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Cold Exposure & Other Mild Stressors for Increased Health & Longevity

Dean Pomerleau

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Personally, I do not think that a topic not even in Wikipedia merits little attention.  But anyway, the below seems to add something to those that might be interested.  It is just a summary of mechanisms involved in BAT and uncoupling protein with thermogenesis, weight loss and such.




    Weiwei Fan, Ronald Evans

Science  19 Aug 2016:

Vol. 353, Issue 6301, pp. 749-750

DOI: 10.1126/science.aah6189


An enzyme steps up to BAT as a potential mitochondrial uncoupler


Treatment of obesity and obesity-associated diseases has been challenging, with the first potential cure claimed in 1934 with the protonophore 2,4-dinitrophenol (DNP). This chemical dissipates mitochondrial membrane potential into heat production and is extremely effective in boosting metabolic rate and promoting weight loss (1). However, severe side effects, including cataract formation, cardiotoxicity, overheating, and death, prevented its further use (2). In a recent study, Long et al. (3) report that a secreted enzyme called peptidase M20 domain containing 1 (PM20D1) converts fatty acids and amino acids into N-acyl amino acids, which directly uncouple mitochondrial membrane potential in a way similar to that of DNP, to increase energy expenditure without physical movement. Might these endogenous metabolites be a safe alternative to chemical uncouplers, facilitating effortless fat burning without a fatal consequence?


The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.

Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP, Paulo JA, Gygi SP, Griffin PR, Nomura DK, Spiegelman BM.

Cell. 2016 Jul 14;166(2):424-35. doi: 10.1016/j.cell.2016.05.071. Epub 2016 Jun 30.

PMID: 27374330


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Hi, and thanks, Al!  I always appreciate your input. ...And, yes, I think (!); to what "it" does the it ("topic") in your missive refer?  To the extent it is BATBs not being introduced and not appearing in wiki|P, I nominate absolutely that it should, e.g., just as it has been introduced and now appears in longecity.org.  I further nominate, aghh hmm, that a reader(s) of this post consider making said wiki|P introduction.  ~Shine the light!

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Personally, I do not think that a topic not even in Wikipedia merits little attention.


Wow Al. That string of negatives really makes my head spin. It apparently spun yours as well.


To paraphrase Inigo Montoya from Princess Bride, I do not think what you just said means what you think it means. If parsed carefully, your statement reads as an endorsement of cold exposure, when, as far as I can tell, you actually meant to say the opposite. if it doesn't merit little attention due to its absence from Wikipedia, then it would seem to merit lots of attention!


But assuming you meant it as a diss against cold exposure, all your statement really does is show you didn't try very hard probing Wikipedia, since there is a pretty respectable entry for Brown Adipose Tissue, which discusses many of the topics we've covered here.


Ironically, given the current context, and the apparent credence you give to wikipedia despite the the widespread skepticism many have about its trustworthiness, the BAT wikipedia page makes the same mistake about PMID 23823482 you made way back in this post from February, which you cryptically amplified in this one (which I tried to decipher here), and subsequently dug yourself in even deeper in this one. If you recall, the cold exposure → CVD link implied by your study was quite thoroughly addressed and debunked by the authors of PMID 25754609, as discussed in this post.


Yes Kenton, someone with the time and inclination should clean up the Wikipedia entry for BAT, and create one for Cold Exposure...



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Cool Gordo - Great job! I've never actually tried editing a wikipedia entry before, and quite honestly, have been a bit intimidated to try. Was it pretty straightforward?


I see from the history page for the BAT wikipedia entry that you made a lot of edits yesterday and today, and appear to have done it anonymously (only identified by your IP address). Is that kosher? It looks like all the other updates have been by users who identified themselves. I do notice a few updates back in April by a user named 'WTFGordo'. Was that you too?



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I do have an account there but rarely log on, I don't really know what the benefit of logging on would be?  They don't have a problem with anonymous edits.  I have edited that page before, but my user name isn't WTFGordo so that is an interesting coincidence (there is another Gordo editing the page).  As for the editing itself, it used to be a lot more difficult requiring a substantial learning curve, but they recently introduced "visual editing" which makes it possibly even easier than posting in this forum (if it doesn't automatically ask you if you want the visual editor, you can get to it by clicking a little icon toward the top right of the editor page).  Visual editing lets you edit in place, seeing everything as you normally would when viewing the page, no code to deal with, you can cut and paste anything from the net easily, and just click a button to generate citations or another button to generate links to other wiki articles, it's all very simple now.  The citation generator is also great, you can paste a link or PMID and it does all the work for you building the superscripts and footnotes, basically effortless.  Actually it would be nice if the forum software here could incorporate some of those features (especially for citations).

Edited by Gordo
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Every BEAT of Your Heart - The Benefits of Brown Epicardial Adipose Tissue


Ah, it's nice to get back to what I consider one of the most important and interesting thread on these fora, second only to this one of course. And have I got an interesting and relevant one for everyone today - a study that once again undermines Michael's skepticism about the benefits of brown adipose tissue, expressed most cogently here, where he famously got my goat by saying: 


 I just can't mechanistically see how increasing BAT quantity or activity would exert an effect on aging per se.


Aging per se remains somewhat of a baffling term to me now that SENS has started equating aging with damage accumulation, rather than some mysterious intrinsic process independent of the "diseases of aging" as most people used to think (or so it seems to me - he says to cover his ass...).


But Michael's sentiment seems clear - there doesn't (or at least didn't) seem to him to be much benefit from BAT expression, beyond possibly obesity avoidance.


I also note that Michael appearedin that same "BAT skeptic" post to question the idea that increased expression of PGC1α is responsible for mitochondrial biogenesis, another perspective that this new study appears to seriously undermine.


What new study you ask? This one [1], with a much more boring title than mine, namely "Type 2 diabetes is associated with decreased PGC1α expression in epicardial adipose tissue of patients with coronary artery disease."


It's title may be boring, but it hits on some perennially hot topics around here, which we've been discussing a lot lately, including diabetes and glucose metabolism, heart disease, and brown adipose tissue. And it hits them in a tantalizing new way, pointing towards an exciting new benefit of BAT(ish) tissue that I wasn't aware of and that has some really interesting implications.


But bear with me. First, some context.


Let me refresh your memory about the "athlete's paradox" discussed in this post on this thread from a month ago, featuring PMID 27445983. The athlete's paradox refers to the striking observation that endurance athletes (got that Gordo, endurance athletes) have impeccable glucose metabolism but at the same time have more fat deposits in their muscle cells. At first blush, this seems like a paradoxical result - flying in the face of Dr. Neal Bernard's explanation for diabetes as caused by "intramyocellular lipids" - i.e. fat deposits gumming up muscle cells and causing impaired glucose metabolism. Bernard's hypothesis that has been widely criticized, if not debunked, based in part on the athlete's paradox.


We saw in that post the possible resolution for the athlete's paradox, and the rescue of Dr. Bernard's diabetes explanation. In particular, PMID 27445983 found that endurance-trained mice (who spent 6 hours per day on a running wheel) had better glucose control and more fat inside muscle cells than sedentary controls, recapitulating the athlete's paradox seen in humans.


But unlike mice fed a high fat diet, the fat inside the muscles of athletic mice had a brown phenotype - expressing high levels of PGC1α and UCP1. The authors of that study suggest that as a result, the brown-fat-rich muscle cells of mice and men after endurance training may benefit from extra capacity to burn fat and glucose as a result of extra mitochondria that exercise induces in the lipid deposits inside the muscles. This extra metabolic capacity of brown-fat-enriched muscle cells may not only protect against diabetes when at rest, but also facilitate athletic performance by enabling muscle cells to metabolize fat and glucose more effectively to supply the energy needs of muscles during exercise.


In short, PMID 27445983 suggests that the colocation of brown(ish) adipose deposits and muscle tissue may have substantial metabolic benefits and protect against diabetes. With that long-winded introduction, let's now turn to the new study [1], which (in a nutshell) suggests something very similar, or at least closely related, may be happening in that most important of all muscles, the heart.


In [1], the researchers looked at the epicardial adipose tissue (EAT - aka "heart fat") that surrounds the heart, which is labelled "epicardial fat" in this diagram:




In the introduction, the authors of [1] point to evidence of EAT's importance in diabetes and heart disease (See the free full text of [1] for references):


Several studies have shown that EAT is associated with the development and progression of coronary atherosclerosis, mainly through a dysbalance of pro/anti-inflammatory adipokines production in pathological conditions [2–4]. Indeed, it has been demonstrated that the volume of EAT correlates with the extent and severity of CAD [4–6]. EAT participates in the energy homeostasis of the heart and the vessels [7, 8]; thus the functional EAT might play a protector role over the myocardium or coronary arteries [9]. However, in patients with type 2 diabetes mellitus (DM2), the EAT dysfunction might be the main connection between the diabetic state and complexity of coronary lesions in patients with CAD. DM2 is associated with more extensive CAD, a more aggressive course and greater morbidity and mortality than in coronary patients without DM2 [10].


In other words, EAT may be a good guy or a bad guy when it comes to heart disease, depending on if it's metabolically active (and hence beneficial) or metabolically deranged (and hence harmful).


Here is where the authors next take a potshot at Michael's (apparent) skeptical assessment of the link between PGC1α and mitochondrial biogenesis alluded to above, by observing:


On the basis of hundreds of studies, PGC1α is now recognized as a master regulator of mitochondrial biogenesis and oxidative metabolism in many cell types.


And putting these two observations together, the authors motivate their study as follows:


Recent studies have reported that human EAT expresses genes of the brown-like adipocytes, such as PGC1α, (UCP1), and PR-domain-missing 16 (PRDM16), suggesting that EAT may play a role in thermogenesis [13, 14]. However, it remains to be determined whether the brown fat-like gene expression in EAT is altered in CAD patients according to diabetes status. Therefore, our main objective was to evaluate the expression of PGC1α, UCP1 and PRDM16 mRNAs in EAT contiguous with CAD in patients with and without DM2. We hypothesized that the gene expression of thermogenic genes in EAT would be altered according to diabetes status, since adipose thermogenesis has been shown to affect excess lipids and fat accumulation [15, 16]. An additional aim was to determine the possible association between brown fat-like gene expression and various biochemical and clinical parameters that it could explain the prevalence of coronary lesions in diabetic patients.


