially, have pretty bloody miserable lives (which amongst other things contributes to Greenland having the highest suicide rates in the world — which also, of course, distorts any data on CVD mortality): I don't think we're going to get any information out of them that's useful for people living privileged lived in cities with plenty of access to healthy foods.

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Looking over the reviews of the Basis Peak, it looks pretty mixed, with almost as many 1- and 2-star ratings as 4 and 5-star ratings. And the first, and longest video review (http://smile.amazon.com/dp/B00SZY2G1Y/ref=pd_va_prv_0) in the product description is pretty mixed - which is surprising, given it's provided by the seller. I presume you own one and find it useful?

Indeed. The guy doesn’t highlight any of the reasons I chose this watch: w/o the documentation for a proper review, these include the best available heart rate monitor, the “sitting disease” prevention feature (inactivity timer with vibrating alert and reward points), and the sleep tracker — and to a lesser extent the skin temperature monitor. The fact that it’s waterproof and can’t be fooled (at least by me and a couple of friends) into thinking you’re walking by bouncing your forearm around, unlike the FitBit, were also definite advantages.


It also seems like the review probably dates before many of the newer features came on board that many would find useful, including silent vibrating alarm clock (something April sure would’ve appreciated back in the day …) and the cell phone music app control thing (works a hell of a lot better than trying to control an iPhone strapped to your shoulder).


I suspect that some of the reviews you’re reading are criticizing it for lacking some features it logically ought to have had from the outset and only came on recently, including the alert for the “Don’t Be a Sitter” Habit and the latter two features.


I came across a attribute of the Basic Peak that pretty much makes it a non-starter for usage pattern, if it's still the case. In this review (http://smile.amazon.com/gp/customer-reviews/R3S3FY1TYMHIOR/ref=cm_cr_arp_d_rvw_ttl?ie=UTF8&ASIN=B00GJG79LM), the Basic Peak owner says:


The most frustrating aspect of using the device is that data does not sync in real time and has to be uploaded to the cloud before it will show you anything on your mobile device. Syncing and uploading that data takes more than a minute.

But that review is from over a year ago. Has the software changed to continuously update the app? That's one thing I really like and rely on with my Fitbit Charge HR. I have my phone on top of my bike desk and monitor at a glance how far I've gone, how many "steps" I've taken, my HR etc via the Fitbit app. Since I've got my Fitbit strapped around my lower quad for a lot of the day, which is moving and under my desk, I can't easily read it while pedaling.

Yeah, the app really is not designed for monitoring what you’re doing, and wouldn’t be much use to you even if it were updated in perfect real time: the interface in the app (and the superior dashboard for your computer or tablet) is really designed as a record rather than for moment-to-moment monitoring. The watch is there for that — and it’s a hell of a lot easier to read than the FitBit.


Why don’t you wear your FB on your wrist? Any reason (aside from looking even more like a nerd ;) — and I speak as one who looks decidedly nerdy!)) you would be reluctant to do so with the Peak?


Do you think it really can track REM sleep? I'd be curious to hear more about your experience with it.

I’m not aware of any published data comparing it to proper polysomnography (even in the form of Basis propaganda), but studies I’ve seen on a variety of other wrist-based sleep trackers based on actimetry show that they tend to give a reasonable estimate, and the software and actimeter on the Peak is clearly superior to most general-purpose activity trackers. Additionally the pattern I see on the interface — with more deep sleep in the first half of the night and progressively longer REM periods as the night goes on — is consistent with what ought to be happening. I actually value the tracking of deep non-REM more than REM sleep, for tissue repair, memory consolidation, and Abeta efflux*: indeed, wanting some reassurance on these points was one of my reasons for wanting a sleep tracker on my fitness tracker.


* If that link won't work for you, you can get a decent overview in the introduction to this paper (which merits reading thru' IAC if you're interested); and, also, I'd happily send you (or anyone who can't get it via that link) the pdf).

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Thanks for the update on your experience with the Basis Peak. It sounds like the software has improved since many of the reviews I read. 


Why don’t you wear your FB on your wrist? Any reason (aside from looking even more like a nerd ;) — and I speak as one who looks decidedly nerdy!)) you would be reluctant to do so with the Peak?


I wear my FitBit on my wrist when walking or running, although I sometimes leave it on my leg (just above the knee) even when walking the dog and therefore not swinging my arms normally. But I mostly wear my FitBit on my leg in two situations - when pushing a shopping cart and especially during the 6-8 hours I spend pedalling on my indoor trainer bike or at my bike desk. In all these instances, without arm movement the FitBit doesn't count steps. With it around my leg, it counts just fine while pedalling my bike or pushing a grocery cart (or stroller for those with young kids!). It sounds like the Basis Peak is more particular about what it counts as a step than the FitBit, so it might not work in the same way. Have you ever tried it?  At the bottom is a video I made of the simply DIY way I strap it to my leg - although the video shows me putting it on my ankle. BTW, it's about my most popular video ever, except for a few of the Fish School ones1, with 17K views and 67 likes!


Thanks for the info about Basis Peak sleep tracking. Sounds pretty good. Between that and the skin temperature tracking, I'm tempted. But the fact that it doesn't provide real-time updates to my phone, and may not even track steps when I'm pedalling, means I'd probably have to wear both the FitBit and the you-gotta-admit-pretty-ugly Basis Peak.


Finally, for anyone who wants to take this thread to read off-line (perhaps on the plane on the way to the CR Conference?!), I've turned it into a PDF. Here is a link, but be warned, it's 40MB and 394 pages long...




Here are my fish school videos, plus this 30-sec one with 406K views and nearly 800 likes!


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