In short, what they did is assess the thermogenic gene expression in EAT taken from the hearts of three groups of people - coronary artery disease suffers with and without diabetes (referred to as the CAD-DM2 and CAD-NDM2 groups, respectively) and controls who were people that had valve replacement surgery (take note Drew), but who were otherwise free from diabetes and coronary artery disease (referred to as the NCAD group). You'll be glad to know they didn't have to take too much heart tissue in the EAT biopsies they performed during heart surgery on all their subjects - only 0.2-0.5g.


I'll spare you the graphs (available in the full text if you really want to see them) and instead simply summarize their results, using their own words (my emphasis):


Our main finding was that [coronary artery disease] patients with [diabetes] expressed significantly lower PGC1α and UCP1 mRNA levels in EAT than those [coronary artery disease patients] without [diabetes] and [non-coronary artery disease] patients.


In other words, the heart fat of coronary artery disease (CAD) folks with diabetes was whiter (less brown) than those without diabetes and without CAD. Next they found:


... PGC1α expression levels in EAT decreased with the number of injured coronary arteries and EAT PGC1α was shown as a possible protective factor against coronary lesions.


In other words, patients with browner heart fat had fewer coronary lesions. They also found (not surprisingly) the same relationship held true with thermogenic UCP1 expression in EAT, leading them to suggest:


Therefore, the lower expression of EAT PGC1α and UCP1 from CAD patients found in our study suggests a loss of EAT brown-like features in [diabetics], which may act detrimentally on metabolism [18, 19] and promote the progression and severity of CAD [9].


In other words, the authors are suggesting the bold hypothesis that whiter EAT in diabetics may be responsible (at least in part) for both their broken glucose metabolism, and importantly, be the reason that diabetes sufferers are 2-4 times more likely to die of heart disease than non-diabetics.


But exactly how (mechanistically) might this link between diabetes, whiter EAT and heart disease work, you ask? Here is what the authors say:


[PGC1α expression's] contribution to CAD should be higher in EAT [than other fat deposits] due to its close proximity to the coronary arteries [1].


OK - that's getting closer to the mechanistic explanation, but it's not quite satisfying. Exactly how might white heart fat being close to the coronary arteries influence CAD progression? Here is the clincher, the smoking gun so to speak. The authors suggest that in diabetes sufferers with whiter EAT:


PGC1α-mediated reduced β-oxidation of fatty acids and EAT-mediated reduced triglyceride clearance might expose the heart to excessively high circulating levels of lipids, leading to lipid-induced cardiotoxicity and, with EAT-mediated lower HDL-cholesterol, which has anti-inflammatory and anti-atherosclerotic properties, increase the risk and the severity of CAD. Moreover, due to EAT and myocardium sharing the same blood supply, a PGC1α and UCP1-mediated reduced β-oxidation of fatty acids in EAT might also alter the functionality of the myocardium such that it does not provide sufficient energy. 


Notice the satisfying parallel in this paragraph with what we saw in the study of brown fat in endurance-trained mouse muscles. Specifically, like in the study of endurance-trained mice, these authors are suggesting that browner heart fat helps improve lipid metabolism and improve the balance of pro- vs. anti-inflammatory cytokines and HDL vs LDL in and around the heart, thereby making browner heart fat cardioprotective. And secondly, also like the endurance mice, the presence of mitochondria-rich brown heart fat right next to heart muscle tissue may provide the heart with extra energy, so it pumps better.


The opposite of these beneficial effects of browner heart fat happens in diabetics. Namely their whiter EAT making their hearts more prone to damage (i.e. more prone to coronary lesions) and energy-starved and therefore less able to pump effectively.


That seems like a really interesting and plausible hypothesis to explain why diabetics are so prone to coronary artery disease. 


Of course, these observations were made at only a single point in time in people who already had diabetes and serious heart disease, so it's not entirely clear whether these differences in the brownness of heart fat contributed to causing their diabetics, or were a consequence of their diabetes.  But either way, the authors suggest the whiter fat around the hearts of diabetics is bad news:


A central question is whether reduced PGC1α and UCP1 mRNA expression in EAT is a prelude to the development of [diabetes] through a constitutively lower rate of β-oxidation and lower adipose activation, or a consequence of the diabetes itself, in either case leading to increased severity of [heart disease]. Future studies should focus on elucidating mechanisms by which EAT is involved in development and progression of CAD in various disease populations.


So while the mechanism isn't entirely clear, the authors seem to strongly suggest that whiter fat around the heart is a likely cause of heart disease, especially in diabetics. This is really interesting and relevant to this thread, as well as to our ongoing discussions about impaired glucose tolerance and its potential dangers.


But what I find almost as intriguing are the implications of the combination of this study with the endurance-mice study discussed above for athletic performance. In particularly, as I'm sure everyone knows by now, since starting chronic and nearly-continuous cold exposure, I've found I can exercise all-day (literally) without running out of energy. And more recently, I've observed I virtually never get winded. I really would like to do an official VO2Max test, but in the pool I seem to be able to swim faster than I ever have (at least since my college swim team days) without getting winded. They same goes for running. I was able to power past several high-school distance runners in the sprint to the finish of a recent 5K without getting winded and recovering within seconds after finishing the race.


It seems to me that the observations in these two studies (plus this one involving sarcolipin in skeletal muscles) of increased metabolic power as a result of BAT-expression in and around heart and skeletal muscles could serve to explain my personal experience. Specifically, engaging in nearly continuous (but nonetheless very moderate) endurance exercise coupled with cold exposure may have resulted in a large increase in expression of brown fat in and around my muscles and my heart, thereby dramatically improving my cardiovascular performance and endurance.


Admittedly quite speculative, but intriguing nevertheless...





1To cover my ass ☺, I will note that I can't rule out the possibility that Michael meant to limit his statement about the lack of linkage between PGC1α expression and mitochondrial biogenesis to apply only to CR rodent studies in general, or the one Valle et al study under discussion in that post. His "most of the studies..." quote appears to me to have ambiguous scope.



[1] J Transl Med. 2016 Aug 19;14(1):243. doi: 10.1186/s12967-016-0999-1.

Type 2 diabetes is associated with decreased PGC1α expression in epicardial
adipose tissue of patients with coronary artery disease.
Moreno-Santos I(1), Pérez-Belmonte LM(2), Macías-González M(3), Mataró MJ(2),
Castellano D(3), López-Garrido M(2), Porras-Martín C(2), Sánchez-Fernández PL(4),
Gómez-Doblas JJ(2), Cardona F(5), de Teresa-Galván E(2), Jiménez-Navarro M(2).
BACKGROUND: Although recent studies indicate that epicardial adipose tissue
expresses brown fat-like genes, such as PGC1α, UCP1 and PRDM16, the association
of these genes with type 2 diabetes mellitus (DM2) in coronary artery disease
(CAD) remains unknown.
METHODS: PGC1α, UCP1, and PRDM16 mRNAs expression levels were measured by
real-time PCR in epicardial and thoracic subcutaneous adipose tissue from 44 CAD 
patients (22 with DM2 [CAD-DM2] and 22 without DM2 [CAD-NDM2]) and 23 non-CAD
patients (NCAD).
RESULTS: The CAD-DM2 patients had significantly lower PGC1α and UCP1 expression
in epicardial adipose tissue than the CAD-NDM2 and NCAD patients. However, PGC1α 
and UCP1 mRNA trended upward in subcutaneous adipose tissue from CAD-DM2
patients. At multiple regression analysis, age, body mass index, left ventricular
ejection fraction, UCP1 expression of epicardial adipose tissue and diabetes came
out to be independent predictors of PGC1α levels. Epicardial adipose tissue PGC1α
expression was dependent on the number of injured coronary arteries and logistic 
regression analysis showed that PGC1α expression in epicardial adipose tissue
could exert a protective effect against coronary lesions.
CONCLUSIONS: DM2 is associated with decreased expression of PGC1α and UCP1 mRNA
in epicardial adipose tissue of patients with CAD, likely reflecting a loss of
brown-like fat features. Decreased expression of PGC1α in human epicardial
adipose tissue is associated with higher prevalence of coronary lesions.
DOI: 10.1186/s12967-016-0999-1 
PMCID: PMC4992233
PMID: 27542888
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You really got my attention with this post with a shout out a valve replacement bros. I don't have any grand insights to add, especially to a topic which you are incredibly knowledgeable about.  Maybe someday you and Ray Cronise can get together on the Rich Roll podcast.  :)xyz

The relationship between EAT, diabetes, and coronary artery disease is fascinating.


The relationship between cold exposure and recovery is fascinating. 


Random thought: Dean, have you ever had a transthoracic echocardiogram done? I would be curious what the heart of someone who exercises nearly continuously for many, many hours daily would look. The test is completely safe and without side effects and risks, unlike many other procedures such as trans-esophogeal echocardiogram or angiogram. 


I'm going to review the study closer to see if there is some other valve specific info and may edit this post if I notice something. 

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Cold Exposure Works Like We Think It Works, and That's Cool!


Given the growing evidence that much of the life sciences research out there is bogus, a result of faulty methodology and 'P-hacking', and doubts about the benefits of CR for humans, it's nice to see evidence continuing to mount (and be replicated) showing the metabolic benefits of brown/beige fat, and cold exposure.


Case in point, two new articles from the latest issue of Cell Metabolism, which I'll review in this post and the next.


In the first new paper [1], researchers investigated just what is happens during the process of converting white fat deposits to beige, and visa versa. Are new beige adipose cells differentiated from adipose progenitor cells? Or do existing WAT cells switch to BAT by boosting mitochondria size/count and/or UCP1 expression? And what orchestrates the process?


In [1], the researchers actually studied the BAT → WAT transition process.


They first showed that either cold exposure (6°C for a week) or treating mice with a β3-AR agonist for a week (to increase signalling of the catecholamine norepinephrine, which is what cold exposure does to boost thermogenesis) "profoundly increased" the number of beige adipocytes, and their UCP1 expression in inguinal white adipose tissue (iWAT), the subcutaneous fat deposit between the groin and the upper thigh in mice that the researchers focused on in this study. No surprise there. 


What was more interesting was what happened to the beige fat cells in iWAT over time. Following the cold exposure or β3-AR agonist treatment, they housed the mice at thermoneutrality (30 °C) for two months, monitoring what happened to their initially-browned iWAT. They needn't have kept it up so long. What they found was that by day 15, the UCP1 expression was cut in half, and by day 20 it was virtually zero, as the authors observed (my emphasis):


Intriguingly, UCP1 expression in the inguinal WAT became undetectable in mice within 2–3 weeks following transfer from cold environment to ambient or thermoneutral conditions.


Notice they said "ambient or thermoneutral" conditions. In other words, at standard lab temperature (21-22 °C or ~72 °F), mice lost their beige fat, despite the fact that this temperature is pretty chilly for mice.


But interestingly, the expression of UCP1 in true interscapular BAT cells, which was also boosted by the week of cold exposure or β3-agonist, remained high for the full 60 days at thermoneutral or ambient housing, as you can see from these two graphs (iWAT on the left, interscapular BAT on the right).




This suggests two very interesting things. First, it looks like beige fat may be more sensitive to temperature than true BAT, and that it may take colder conditions to maintain beige fat relative to true brown fat, which (unfortunately) humans have very little of.


Second, it looks like when it comes to beige fat (the thermogenic fat humans express most), it's "use it or lose it". It looks like you can go up to about 10 days without cold exposure before you start to lose beige fat you've built up, but much more than that and the thermogenic capacity of your subcutaneous fat starts to drop precipitously, at least if you're a mouse. Something similar is probably true in humans as well. That's good to know, since that gives plenty of time for a 5-day sojourn to sunny Costa Rica without risk of losing much beige fat ☺.


The next question the researchers addressed was what exactly was going on during the beige fat → white fat transition. Did the beige fat cells die and get replaced? Did they convert back to naive precursor adipocytes and then re-differentiate into white adipose cells? Or did they simply slide from one adipocyte phenotype to the other?


Using a series of petri-dish studies of fat cells undergoing the same transition, they determined it was the latter. The cells transition smoothly from beige to white fat cells over the course of about 10 days in vitro at thermoneutral temperatures:


[O]ur data provide evidence that beige adipocytes directly acquire both the morphological and molecular characteristics resembling white adipocytes after b3-AR agonist withdrawal, bypassing an intermediate precursor stage.


They then looked more closely at exactly what was going on inside the adipocytes during the transition. Under a microscope, they observed that during the transition from BAT (beige adipose tissue) to WAT, mitochondria were disappearing. Looking at gene expression, it was clear that this mitochondria disappearance was a result of increased cellular autophagy, which in this case is called mitophagy (deliberate, gene-regulated breakdown of mitochondria):


These data collectively suggest that autophagy activity is low in beige adipocytes, whereas it is transiently re-activated during the beige-to-white adipocyte transition following b3-AR agonist withdrawal.


The mechanism by which mitophagy was triggered was quite interesting. Basically what they found was that it involved the PKA-mTOR pathway I've discussed previously (e.g. here), and illustrated in this diagram:




In particular, cold exposure increases norepinephrine, which activates Protein Kinase A (PKA), which in turn programs mTOR (mTORC1) to block autophagy of mitochondria in beige fat cells.


The authors confirmed that once either cold exposure or β3-AR agonist was withdrawn, this pathway was downregulated, reactivating the autophagy of beige fat mitochondria. As the authors put it:


[A]ctivation of the PKA pathway via β3-AR stimulation represses the autophagy network in beige adipocytes, whereas removal of the β3-AR agonist leads to autophagy activation during the beige-to-white adipocyte transition.


For people who like pretty pictures rather than words, here is the graphical abstract the authors included with their paper, illustrating the autophagy-mediated smooth transition from cold-induced (or β3-agonist-induced) beige fat to white fat:




To cap off their study, they then showed that mutant mice (who lacked the genes responsible for autophagy in beige adipocytes) retained their thermogenic beige fat far longer under thermoneutral conditions than wild-type mice, who catabolized their beige fat mitochondria via autophagy.


Not only that, but these autophagy-knockout mice (labelled Atg12Ucp1 KO below) were resistant to diet-induced obesity (left graph below) and had better glucose metabolism in response to a glucose challenge (right graph below) after high fat feeding for a few weeks:




Here is the author's summary of this in vivo part of their study (my emphasis):


[T]he metabolic phenotypes, i.e., reduced body-weight gain and improved glucose homeostasis, found in Atg12Ucp1 KO mice after b3-AR agonist treatment, are largely due to retention of thermogenically active beige adipocytes that are recruited by chronic b3-AR agonist treatment. These observations are consistent with the above finding that Atg12Ucp1 KO mice maintain higher amounts of UCP1 and other mitochondrial proteins in the inguinal WAT for prolonged periods compared to autophagy-competent controls, specifically following withdrawal of b3-AR agonist. Altogether, these data indicate that prolonged maintenance of thermogenically active beige fat is sufficient to increase whole-body energy expenditure and protect mice from diet-induced obesity and insulin resistance.


The authors point out the significance of their finding for humans, in light of the fact that:


...obesity-induced insulin resistance and type 2 diabetes impair mTOR signaling, thereby leading to autophagy activation in human adipose tissues (Kosacka et al., 2015; Ost et al., 2010). These results indicate that obesity not only impairs beige adipocyte differentiation but also accelerates the beige-to-white adipocyte transition, at least in part, through the activation of autophagy[...]


They author were excited because of the potential for preventing obesity in humans by blocking mitochondrial autophagy in beige fat via pharmacological interventions, or eventually genetic manipulation.


I found this fascinating for a different reason. Why? Because we often hear statements like "CR and intermittent fasting are beneficial in part because they increase autophagy by suppressing mTOR (which blocks autophagy)" from knowledgeable people and even literal gurus who mispronounce autophagy. Autophagy is thought by many to be synonymous with "cellular housekeeping" - and what could be wrong with more / better housekeeping, right?




It's much more subtle than that. Many of the things that mTOR does are beneficial, including building bone, boosting immune system function, and here we see, blocking autophagy of mitochondria in beige adipose cells to improve glucose metabolism and prevent weight gain.


By analogy, mTOR is like a multi-function printer/copier/scanner (as observed before), programmed to do different (sometimes very important and beneficial) things in different cells depending on the cell type and local intracellular conditions.


In my next post, about the second, even more interesting and relevant paper from the latest issue of Cell Metabolism, we'll see just how relevant that "local intracellular conditions" part is for people around here. Stay tuned.


In the meantime, harkening back to my introduction, it's cool to see evidence that not only jibes nicely with previous findings but also with a comprehensive biochemical model of how CE works, and why it is beneficial. It boosts one's confidence that these effects are real and significant - not just the result of p-hacking or other shenanigans.





[1] Cell Metabolism (2016), August 25, 2016


Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance


Svetlana Altshuler-Keylin, Kosaku Shinoda, Yutaka Hasegawa, Kenji Ikeda, Haemin Hong, Qianqian Kang, Yangyu Yang, Rushika M. Perera, Jayanta Debnath, Shingo Kajimura


Full text: http://dx.doi.org.sci-hub.cc/10.1016/j.cmet.2016.08.002


Beige adipocytes gained much attention as an alternative cellular target in anti-obesity therapy. While recent studies have identified a number of regulatory circuits that promote beige adipocyte differentiation, the molecular basis of beige adipocyte maintenance remains unknown. Here, we demonstrate that beige adipocytes progressively lose their morphological and molecular characteristics after withdrawing external stimuli and directly acquire white-like characteristics bypassing an intermediate precursor stage. The beige-to-white adipocyte transition is tightly coupled to a decrease in mitochondria, increase in autophagy, and activation of MiT/TFE transcription factor-mediated lysosome biogenesis. The autophagy pathway is crucial for mitochondrial clearance during the transition; inhibiting autophagy by uncoupled protein 1 (UCP1+)-adipocyte-specific deletion of Atg5 or Atg12 prevents beige adipocyte loss after withdrawing external stimuli, maintaining high thermogenic capacity and protecting against diet-induced obesity and insulin resistance. The present study uncovers a fundamental mechanism by which autophagy-mediated mitochondrial clearance controls beige adipocyte maintenance, thereby providing new opportunities to counteract obesity.
beige adipocytes, obesity, diabetes, mitophagy, mitochondria
PMID: Not available
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Perilipin 5 - The New Protein on the Block Involved in Fat and Muscle Browning


Sorry, but I've decided to sneak in another post between the two new Cell Metabolism papers mentioned in my previous post. This new study [1] (popular press coverage), adds to the story I discussed a couple days ago in this post involving the "athlete's paradox".


Recall athletes have more fat accumulated inside their muscle cells, but remain extremely insulin sensitive. The explanation we saw there was that the intramyocellular lipids of athletes were comprised of thermogenic beige fat deposits, rather than metabolically dysfunctional white fat deposits. 


What the researchers found in [1] was that a protein called "Perilipin 5" gets released from the surface of fat deposits inside muscle and other cell types. It then travels to the cell nucleus, where it interacts with Protein Kinase A (see my previous post) as well as PGC-1α and SIRT1 to promote mitochondrial biogenesis.


The results can briefly be summarized as follows from the Science Daily popular press story:


In experiments with cultured cells and mice, the UTSW research team found that when cells are stimulated to release fat stored in fat droplets, Perilipin 5 can leave the surface of those droplets and move to the cell's nucleus, where it works with another protein, PGC-1α, to encourage the creation of additional -- and more efficient -- mitochondria. In this way, Perilipin 5, "helps match mitochondrial capacity to burn fat with the fat load in the cell," Dr. Bickel said.


What kicks off the whole process? The catecholamine norepinephrine. What boosts norepinephrine? You guessed it, cold exposure, as well as exercise and fasting to a lesser degree.


In short:


Cold Exposure → ↑ norephinephrine → ↑ PKA → ↑ Perilipin 5 and ↑ PGC-1α → ↑ mitochondrial biogenesis → ↑ insulin sensitivity



This whole cold exposure pathway involving norepinephrine, PKA and perilipin has been previously identified in BAT as well. I just hadn't come across the research (e.g. [2]) before.


There is so much exciting work happening in this area right now, it's hard to keep up. Sometimes it seems like we should start a Cold Exposure Society ☺.





[1] Nature Communications 7, Article number: 12723 (2016)

Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function
Violeta I. Gallardo-Montejano, Geetu Saxena, Christine M. Kusminski, Chaofeng Yang, John L. McAfee, Lisa Hahner, Kathleen Hoch, William Dubinsky, Vihang A. Narkar & Perry E. Bickel




Dysfunctional cellular lipid metabolism contributes to common chronic human diseases, including type 2 diabetes, obesity, fatty liver disease and diabetic cardiomyopathy. How cells balance lipid storage and mitochondrial oxidative capacity is poorly understood. Here we identify the lipid droplet protein Perilipin 5 as a catecholamine-triggered interaction partner of PGC-1α. We report that during catecholamine-stimulated lipolysis, Perilipin 5 is phosphorylated by protein kinase A and forms transcriptional complexes with PGC-1α and SIRT1 in the nucleus. Perilipin 5 promotes PGC-1α co-activator function by disinhibiting SIRT1 deacetylase activity. We show by gain-and-loss of function studies in cells that nuclear Perilipin 5 promotes transcription of genes that mediate mitochondrial biogenesis and oxidative function. We propose that Perilipin 5 is an important molecular link that couples the coordinated catecholamine activation of the PKA pathway and of lipid droplet lipolysis with transcriptional regulation to promote efficient fatty acid catabolism and prevent mitochondrial dysfunction.


DOI: doi:10.1038/ncomms12723

PMID: Not available



[2] J Lipid Res. 2007 Jun;48(6):1273-9. Epub 2007 Mar 30.

Perilipin regulates the thermogenic actions of norepinephrine in brown adipose
Souza SC(1), Christoffolete MA, Ribeiro MO, Miyoshi H, Strissel KJ, Stancheva ZS,
Rogers NH, D'Eon TM, Perfield JW 2nd, Imachi H, Obin MS, Bianco AC, Greenberg AS.
Author information: 
(1)Jean Mayer United States Department of Agriculture-Human Nutrition Research
Center on Aging at Tufts University, Boston, MA, USA.
In response to cold, norepinephrine (NE)-induced triacylglycerol hydrolysis
(lipolysis) in adipocytes of brown adipose tissue (BAT) provides fatty acid
substrates to mitochondria for heat generation (adaptive thermogenesis).
NE-induced lipolysis is mediated by protein kinase A (PKA)-dependent
phosphorylation of perilipin, a lipid droplet-associated protein that is the
major regulator of lipolysis. We investigated the role of perilipin PKA
phosphorylation in BAT NE-stimulated thermogenesis using a novel mouse model in
which a mutant form of perilipin, lacking all six PKA phosphorylation sites, is
expressed in adipocytes of perilipin knockout (Peri KO) mice. Here, we show that 
despite a normal mitochondrial respiratory capacity, NE-induced lipolysis is
abrogated in the interscapular brown adipose tissue (IBAT) of these mice. This
lipolytic constraint is accompanied by a dramatic blunting ( approximately 70%)
of the in vivo thermal response to NE. Thus, in the presence of perilipin,
PKA-mediated perilipin phosphorylation is essential for NE-dependent lipolysis
and full adaptive thermogenesis in BAT. In IBAT of Peri KO mice, increased basal 
lipolysis attributable to the absence of perilipin is sufficient to support a
rapid NE-stimulated temperature increase ( approximately 3.0 degrees C)
comparable to that in wild-type mice. This observation suggests that one or more 
NE-dependent mechanism downstream of perilipin phosphorylation is required to
initiate and/or sustain the IBAT thermal response.
DOI: 10.1194/jlr.M700047-JLR200 
PMID: 17401109
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"There is so much exciting work happening in this area right now, it's hard to keep up. Sometimes it seems like we should start a Cold Exposure Society ☺."


No need for a new URL, you've already turned this place into the Cold Research Society.   :oxyz 

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Where Does that Norepinephrine Come From Exactly?


As an introduction to today's main event, the new Cell Metabolism paper about CR & beige fat, we need to review a little anatomy and biochemistry. Fortunately, there is a new paper out this week [1] that does a good job covering what we need to know to fully appreciate the Cell Metabolism paper.


Everybody who has been following along should know by now that the catecholamine norepinephrine (NE) - otherwise known as noradrenaline (NA) is the key player in stimulating adipose tissue to turn brown/beige. Cold exposure and all those other interventions we've discussed (e.g. capsaicin in hot peppers) increases NE levels, which binds to the adrenergic receptors (especially β3-adrenergic receptor, or β3-AR) on the surface of fat cells, which sets off a cascade of signalling within the fat cell that triggers the synthesis of new mitochondria and the expression of heat-generating UCP1 protein (i.e. turns them to brown or beige) as we saw in the big post from yesterday.


But where does the NE come from, and how does it get to the adipose tissue in order to turn it into thermogenic brown/beige fat? That's where things get interesting.


NE is both a neurotransmitter and a hormone. 


In its neurotransmitter form, it is released by synapses at the end of nerve fibers emanating from the central nervous system (CNS aka the brain) and remote ganglion (clusters of nerve cells around the body) that are part of the sympathetic nervous system. These nerve fibers squirt out NE onto the surface of nearby adipocytes, activating their β3-adrenergic receptor, and we're off the the races. It is this sort of direct innervation and localized release of NE that drives the development of true brown adipose tissue, that humans have very little of, located mostly around the neck, upper chest and back. In fact, one likely reason humans have relatively little true BAT compared to rodents is that we have so much less direct innervation of fat tissue by sympathetic nerve fibers than they do.


Fortunately for us, direct innervation by NE-releasing nerve fibers from the sympathetic nervous system isn't the only way NE gets around. The brain (via the sympathetic nervous system) also tells the adrenal glands (located behind your kidneys) to synthesize and release NE into the bloodstream, allowing it to circulate all over the body. Once it's in the bloodstream, it will eventually come into contact with adipocytes (as well as other cell types), acting as a hormone triggering the same β3AR-mediated signalling pathway to turn fat cells to brown.


But it's been discovered relatively recently that NE release from sympathetic nerve fibers or the adrenal glands isn't the only source of NE to turn WAT to beige fat. There is a third pathway, involving cells in the immune system. Certain immune cell types, called "alternatively activated macrophages" (AAMs - also called M2 macrophages), ride around in the bloodstream as well, and can synthesize and release their own NE. We've discussed this third NE pathway before (e.g. here and here) and it is this third pathway that feature centrally in the new paper [1] and the new Cell Metabolism paper about CR and beige fat (covered in my next post).


In fact, lucky for us, the new study [1] goes to great pains through a series of clever experiments with mice to replicate almost exactly two of the studies I focused on in the second of those two links, PMIDs 25543153 and 25533952. This is nice to see, given the current controversy raging across the sciences (esp. life sciences) about lack of reproducibility


Basically they found that the following pathway is critical for the beiging of subcutaneous white fat.


Cold exposure increases the level of the "alarmin" Interleukin 33 (IL-33), which induces the activity of a type of immune cell called Group 2 innate lymphoid cells (ILC2s) in WAT, which in turn recruited other immune cells (eosinophils and those alternatively activated macrophages, or AAMacs) which finally release the NE required to turn white fat to beige. In fact, the model the authors describe in [1] matches almost exactly (as far as I can tell) the one shown in this figure from PMID 25533952:





Notice the obesity part at the bottom of the diagram. In this new study [1], the authors confirmed that obesity (induced by feeding mice a high fat diet ad lib) blocks IL-33, and thereby prevents the whole WAT browning cascade. This leads to reduced thermogenic energy expenditure, causing more weight gain and fueling a vicious cycle of increasing obesity and less beige fat.


So there you go, that's how cells in the immune system are involved in the conversion of white fat to beige fat.


With that refresher, now (finally) on to the new Cell Metabolism study involving CR. Be back shortly...





[1] J Endocrinol. 2016 Oct;231(1):35-48. doi: 10.1530/JOE-16-0229.

IL-33-driven ILC2/eosinophil axis in fat is induced by sympathetic tone and
suppressed by obesity.
Ding X(1), Luo Y(2), Zhang X(3), Zheng H(4), Yang X(5), Yang X(6), Liu M(7).
Group 2 innate lymphoid cells (ILC2s) in white adipose tissue (WAT) promote WAT
browning and assist in preventing the development of obesity. However, how ILC2
in adipose tissue is regulated remains largely unknown. Here, our study shows
that ILC2s are present in brown adipose tissue (BAT) as well as subcutaneous and 
epididymal WAT (sWAT and eWAT). The fractions of ILC2s, natural killer T (NKT)
cells and eosinophils in sWAT, eWAT and BAT are significantly decreased by
high-fat-diet (HFD) feeding and leptin deficiency-induced obesity. Consistent
with this, the adipose expression and circulating levels of IL-33, a key inducing
cytokine of ILC2, are significantly downregulated by obesity. Furthermore,
administration of IL-33 markedly increases the fraction of ILC2 and eosinophil as
well as the expression of UCP1 and tyrosine hydroxylase (TH), a rate-limiting
enzyme in catecholamine biosynthesis, in adipose tissue of HFD-fed mice. On the
other hand, cold exposure induces the expression levels of IL-33 and UCP1 and the
population of ILC2 and eosinophil in sWAT, and these promoting effects of cold
stress are reversed by neutralization of IL-33 signaling in vivo Moreover, the
basal and cold-induced IL-33 and ILC2/eosinophil pathways are significantly
suppressed by sympathetic denervation via local injection of 6-hydroxydopamine
(6-OHDA) in sWAT. Taken together, our data suggest that the ILC2/eosinophil axis 
in adipose tissue is regulated by sympathetic nervous system and obesity in
IL-33-dependent manner, and IL-33-driven ILC2/eosinophil axis is implicated in
the development of obesity.
© 2016 Society for Endocrinology.
DOI: 10.1530/JOE-16-0229 
PMID: 27562191
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CR vs. CE vs. Both - The Final Verdict?


Hold onto your hats everybody. This one's going to be epic, but also a real rollercoaster ride...


This post is a serious look at the ongoing ambiguity over the relationship between CR and CE. Do CR abrogate the benefits of CE, by eliminating most of the fat or lean muscle mass required for thermogenesis? Or do CR and CE act synergistically, as I've speculated about before (e.g here and here)? In fact, there's evidence (discussed here) that CR without CE doesn't work to extend lifespan. But on the other hand, might the extra calories required to support CE ruin the benefits of CR?


If such questions have been keeping you up at night, you've come to the right post.


If anyone wants to review previous discussions of this CR / CE tension, this post is where to look. Here is an intro to the controversy from that post, in which I wrote:

We've seen previously that some (e.g. Speakman et al 2005, discussed here), but not all previous research has found that BAT is preferentially spared during calorie restriction. Based on results in humans and rodents, it looks like the sweet spot is a body weight that is thin but not too thin, equating to a BMI in the low 20's for humans. In contrast, severe CR leaves no fat mass available to become BAT or beige fat. We've also seen in several studies (e.g. discussed here) that CR without CE doesn't seem to work to extend lifespan of rodents. 


After that intro, I went on to discuss [2], which was a paper presented at the European Atherosclerosis Society Conference last year. Since it was a conference paper, it most likely wasn't peer reviewed, and therefore has to be taken with a grain of salt. But what it appeared to find was really interesting, which I summarized as follows:


In short, it appears that cold exposure [lab temperature housing] plus long-term mild CR (20% reduction relative to ad lib, enough to avoid obesity) boosts BAT activity and the browning of subcutaneous white adipose tissue. As I've pointed out in many places recently (especially in the Will Serious CR Beat a Healthy Obesity Avoiding Diet and Lifestyle? thread) obesity-avoiding 20% restriction is also the longevity "sweet spot" when it comes to adult onset CR, so this is yet another shining example of the BAT Rule1.


Why am I going into all this detail about stuff we've talked about before?


Because this new study in Cell Metabolism [1] by an entirely different research group (from Geneva, rather than Madrid), found something very similar, mild CR + cold exposure turns white fat to beige. Not only that, but the browning process is mediated by the norepinephrine release from alternatively activated macrophages discussed in my previous post. It all fits together like a hand in a glove. Which is good, because, as everyone should remember, if the glove doesn't fit, you must acquit (OJ was quite an actor). 


What the author's of [1] did first was to restricted standard C57BL/6J mice to 40% CR (i.e. serious CR). Interestingly, they fed all animals, including the ad lib ones, during only a one hour window early in the mices' active (night) cycle - so this was partly a study of intermittent fasting as well.


They observed that CR improved glucose metabolism after an oral glucose load. Importantly, this effect was found to not be a result of greater glucose metabolism in skeletal muscles or interscapular BAT. Instead, the extra glucose was being sucked up and metabolized by several subcutaneous and visceral fat deposits. Despite the fact that these fat deposits were smaller in the CR mice, they were nonetheless burning glucose like the dickens. Why? You guessed it. Their fat deposits were browner.


Here are the gene expression graphs of one of these fat deposits (inguinal subcutaneous white adipose tissue or ingSAT), showing greatly increased expression of thermogenesis genes like UCP1 as well as other genes involved in mitochondrial biogenesis. The WM group refers to "Weight Matched" controls - basically younger mice that had not been CRed, but had not yet gained weight and so had the same weight as the CR animals:




As you can see, UCP1 expression was about 10x higher in the 40% CR animals than the AL animals in this subcutaneous fat deposit. The authors summarize this part of their study as:


These results demonstrate that CR leads to preferential glucose uptake in white fat and that these fat depots in the CR mice are smaller in size and with increased density [and had a more thermogenic gene expression profile - DP].


So hurray! - CR seems to turn white fat to beige and improve insulin sensitivity in the process. What's more, when they coupled cold exposure with CR, things got even better:


A 48-hr cold exposure [6°C!] led to an 150-fold increase in the Ucp1 expression [in the 40% CR mice - DP] compared to the 60-fold increase in the AL relative to the room temperature (RT) AL controls (Figure S1N), suggesting that the newly developed beige fat is functionally active.


In short, CR alone boosts beige fat, and CR+CE boosts beige fat a whole lot more, resulting in greatly improved insulin sensitivity.


To prove the beige fat was contributing to the favorable metabolic phenotype of the CR mice, they exposed both CR and AL mice to cold, and gave both groups ad lib access to food to exclude the potential influence of differences in acutely consumed food on cold tolerance. They found:


CR mice had a lower basal temperature compared to the AL controls (Figures S2C–S2E). Despite the lower starting point, the CR mice showed constant temperature for the whole course of the cold exposure, while AL mice dropped their body temperature during the acute cold stress (Figures 2E and S2A–S2E). This was associated with decreased blood glucose levels and a marked increase in food consumption in the CR mice (Figures S2F–S2H). The enhanced energy harvest during acute cold contributes to maintaining the body temperature (Chevalier et al., 2015), while restricting the available food lowers it.


So that's neat - skinny CR mice exposed to cold can eat more while defending their body temperature and simultaneously keeping glucose low. That sounds a lot like several of us cold exposure practitioners!


But apparently, cold exposure wasn't absolutely necessary for boosting beige fat, based on their next experiment:


CR administered under thermoneutral conditions [30 °C] led to decreased body weight, increased tolerance to glucose after an oral glucose load, and constant body temperature following acute cold exposure when compared to AL controls kept at thermoneutrality.... The adipocytes isolated from the fat depots of the CR mice kept at thermoneutrality were smaller and with multilocular appearance, and they showed increased expression of the browning markers, albeit to a lower magnitude compared to mice kept at RT [Room Temperature, ~70-72 °F or ~21 °C - DP], consistent with the absence of a mild thermal stimulation.


So even when housed at thermoneutral temperatures, 40% CR mice had more beige fat than AL mice, just not as much as when housed at normal lab temperature and subjected to 40% CR.


They then replicated these results using an interesting modification to the 40% CR diet, quite relevant to many of us. Rather than simply giving the CR group 40% less standard chow (during the 1h feeding window) as in the first experiment, they fed another group of mice "30% more of the 60% calorie restricted diet daily, compared to AL fed controls, to obtain total of 20% CR."


What they mean by the "60% calorie restricted diet" was a diet which was 60% less calorie dense than standard chow. In other words, this new group of mice ate a diet like many of us do. They ate a greater amount (volume) of a chow that was a high in fiber but sparse in calories, meaning they were (likely) satiated but still mildly (20%) calorie restricted. What did they find?

[These] mice also showed improved glucose tolerance and smaller multilocular adipocytes in both the ingSAT and pgVAT, resulting in decreased adiposity and increased expression of the browning markers.

So it only took mild, 20% calorie restriction to produce the beiging of both subcutaneous and visceral white fat.


The authors go on to show that the browning of WAT in the CR mice is mediated by the same immune cell pathway I discussed in my last post - specifically by norepinephrine released by M2 macrophages (i.e. alternately activated macrophages AAMacs) recruited to the site of white adipose tissue. They even found that increased SIRT1 was involved in WAT browning. All that was a cool replication, but not the most important part of this study as far as I'm concerned - so I won't focus on it, especially since we've already covered it.


Instead, what the core result seems to show is something that should brighten the hearts of many out there - namely that even mild CR wins when it comes to boosting beige fat. Sure, CR+CE might boost beige fat better. But even 20% CR alone (without CE) boosts beige fat and improves glucose tolerance pretty substantially all on its own.


So that seems like good news for the wimps out there who aren't enthused about piling cold exposure on top of CR - right?


Seems that way. In fact, the authors of [1] go even further in the discussion, suggesting that it is net CR that results in the beneficial WAT browning and improvements in glucose metabolism (my emphasis):


Cold exposure and long-term endurance exercise are physiological stimuli that increase the browning (van Marken Lichtenbelt et al., 2009; Harms and Seale, 2013; Wu et al., 2012, 2013; Bostro¨ m et al., 2012). ... We note that a common feature between the cold exposure and endurance exercise is the negative energy balance: higher energy expenditure than intake leading to fat loss. In addition, interventional microbiota depletion...also increase the browning to a similar extent as several endurance exercise regimens. These are also conditions of decreased caloric uptake and negative energy balance. Seen in this context, our results that CR promotes the development of functional beige fat provide insights into the regulation of the overall energy homeostasis during energy scarcity, and they suggest that white fat browning is a common feature of conditions of negative energy balance.


While it seems paradoxical that metabolically expensive beige fat should be boosted when calories are scarce, that's exactly what the authors are suggesting. A negative energy balance (i.e. net calorie restriction) appears to be the common factor among all these beige fat-boosting interventions (i.e. CR, endurance exercise, and microbiota depletion to reduce calorie extraction from food) which also improve metabolic health.


While it might seem paradoxical, I note that this jibes perfectly with my evolutionary theory of why CR and CE go together so well - namely that animals evolved a response to the combination of CR and CE since they occurred together so frequently in nature. In wintertime, food is scarce and it is cold, so our ancestors had to evolve a strategy to deal with both of them simultaneously. As a result, calorie scarcity became a signal to boost beige fat, since when calories were scarce it was almost always cold so extra thermogenesis was usually required to stay warm.


But regardless of why we evolved that way, the upshot seems to be that all it takes to boost beige fat and improve glucose metabolism is a net calorie deficit, and this can be implemented via mild calorie restriction alone. Good news right?


Well... Not so fast. There's a serious caveat. (You knew this was coming).


The mice in [1] were young (8 weeks) and subjected to only 4 weeks of CR. Unfortunately I don't have access to the supplemental material with graphs of body weights of the different groups, but I think it's safe to say these mice probably weren't emaciated after only 4 weeks of CR, and they certainly weren't old, reaching only 3 months of age at the end of the study, which is the human equivalent of about 20 years old.


That's too bad, since it really calls into question the relevance of these findings for us older human CR practitioners, in light of the dramatic reducing in brown/beige fat seen in older humans, and especially in light of the result of this study Al just posted [3]. That study found that UCP1 expression in the same subcutaneous WAT of the same (C57BL/6J) strain of mice as in [1] (my emphasis):


"precipitously declines (~300-fold) between 3 and 12 months."


Ouch... And:


"Loss continues into old age (24 months) and is inversely correlated with the development of insulin resistance."


Double ouch...


In fact, UCP1 in 24 month-old mice was another 10x less than at 12 months, or 3000x less than in mice that were 3 months old - which was about the age of the mice at the end of [1]. And finally, if that weren't enough (my emphasis):


Age-related changes in sWAT are not explained by the differences in body weight; mice subjected to 40% caloric restriction for 12 months are of body weight similar to 3-month-old ad lib fed mice, but display sWAT resembling that of age-matched ad lib fed mice (devoid of brown adipose-like morphology).


Now that last one really hurts. What does it all mean?


Basically, study [1] found that young mice subjected to 40% CR for a few weeks resulted in much more beige subcutaneous (and visceral) fat than AL mice, and much higher insulin sensitivity. But study [3] found that as mice grow older they lose their beige fat and become glucose intolerant. And importantly older mice (12 months) subjected to lifelong 40% CR has basically zero beige fat. When I say basically zero, I mean really low. Specifically, old CR mice had 835x less UCP1 expression in the subcutaneous fat compared with the young mice. 


The good news? It's possible to get the subcutaneous beige fat back in the old mice:


... treatment with a β3-adrenergic agonist to compensate for reduced tone rescues the aged sWAT phenotype.


In particular, injecting the old mice with a β3-adrenergic agonist increased sWAT UPC1 expression by 200x. Not only that, the treatment also reversed the glucose intolerance of the old mice. Of course this isn't very practical, unless you've got a needle and some β3-adrenergic agonist lying around handy.


Fortunately, as we've seen many times throughout this thread, cold exposure does the same thing - i.e. boosts norepinephrine signalling in young and old animals and people, turning white subcutaneous fat to beige.


But you say, maybe having beige fat isn't all that important. After all, mice subjected to lifelong CR have increased lifespan, right? And they don't suffer (at least too badly) from insulin resistance / glucose intolerance, despite a lack of beige fat. But remember, rodents have much more true brown adipose tissue (as opposed to beige adipose tissue) than people do, and CR seems to spare true BAT in mice.


So it's quite possible that older CR rodents remain glucose tolerant without beige fat because they still have true BAT, and so maintain good metabolic health into old age. This would explain why old CR rodents exhibit good glucose metabolism, while quite a few serious old human CR practitioners seem to suffer from impaired glucose tolerance because they lack both true BAT and beige fat.


In short, all this appears to add up to bad news for CR-only fans. It seems that as you get older, mild (net) CR coupled with cold exposure is the way to go (and perhaps the only way to go) for people, that is if you want to maintain healthy glucose metabolism and enjoy the potential benefits that CR may have to offer.





[1] Cell Metabolism (2016), August 25, 2016


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

Salvatore Fabbiano,1,2 Nicolas Sua´rez-Zamorano,1,2 Dorothe´ e Rigo,1,2 Christelle Veyrat-Durebex,1,2
Ana Stevanovic Dokic,1,2 Didier J. Colin,3 and Mirko Trajkovski
Caloric restriction (CR) extends lifespan from yeast to mammals, delays onset of age-associated diseases, and improves metabolic health. We show that CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size in lean C57BL/6 and BALB/c mice kept at room temperature or at thermoneutrality and in obese leptin-deficient mice. These metabolic changes are mediated by increased eosinophil infiltration, type 2 cytokine signaling, and M2 macrophage polarization in fat of CR animals. Suppression of the type 2 signaling, using Il4ra/, Stat6/, or mice transplanted with Stat6/ bone marrow-derived hematopoietic cells, prevents the CR-induced browning and abrogates the subcutaneous fat loss and the metabolic improvements induced by CR. These results provide insights into the overall energy homeostasis during CR, and they suggest beige fat development as a common feature in conditions of negative energy balance.
PMID : Not available
[2] Annual meeting of the European Atherosclerosis Society (2015)
Impact of caloric restriction on initial age-associated metabolic alterations and browning effect in
P. Corrales-Cordon1, Y. Vivas1, D. Horrillo1, A. Izquierdo1, P. Seoane2, C. Martinez-Garcia1
, M.Lopez2, M. Ros1, M. Obregon3, G. Medina-Gomez1
1Universidad Rey Juan Carlos, Madrid, 2Universidade Santiago de Compostela, 3
Instituto deInvestigaciones Biomédicas Alberto Sols/CSIC-UAM, Madrid, Spain.
Background and aims: Changes in the distribution and function of different deposits of white adipose
tissue (WAT) and brown adipose tissue (BAT) occur during ageing. These changes are usually associated
to metabolic alterations like Insulin Resistance (IR) and Metabolic Syndrome. It is also known that
caloric restriction (CR) reduces the metabolic changes associated with age. Nevertheless, it is difficult to
establish when age-associated alterations start. Similarly, the severity and the time-extent to CR are
variables under debate. The aim of this work is to investigate the impact of the CR iniciated sind 3
months of age and maintained until 12 months of age, in the development of IR and other metabolic
Materials and methods: 3 and 12-month-old male mice fed ad libitum and 12-month-old mice under CR
(20%) from 3 months of age were used (n=10-12 animals/group). For in vivo studies, we performed
glucose (1 g/kg body weight) and insulin (0.75 U/kg body weight) tolerance test in mice. Serum
concentration values of glucose, insulin and different cytokines were quantified by Bio-plex ProTM
Diabetes Assays. Gen expression involved in lipid metabolism was measured in BAT and epididimal
(eWAT) and subcutaneous (scWAT) WAT. Immunohistochemistry and mRNA expression of UCP-1 was
also detected. Total triiodothyronine (T3) and thyroxine (T4) concentrations were determined by
radioimmunoassay (RIA) in serum and BAT. Protein levels of lipogenic enzymes in the Central Nervous
System (CNS) were also measured.
Results: Our data showed age-associated IR significantly (p<0.05; t-Student) appeared at maturity and is
prevented with CR (AUC mean+-SE: 1536.64+-115.94 in 12-month old mice compared to 1587+-151.23
in animals fed with CR). These findings were in agreement with serum concentration values quantified.
Cytokines serum levels were measured. Adiponectin level significantly (p<0.05) decreased with ageing
(5.57+-0.47 ug/ml) and increased with CR (13.62+-2.53 ug/ml), while the leptin serum levels
significantly (p<0.05) increased with ageing (10.5+-3.095 ng/ml) but decreased with CR (2.61+-0.74
ng/ml). Furthermore, CR restored initial age-associated alterations in lipid metabolism and markers of
macrophage infiltration, such as MCP-1 (2.00+-0.38 with ageing; 1.32+-0.16 with CR), only in scWAT.
Remarkably, brown like adipocytes or browning effect was detected in scWAT in old animals subject to
CR. The lower browning process associated to ageing was accompanied by a significant (p<0.05)
decrease in the expression of some brown fat-selective genes (such as UCP-1, PRDM16, FGF21), but
restored with CR. T3 and T4 levels in BAT were significantly (p<0.05) decreased with ageing but
restored by CR. In addition, serum T3 levels were significantly (p<0.05) decreased with ageing. Finally,
we also found significantly (p<0.05) changes in lipogenic enzymes such as ACC and AMPK in the
hypothalamic AMPK pathway during the first stages of agein.
Conclusion: Long-term CR prevents the morphological and initial aged-related metabolic changes in
WAT and BAT. The browning effect observed in scWAT and the activation of BAT could be explained
by improved thyroid hormones status and function of CNS.
[3] Aging Cell. 2012 Dec;11(6):1074-83. doi: 10.1111/acel.12010. Epub 2012 Oct 24.
Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white
adipose tissue.
Rogers NH(1), Landa A, Park S, Smith RG.
Author information: 
(1)Department of Metabolism and Aging, Scripps Research Institute Florida,
Jupiter, FL 33458, USA.
Insulin sensitivity deteriorates with age, but mechanisms remain unclear.
Age-related changes in the function of subcutaneous white adipose tissue (sWAT)
are less characterized than those in visceral WAT. We hypothesized that metabolic
alterations in sWAT, which in contrast to epididymal WAT, harbors a subpopulation
of energy-dissipating UCP1+ brown adipocytes, promote age-dependent progression
toward insulin resistance. Indeed, we show that a predominant consequence of
aging in murine sWAT is loss of 'browning'. sWAT from young mice is
histologically similar to brown adipose tissue (multilocular, UCP1+), but becomes
morphologically white by 12 months of age. Correspondingly, sWAT expression of
ucp1 precipitously declines (~300-fold) between 3 and 12 months. Loss continues
into old age (24 months) and is inversely correlated with the development of
insulin resistance. Additional age-dependent changes in sWAT include lower
expression of adbr3 and higher expression of maoa, suggesting reduced local
adrenergic tone as a potential mechanism. Indeed, treatment with a β3-adrenergic 
agonist to compensate for reduced tone rescues the aged sWAT phenotype.
Age-related changes in sWAT are not explained by the differences in body weight; 
mice subjected to 40% caloric restriction for 12 months are of body weight
similar to 3-month-old ad lib fed mice, but display sWAT resembling that of
age-matched ad lib fed mice (devoid of brown adipose-like morphology). Overall,
findings identify the loss of 'browning' in sWAT as a new aging phenomenon and
provide insight into the pathogenesis of age-associated metabolic disease by
revealing novel molecular changes tied to systemic metabolic dysfunction.
© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society 
of Great Britain and Ireland.
DOI: 10.1111/acel.12010 
PMCID: PMC3839316
PMID: 23020201
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Could Lack of BAT be Driving the Obesity Epidemic?


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


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


That started me thinking about the opposite circumstances. What happens in summertime, when calories are plentiful and temperatures are warm? From an evolutionary perspective, it seems like the opposite response would be advantageous for survival. Specifically, when food and warmth were easy to come by, it would have behooved our ancestors to jettison the useless brown/beige fat (warm ambient conditions mean thermogenesis isn't necessary), and instead focus on eating lots food and storing those excess calories as white fat, in preparation for the long winter ahead.


Hmm... Does anyone else sense a possible explanation for the mysterious obesity epidemic? Might our calorie-replete, climate-controlled modern lifestyle result in perpetual preparation for a winter that never comes, by catabolizing our spendthrift brown/beige fat and squirreling away excess calories in the form of white fat? 


This idea is similar to Ray Cronise and David Sinclair's "Metabolic Winter Hypothesis" (MWH - discussed in this paper [1] and here). The paper is frustratingly vague and focuses mostly on the problem of overnutrition as a cause of obesity, but at the end the two authors allude to a similar idea, saying:


Similar to the circadian cycle and like most other living organisms, it is reasonable to believe we also respond to the seasons and carry with us the survival genes for winter. Maybe our problem is that winter never comes.


They seem to be saying that in general we have a thrifty genotype, so we naturally pack on the pounds when food is abundant, and rarely expose ourselves to cold which would help burn off some of that fat. They suggest physical activity is secondary:


Although it seems reasonable to assume that obesity is a result of less activity, several studies have shown the fallacy of expecting exercise to promote significant weight loss without dietary changes.[refs] Thus, it might be reasonable to consider that many of the health benefits of physical activity are actually adaptive responses related to times of cold stress and shivering. In nature, animals do not intentionally participate in high levels of activity to mitigate excess calorie ingestion—available calories are limited and animals conserve activity. In fact, the main factors influencing energy expenditure are body mass and ambient temperature, not activity. A recent study even demonstrated that energy expenditure from physical activity in humans has not declined since the 1980s and matches energy expenditures of wild mammals.[ref]


Where the theory I'm proposing differs from (or somewhat extends) the MWH is by elaborating the programmed, adaptive nature of the "metabolic winter" response. It's not just that we moderns eat more, live in warm houses, and (possibly) exercise less, so we pack on the pounds because we are genetically programmed to always be thrifty. 


Instead, there is a specific metabolic program that kicks in during summer conditions to maximize weight gain by eliminating thermogenic brown/beige fat and shunting calories into white fat for storage. In the winter, the opposite is true. When it's cold outside and calories are scarce, we've got a metabolic program that kicks in to help us stay warm by boosting brown/beige fat and shunting glucose and fat (both stored and dietary) to the thermogenic fat to generate heat.


The problem is that if winter never arrives, we get caught in a vicious cycle in which a calorie surplus results in loss of brown/beige fat, which causes a greater calorie surplus, etc. All those extra calories end up getting stored in white fat, driving obesity and all the diseases of aging associated with a Western diet and lifestyle. Here is what such a model looks like:



In a weird synchronicity, just as I was putting the finishing touches on the diagram above, I got an email from Luigi Fontana in which he shared a copy of this new paper [2] from the New England Journal of Medicine that addresses one of those red arrows.


It's a paper from a panel of scientists who reviewed the evidence to determine which cancers are driven by (or associated with) obesity. Here is the main results, in tabular form:



Quite a laundry list of obesity-driven cancers. 


If loss of the brown / beige fat we naturally evolved to have is really a driving factor in the obesity epidemic and the diseases that result from it (including cancer), perhaps all the current research investigating ways of boosting BAT as a treatment for obesity are on the right track. Of course, cold exposure is a more direct, powerful, and side-effect free approach to boosting BAT than pharmacological or genetic interventions. Too bad the general public (and many CR folks) aren't aware of it's benefits and/or disciplined enough to pursue it...





[1] Metab Syndr Relat Disord. 2014 Sep;12(7):355-61. doi: 10.1089/met.2014.0027. Epub

2014 Jun 11.
The "metabolic winter" hypothesis: a cause of the current epidemics of obesity
and cardiometabolic disease.
Cronise RJ(1), Sinclair DA, Bremer AA.
The concept of the "Calorie" originated in the 1800 s in an environment with
limited food availability, primarily as a means to define economic equivalencies 
in the energy density of food substrates. Soon thereafter, the energy densities
of the major macronutrients-fat, protein, and carbohydrates-were defined.
However, within a few decades of its inception, the "Calorie" became a commercial
tool for industries to promote specific food products, regardless of health
benefit. Modern technology has altered our living conditions and has changed our 
relationship with food from one of survival to palatability. Advances in
agriculture, food manufacturing, and processing have ensured that calorie
scarcity is less prevalent than calorie excess in the modern world. Yet, many
still approach dietary macronutrients in a reductionist manner and assume that
isocalorie foodstuffs are isometabolic. Herein, we discuss a novel way to view
the major food macronutrients and human diet in this era of excessive caloric
consumption, along with a novel relationship among calorie scarcity, mild cold
stress, and sleep that may explain the increasing prevalence of nutritionally
related diseases.
PMCID: PMC4209489
PMID: 24918620
[2] N Engl J Med 2016; 375:794-798August 25, 2016
Body Fatness and Cancer — Viewpoint of the IARC Working Group
Béatrice Lauby-Secretan, Ph.D., Chiara Scoccianti, Ph.D., Dana Loomis, Ph.D., Yann Grosse, Ph.D., Franca Bianchini, Ph.D., and Kurt Straif, M.P.H., M.D., Ph.D., for the International Agency for Research on Cancer Handbook Working Group*
No Abstract
DOI: 10.1056/NEJMsr1606602
PMID: Not available
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I have been, in this hot season, experimenting with very cold foods and wearing only shorts. I won't use air conditioning, but even without it I can get very cold by eating my two main meals, coffee tea etc. at very cold temperature. Frozen smoothies are particularly chilling!

Anyone else doing this?


Yes - I too am too frugal to crank up the A/C, so I employ all those low-cost, low-tech methods you mention (except the smoothies). I also use a lot of fans to move air - I have 5 powerful fans surrounding my stationary bike and bike desk. And of course, I've been wearing my two cooling vests with 20lbs of ice packs strapped to my body for most of the day this summer, which really does the trick.


P.S. I did my occasional checkpoint of this entire thread to a PDF document. If anyone would like a copy, here is a Dropbox link to it. But be warned, it's 59 MB in size, and 686 pages long...



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Great insights Dean, thanks for posting.  Regarding cooling techniques, I also do not crank the AC (terribly inefficient way to cool).  I do eat frozen foods (mostly blueberries), would like to increase that.  I tried frozen nuts just because someone here posted about it - but I don't get it, they have almost no water content, and didn't really feel super cold to me, and didn't taste as good to me in frozen form, so I'm nixing that idea.  I eat/drink crushed ice pretty much all day every day - that is something simple anyone with an ice crusher can do, blender/smoothie will do the same thing.  I wear my cooling vest every day for at least 4 hours, often 3-4 hours in the morning and another 3-4 in the evening.   Before bed I've been "icing down" every night, if I'm particularly hot I will start with a cold shower, then I take 3 of the Amazon ice packs Dean posted about (an amazing bargain as far as I'm concerned, at just a little over $1 each), placing one behind my neck or upper back, and one each over my supraclavicular area, and just "chill" for an hour or more in bed before going to sleep (this results in phenomenal sleep by the way -- I used to be a light sleeper, the slightest noise would wake me up, now nothing wakes me up and I'm out like a light).  I don't do any extraordinary cooling while actually sleeping other than a ceiling fan and not using heavy blankets or wearing clothing - too much cold while sleeping for me results in unpleasant dreams about trying to warm up and not being able to, hah!


I also take two of the cheap amazon ice packs to work with me when I'm at the office, and in addition to ice drinks, I keep an ice pack on each thigh most of the day (this is pretty inconspicuous, they fit right under my desk.  Those things stay cold for many hours, and are cold enough to numb muscles (which can feel a little weird sometimes). If you rest your forearms on them at the same time they are cooling your thighs, you'll get some pretty serious cooling.

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Dean, thanks for your well presented thoughts on this subject.

I wonder if your seasonal theory of summer promoting WAT and winter promoting BAT might be explored by looking at those evolved in/adapted to equatorial climates (mice or even people) where seasons of food abundance and scarcity are driven by seasonal rainfall fluctuations instead of seasonal temperature changes.  Would they still respond to caloric restriction with an increase of BAT?

Your theory also begs the question is perpetual winter (perpetual CR) the healthiest state for hot/cold season adapted humans?  Perhaps there is value in following the pattern of our evolutionary heritage and having a seasonal ebb and flow to caloric intake/restriction?

I have a personal interest in this subject now seeing there is a linkage between norepinephrine and BAT which I would like to discuss but I think my personal ancedotes better belong in the "General Health & Longevity" section instead of polluting this thread.

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I wonder if your seasonal theory of summer promoting WAT and winter promoting BAT might be explored by looking at those evolved in/adapted to equatorial climates (mice or even people) where seasons of food abundance and scarcity are driven by seasonal rainfall fluctuations instead of seasonal temperature changes.  Would they still respond to caloric restriction with an increase of BAT?


Todd, I don't know about their response to calorie restriction, but there is quite a bit of evidence that people who come from more equatorial regions with less seasonal temperature variation have less BAT in general.


Your theory also begs the question is perpetual winter (perpetual CR) the healthiest state for hot/cold season adapted humans?  Perhaps there is value in following the pattern of our evolutionary heritage and having a seasonal ebb and flow to caloric intake/restriction?


Good question. Evolved variations could be either seasonal and/or circadian. There is a lot of body temperature variation within a day, and at least part of this circadian temperature variation is driven by BAT/beige fat. BAT is also more abundant in humans during wintertime, and this is associated with lower population-wide HBA1c levels in winter too, as discussed here.


In researching this, I was also reminded of this post showing how people with active BAT have much smaller glucose excursions during the day, which is important for people struggling with impaired glucose tolerance.



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Extrapolating on the summer/winter theory, imagine if it wasn't just WAT/BAT but that there were multiple genes upregulated in summer and another set of genes upregulated in winter.  In summer anabolism takes center stage and we build not just WAT but we build muscle, bones, blood cells and pretty much every other tissue too.  And then in winter catabolic genes take center stage and we don't just add BAT and burn WAT but it is a time to switch to an oxidative metabolism,  burn the fat and catabolize the damaged glycolytic muscle and other tissues that ought to be recycled.  Too much summer might lead to issues such as heart disease, diabetes and cancer while too much winter aggravates tendencies towards sarcopenia, osteoporosis and anemia.  Perhaps some of us carry very good summer genes and perpetual summer suits us well while others carry very good winter genes.  But maybe most people carry imperfections in both sets but good enough to get by fairly well with regular seasonal change.

More complicated, but what if not just the seasonal calorie flux is important, but perhaps the macro and micro nutrient changes matter too?  Perhaps summer is a time for a surge in carbohydrates, lots of fresh ripe fruits amd a surge in phytonutrients, lots of fresh greens, while winter perhaps does better with a higher fat ratio when nuts and maybe meats take a more predominate role in a period of lower calories.

Now imagine if researchers studied caloric restriction in a short lived species whose entire life cycle was tuned to the changing of just a few seasons, perhaps an animal that might hunker down to survive winter before procreating in spring and dying in the summer?  Such an animal might experience a dramatic boost in life span, hanging on awaiting the late arriving spring.  Perhaps in a longer lived species a better way to take advantage of this phenomenon would be extended winters punctuated by brief summers as opposed to a forever winter with the mixed signal of a summer like macro and micro nutrient mix?

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Interesting speculations, but seemingly exactly that - speculations. It may be that "mixing it up" with exposure to winter and summer conditions would be best. But again, over what time scale? Months? Days? Within a day (e.g. time restricted feeding)? And it might turn out like that all-too-common, all-too-human cognitive mistake where people think it better to "mix it up" when playing games of chance, rather than always betting on the option with the statistically higher expected payoff. Sometimes hormesis is a good thing to upregulate the body's defenses, and keep it from getting too habituated. But I wouldn't take that as endorsement to eat bacon or smoke an occasional cigarette. Sometimes challenges to the body are just harmful, period.



Now imagine if researchers studied caloric restriction in a short lived species whose entire life cycle was tuned to the changing of just a few seasons, perhaps an animal that might hunker down to survive winter before procreating in spring and dying in the summer?  Such an animal might experience a dramatic boost in life span, hanging on awaiting the late arriving spring.  Perhaps in a longer lived species a better way to take advantage of this phenomenon would be extended winters punctuated by brief summers as opposed to a forever winter with the mixed signal of a summer like macro and micro nutrient mix?


Perhaps, or perhaps the strategy of "hunkering down" that works in short-lived species simply won't work at all, or to a much smaller extent, in long-lived species, who may already have built many of those "hunker down" strategies into their basic metabolism - that's how they became long-lived in the first place. That seems to be Aubrey's perspective, as Khurram just pointed out in his remarks about CR at the Rejuvenation Biotechnology 2016 conference.



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I am beginning to have similar thoughts about cold exposure that I had many years ago wrt CR. WHERE IS THE EVIDENCE IN HUMANS! many populations live in very cold climates. I know the confounders are complicated with epidemiology, but heck the Greenland Eskimos, Icelanders, humans who work outside in places like Alaska, life expectancy of warm developed countries vs frigid ones etc. And I don't mean the evidence like brown fat etc. The only thing that counts are actual benefits in terms of longevity and health outcomes. We are now at the point where prominent members (Dean) no longer beleive CR is any better than obesity avoidance and perhaps worse in older ages. Are we treading down a similar path wrt cold exposure? Trust me I really hope I am wrong, but as I write this and experience a slight shiver because I am full of very cold food and a cool morning fan I have to wonder.

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Mike, I agree with your sentiment completely.  And I agree with Dean's statement that my previous posts are merely speculation.  And a very raw speculation at that.


It appears to me that much of what we choose to do regarding diet/health is somewhat speculative.  Sometimes there is substantial scientific support for an idea, but even then it still takes small leaps of faith to act as there are so many ways the science might be flawed or not directly applicable to humans in general or to ourselves in particular.


Acting on speculation for longevity is particularly challenging.  How will you know until you get there and will one be able to spot and correct flaws in an approach before it is too late?


I've been making big lifestyle changes at a frenetic pace with a short term view.  Things that yield positive results quickly I pursue more aggressively and those that don't I adjust or drop.  I may not be pursuing the best strategy to make it to 100 but I'm most concerned about making tomorrow a little better than it otherwise would have been and I'll worry about getting older 1 day at a time.


As for cold exposure, if your approach is yielding more pain than gain, perhaps you should stop it or try modifying your approach?  Is there any evidence that cold exposure through cold food is viable?  Myself, I've adopted a practice of cold exposure through very cold baths.   Momentarily it is the most horrible thing I do, intensely worse than being a little hungry or the discomfort of strenuous exercise.  But the payoff is good.  The worst discomfort only lasts a minute or two, followed by hours of pain relief and feeling remarkably energized.  I take my cold baths after intense exercise that would otherwise leave me feeling drained and it allows me to exercise more intensely and bounce back more quickly.

Edited by Todd Allen
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Hi Mike!


First off, It's good to be skeptical. Whether or not skepticism is warranted depends on what one is hoping to achieve, and how much evidence one needs to be convinced.


You are entirely correct - as far as I know there isn't evidence that people living in cooler climates live longer or have overall better health, at least not evidence that can be disentangled from confounders like socioeconomic disparities, infectious disease risks, accident rates etc. I won't rehash our several discussions (which Michael chimed in on too!) on the challenges of population-scale epidemiological studies like you suggest, since you clearly remember them. 


The only thing that counts are actual benefits in terms of longevity and health outcomes.


Fair enough. Those are reasonable criteria. I hope you (and others) have taken the CR Motivation survey pointed to by in this post.


Given your motivations, I think there are three broad classes of responses to your healthy skepticism.


Longevity Benefits - There isn't the equivalent of the long-lived Okinawans to point to when it comes to the potential for CE life-extension benefits, so let's get that off the table. I think the strongest argument for CE's impact on longevity comes from studies in animals. Virtually all rodents studies showing CR lifespan extension have been conducted at standard lab temperature, which are the equivalent of pretty serious CE for mice and rats (naked human equivalent of ~60-62 °F). So we have very little evidence that even the "gold standard" life extension intervention, CR in rodents, works without cold exposure.


In fact, the evidence we do have, from those few experiments where housing temperature has been varied in rodent CR experiments, shows that without cold exposure, CR often doesn't work, and that mild, obesity-avoiding CR coupled with CE is better than more severe CR alone for longevity. As I've suggested before, one reason the CR primate studies may have had such disappointing results was that the monkeys were maintained at thermoneutrality year round. So if you hold out hope that CR will have lifespan benefits in humans, I think it's almost imperative that you combine it with some degree of CE.


Health Benefits - Here I think we're on stronger ground. The evidence is pretty compelling that many of the diseases of aging are driven by inflammation, resulting from, as well as causing (in a vicious cycle) the suite of metabolic dysfunctions we call "Metabolic Syndrome" - obesity (especially visceral), high cholesterol / triglycerides, high blood pressure, and impaired glucose tolerance / diabetes. Metabolically active brown / beige fat appears pretty convincingly to address all of these (with the possible exception of high BP). And the best way to boost brown / beige fat is cold exposure, at least until the scientists come up with an effective pharmacological substitute without adverse side effects.


But you might ask, what can brown / beige fat do for my health - since I'm in no danger of metabolic syndrome. 


That's where the idea of CR / CE synergy enters in. In short, I think there is pretty good evidence that by activating mTOR in a "healthy way" (as opposed to activating it via increased insulin and IGF-1 signalling), CE in conjunction with CR can avoid several of the negative side effects of CR, including impaired glucose tolerance, reduced immune system function, and bone loss.


No Silver Bullet - But I don't want to kid anyone, or give anyone a mistaken impression. I'm not optimistic that CE, CR or the combination of the two with dramatically extend lifespan. I do think the combination of mild net CR coupled with CE and exercise (with the CR part discontinued in one's senior years to avoid frailty) has the best chance of squaring the mortality curve and allowing one to live in good health up to the age one's genes allow, which might typically be around 90.


Then we can hope to be pleasantly surprised if SENS makes rapid progress, or cryonics buys us more time to leverage gradual advances towards really understanding and defeating aging.


My personal motivation for my obsession with CE? It's an area that I think holds great promise to benefit people's lives, and I want to draw more attention to it, both through researching it and practicing it to explore and understand what it can do.


Plus it's something different. Lord knows the same-old-same-old isn't working to make us all immortal, or even healthy. Even CR, which once seemed to hold so much promise and be so 'cutting edge', now seems like it will provide only marginal benefits (at best) for humans. I figure disciplined people like ourselves might as well (almost have an obligation to) try something innovative to push the envelope of human understanding, and to see what's possible.


Finally, I see Todd has snuck in a post while I was composing this one. Thanks for your input Todd! I'm happy to hear you seem to be benefiting from your CE practice. I agree with your perspective, and your advice to Mike. If CE is making your life miserable, try something else, or try doing it differently.




P.S. In the interested of keeping this post brief, I made some bold claims without citing studies to back them up. References available upon request...

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